Skip to main content

Single-nucleotide polymorphisms as important risk factors of diabetes among Middle East population

Abstract

Diabetes is a chronic metabolic disorder that leads to the dysfunction of various tissues and organs, including eyes, kidneys, and cardiovascular system. According to the World Health Organization, diabetes prevalence is 8.8% globally among whom about 90% of cases are type 2 diabetes. There are not any significant clinical manifestations in the primary stages of diabetes. Therefore, screening can be an efficient way to reduce the diabetic complications. Over the recent decades, the prevalence of diabetes has increased alarmingly among the Middle East population, which has imposed exorbitant costs on the health care system in this region. Given that the genetic changes are among the important risk factors associated with predisposing people to diabetes, we examined the role of single-nucleotide polymorphisms (SNPs) in the pathogenesis of diabetes among Middle East population. In the present review, we assessed the molecular pathology of diabetes in the Middle East population that paves the way for introducing an efficient SNP-based diagnostic panel for diabetes screening among the Middle East population. Since, the Middle East has a population of 370 million people; the current review can be a reliable model for the introduction of SNP-based diagnostic panels in other populations and countries around the world.

Background

Endocrine disorders are the fifth leading cause of death in the world [1]. Diabetes mellitus is known as the most common endocrine disorder that occurs through hyperglycemia following the deficiency of insulin production or function [2]. It can be classified into three main types including; gestational diabetes mellitus (GDM), type 1 diabetes (T1D), and type 2 diabetes mellitus (T2D) [3]. T1DM and T2DM are proved to be the most prevalent types of diabetes [4,5,6]. GDM is one of the most important metabolic disorders during pregnancy that is observed in about 7% of all pregnancies [7]. The persistent hyperglycemia affects the normal function of multiple organs such as eyes, kidneys, and cardiovascular system [3]. Due to its high prevalence, diabetes mellitus is regarded as a global health challenge [8]. During the past three decades, the prevalence of diabetes has increased notably in low- and middle-income countries. The Eastern Mediterranean is one of the hot spots of diabetes with about 13.7% of affected adults [9]. Middle East and North Africa had the highest prevalence of diabetes (12.2%) in 2019 that is expected to have a 96% increase until 2045. However, in the same period of time it is expected to observe increased diabetes prevalence by 15% in Europe [10]. Kuwait and Yemen had the highest and lowest diabetes prevalence with 15.4% and 6.8%, respectively, in Middle East in 2000. All of the Middle East countries experienced elevated prevalence of diabetes between 2000 and 2014. Besides the genetic predisposition, various other factors such as obesity-related physical inactivity, poor nutritional habits, and urbanization are also involved in the rising trend of diabetes prevalence in the Middle East. Kuwait, Qatar, and Egypt were the top ranks of diabetes prevalence among Middle East countries between 2000 and 2014 [11]. It has been observed that the prevalence of diabetes was 11.4% among Iranian population with an annual incidence of 1% [12]. It is expected that approximately 9.2 million Iranians suffer from diabetes by 2030 [12]. Diabetes is a heterogeneous disorder affected by a wide range of genetic and environmental factors. Despite the population heterogeneity in Middle East regarding the ethnic, income, and socioeconomic status, various risk factors are involved in diabetes such as aging, lifestyle change, reduced physical activity, and high calorie diet [13]. Genetic factors can also be associated with increased diabetes susceptibility [14, 15]. Various genes are involved in the molecular mechanism of diabetes progression. A single-nucleotide polymorphism (SNP) or single-gene mutation has not the same results between different individuals and populations. This difference is directly or indirectly influenced by the overall genetic background related to the individual, family, or population that are potentially interacted with variety of environmental factors [16]. Genome-wide association studies identified 70 loci in different populations related to T2D and demonstrated an association between SNPs and T2D susceptibility [17]. Majority of the diabetic patients have not any significant clinical manifestations in the primary stages of diabetes that results in severe tissue damages in various organs such as kidney and eyes. Regarding the importance of genetic changes as pivotal risk factors associated with diabetes susceptibility, we examined the role of SNPs in the pathogenesis of diabetes in the Middle East population (Fig. 1; Table 1). The aim of present review is to assess the molecular pathology of diabetes in the Middle East population that paves the way for introducing an efficient SNP-based diagnostic panel for diabetes screening among the Middle East population.

Fig. 1
figure 1

All of the polymorphic genes that have been involved in diabetes progression among Middle East population

Table 1 All of the SNPs associated with diabetes susceptibility among Middle East population

Inflammation and immune response

Chronic inflammation associated with T2DM might happen due to the disturbance of anti-inflammatory response [18,19,20]. Cytokines have an important function in immune reaction that causes the failure of β cell function [21, 22]. Pro-inflammatory cytokines regulate the activity, proliferation, and viability of β-cell [23]. IL-1 family contains three important members: IL-1α and IL-1β as the agonists, and IL1-Ra as the antagonist. There was an association between IL1-Ra polymorphism and T1DM, in which the frequency of (A2) allele and (A1/A2) genotype was significantly higher among diabetics compared with controls in a subpopulation of Saudi cases [24]. IL-4 is involved in regulation of apoptosis and cell proliferation in Th1 cells [25]. IL-4 prevents macrophages from producing pro-inflammatory cytokines such as TNF-alpha and IL-6. A positive association between heterozygous CT variants of the IL-13-1112 and IL-4-590 polymorphisms was observed among Egyptian T2DM cases. In contrast, the homozygous CC genotypes were protective [26]. IL-4 VNTR polymorphism was assessed in Egyptian T2DM cases that showed there was a significant correlation between (A2A2) genotype and increased T2DM susceptibility. There was also a significant reduction in the (A2) allele compared with (A1) in both cases and control group [27]. Serum levels of inflammatory cytokines are increased in T2DM [28,29,30]. There was significant different frequency of IL-4 -590 genotypes and alleles between Iranian type 2 diabetic cases with nephropathy and healthy controls [31]. As an inhibitory cytokine of autoimmunity and inflammation, IL-10 is involved in the pathogenesis of T2D and its nephropathic complications [32]. It has been reported that there were significant different IL-10-592 genotypes and alleles between T2D cases with and without nephropathy compared with healthy controls. The C/C genotype was correlated with T2D and could be considered as a risk factor among a subpopulation of Iranian subjects [33]. A significant correlation was also observed between IL-10 (− 1082G/A) polymorphism and T2DM susceptibility in Turkish subjects [34]. IL-12B is a critical cytokine for the lymphocytes activation that can be associated with T2D progression. The A/A genotype and A allele of IL-12B3́ UTR A-C polymorphism were correlated with T2D pathogenesis among Iranian subjects [35]. Insulin-secreting cell damage is mediated by the auto reactive Th1 cells. The production of IFN-γ from immune-competent cells is synergistically induced by IL-12 and IL-18 that promote Th1 responses. IL-18 also up-regulates the TNF-α and IL-1 that result in β-cell death [36, 37]. A study was conducted in a subpopulation of Iranian cases to examine any possible correlation between polymorphisms at − 607 and − 137 positions of the IL-18 promoter and susceptibility to type 1 diabetes. There was a significant different frequency of IL-18-137 (C/G) genotypes between subjects who were older than 15 years and controls [38].

CTLA4 belongs to the immunoglobulin family that has a key role in T1D [39]. It has been reported that there were significant different frequencies of G allele and GG genotype of CTLA4+49A>G polymorphism in a sample of Iranian T1D patients compared with controls [40, 41]. The − 1722 (T/C), − 318 (C/T), and + 49(G/A) polymorphisms of the CTLA4 were also examined in Iranian T2D patients. There was a positive correlation between T2D and − 318 C/T and + 49 G/G genotypes, while + 49 A/A and − 318 C/C genotypes were inversely associated with T2D [42]. The A49G polymorphism of CTLA-4 was also assessed among Lebanese diabetic cases that showed a significant higher frequency of the G allele among patients compared with the controls [43].

TNF-α is a cytokine involved in systemic inflammation [44]. Plasma levels of TNF-a are associated with various risk factors of diabetes such as dyslipidemia, obesity, and inflammation [45]. It has a fundamental role in beta cells destruction which is mediated by immune cells. However, TNF-α is inhibited by IL-6 that has protective roles [46]. A significant higher prevalence of IL-1Ra A1A1 and TNF-a2308 AA genotypes, and the subsequent higher prevalence of IL-1Ra A1 and TNF-a2308 A alleles were observed in Egyptian T1D patients. There were also significant lower prevalence of IL-1Ra A1A2 and TNF-a2308 GA genotypes [47]. The -308 G/A polymorphism of TNF-α was also correlated with T2DM and T1D susceptibility among Iranian and Saudi cases, respectively [48, 49]. Regarding a previous study on Egyptian cases, the level of TNF-α was positively associated with total cholesterol, LDL-C, FBG, HbA1c, and creatinine in patients with diabetic foot. Moreover, the levels of circulating TNF-α were three- to fourfold higher in diabetic patients compared with healthy controls. C allele of TNF-α − 1031 T/C was associated with a significant risk for diabetic nephropathy progression. There was an increased TNF-α serum level in patients with diabetic foot who had CC genotype compared with those with TT genotype. Generally, carriers of C allele of TNF-α-1031 T/C had significantly increased risk of diabetic nephropathy [50]. TNF-a G-308A polymorphism in promoter sequence might be involved in glycemic control among Jordanian T2D patients. Poor glycemic control in patients who have − 308GG genotype might be due to the insulin resistance, which is subsequently developed by the high circulating levels of TNF-a protein [51]. PTPN-22 is a member of non-receptor tyrosine phosphatases which is produced by different immune cells [52]. PTPN-22 is inhibitor of effector/ memory T-cell pool required to preserve the balance in immune system [53]. There was a correlation between PTPN-22 1858 T polymorphism and T1D susceptibility among Saudi individuals [54]. PTPN22 SNPs (rs12760457, rs1310182, rs1217414, rs33996649, and rs2476601) were correlated with T1D among Iranians [55]. IL2AR and PTPN22 have pivotal roles in regulation of T-cell activation and tolerance against the self-antigens. IL2RA expression on regulatory T cells is important for its ability to inhibit the immune responses of T cells to tumor antigens, alloantigen, and self-antigens [56]. There was a poor association between T1D susceptibility and T allele of IL2RA (rs11594656) and PTPN22 (rs2476601) polymorphisms in Egyptian children. PTPN22 C1858T polymorphism had potential effect in the early age of onset in female group. T allele of IL2RA and TT genotype increased T1D progression [57].

Adipokines are involved in progression of insulin resistance [58, 59]. Adiponectin (ADIPOQ) belongs to the cytokine family which is associated with insulin-sensitizing and anti-inflammatory properties [60]. There was an association between rs17300539 allele A and increased risk of T2DM among a sample of Iranian patients [61]. The existence of G allele at position − 11,377 and lack of A allele at position − 11,391 also increased the incidence of T1DM among Iranians [62]. There was also higher frequency of TG GG genotype and G allele of adiponectin SNP45 in Iranian obese T2DM cases compared with non-diabetic cases [63]. There was higher frequencies of GT/GG genotype and G allele of ADIPOQ + 45 T>G (rs2241766) in Iranian GDM patients compared with controls [64]. Both TG and GG genotypes of ADIPOQ 45 polymorphism were significantly correlated with T2DM susceptibility. AA genotype of ADIPOQ − 11,391 was also significantly correlated with T2DM susceptibility. Moreover, TT genotype and T allele of ADIPOQ 276 polymorphism were significantly protective among Egyptian subjects [65].

Resistin (RETN) is a cysteine-rich polypeptide produced by adipocytes, immune cells, and endothelial cells [66]. It has been reported that the GG genotype and the G allele of RETN-420C/G was correlated with GDM susceptibility in a sample of Iranian cases [67]. There was increased frequency of RETN + 299 AA in obese cases compared with controls among Egyptian cases. There were also higher GG genotype and G allele frequencies of RETN − 420 in obese patients compared with control group [68]. There were higher frequencies of RETN − 420G/G genotype in Egyptian diabetic patients compared with control group. This prevalence was much more in diabetic patients who suffered from CVD compared with patients without CVD [69]. Chemerin is an adipokine involved in the regulation of adipogenesis and glucose metabolism [70, 71]. A correlation between chemerin rs4721 polymorphism and the risk of GDM has been reported among Iranian cases in which GG genotype and G allele were more frequent in non-GDM group compared with GDM group. Moreover, GT and GT + TT genotypes were correlated with a higher risk of GDM progression compared with GG genotype [72]. Omentin is one of the most important visceral fat adipokines [73]. It has been shown that Omentin V109D polymorphism was correlated with insulin resistance and familial history of diabetes among Iranian T2D patients [74]. Irisin is a cytokine that regulates energy metabolism by conversion of white into brown adipose tissue [75]. It is produced by the FNDC5 cleavage [76]. A study suggested a correlation between reduced T2DM susceptibility and the FNDC5 rs16835198 TT genotype among Egyptian cases. There was also correlation between the G allele and HOMA-IR and elevated fasting insulin. Decreased circulating levels of irisin was significantly associated with nephropathy in T2DM patients [77].

Macrophage migration inhibitory factor (MIF) as a T cell-derived pro-inflammatory cytokine prevents the macrophages migration which is the regulator of cellular inflammation [78]. A study was done to examine whether MIF expression level and the MIF173 G>C genotype distribution are different in both men and women of Iranian T2DM patients with or without depressive symptoms. C allele was reported to be correlated with susceptibility to depression in female T2DM subjects [79]. CD226 is an immunoglobulin-like transmembrane glycoprotein expressed on monocytes and NK cells [80, 81]. It has been reported that there was a correlation between CD226 rs763361 C<T polymorphism and susceptibility to T1D in Egyptian children. The onset of diabetes was significantly observed at a younger age in patients, who had T allele and TT genotype. The frequency of T allele was significantly higher in patients whose diabetes started at age 10 years [82].

Human leukocyte antigen-G (HLA-G) is associated with reduced immune response to protect the fetus from immune rejection or avoid allograft rejection in organ transplant patients [83, 84]. HLA-G disrupts the cytotoxic function of CD8+ T and NK cells and the maturity of dendritic cells [85, 86]. It is associated with autoimmune disorders including T1DM in which activated T cells cause the destruction of β cells during immune response [87,88,89]. Human leukocyte antigen is involved in self-/non-self-recognition that contains class I (HLA-A-C), class II (HLA-DP, -DQ and -DR), and class III loci [90, 91]. The occurrence of DQA1*0501, DRB1*0301, and DQB1*0201 alleles and their haplotypes were evaluated in Iranian T1D subjects. All three alleles were correlated with T1D. The patients had a higher frequency of DRB1*0301 allele [92].

Nuclear receptors

Various studies have been suggested that the prevalence of serum vitamin D deficiency is high all around the world [93,94,95,96,97]. Vitamin D has a pivotal role in bone metabolism and also functions as an antioxidant, anti-angiogenic, and anti-proliferator factor. It is also involved in several diseases such as diabetes, metabolic syndrome, obesity, and osteoporosis [98,99,100,101,102,103]. Vitamin D deficiency triggers autoimmune destruction of ß -cells that initiates T1DM through the loss of immunomodulation [104, 105]. It affects target tissues via its receptor called vitamin D receptor (VDR), which belongs to the nuclear receptor protein family. Vitamin D is correlated with macrophage activation, maturation of antigen-presenting cells, and inhibiting dendritic cell differentiation [106]. It prevents T-cell activation and TNF-α, IL-1, IL-12, and IFN-c productions [107, 108]. VDR polymorphism and vitamin D levels are involved in T1DM progression in which high vitamin D levels are protective for ß-cells [109]. The correlation between VDR gene polymorphisms at four positions (FokI, BsmI, TaqI, and ApaI) and T1DM was investigated among a subpopulation of Iranian subjects. It has been reported that there was significant higher frequency of TaqI-T allele in healthy controls compared with TIDM subjects. FokI-F allele increased risk of T1D, while T allele seemed to be protective in the TaqI polymorphism [110]. The correlation between GDM susceptibility and VDR ApaI/TaqI polymorphisms was investigated among Iranian cases. There was a significant different genotype frequency between GDM and non-GDM pregnant women. CC genotype was more frequent in GDM groups. Compared to AA genotype, CC genotype carriers had significantly increased risk of GDM progression. ApaI polymorphism was demonstrated to be correlated with GDM. There was also a correlation between TaqI polymorphism and the onset of GDM. Accordingly, the TT genotype carriers had a remarkably higher risk for GDM compared with TC genotype carriers. The TaqI-T allele carriers were more likely to develop GDM than cases with C alleles [111]. A case–control study was performed among Iranian type 2 diabetic subjects to investigate the correlation between VDR gene polymorphism (rs7975232 C>A, rs731236 T>C, and rs4516035 T>C) and risk of DN. There were significant higher frequencies of CCC, TCC haplotypes in DN group [112]. There was a significant association between FokI VDR genotype variations and an increased risk of GDM among Iranians [113]. There were different frequencies of the FokI and BsmI VDR genotypes between Egyptian T1DM and controls. The frequency of VDR Bb genotype, bb genotype, and b allele in T1DM patients was significantly higher than in control individuals. T1DM cases had also significant higher frequency of Ff and ff genotypes and f allele compared with controls [114]. There were also significant correlations between ApaI and BsmI allele and genotype distributions and an increased T1DM susceptibility among Egyptian cases [115]. It has been shown that the interaction between HLA and VDR alleles was interceded by the vitamin D response element (VDRE) in the promoter of some HLA-DRB1 alleles that was involved in pathogenesis of T1DM [116]. The associations between VDR SNPs and HLA alleles were assessed among Saudi T2DM patients. BsmI and TaqI Polymorphisms of the VDR gene were significantly correlated with susceptibility to T2DM. A higher expression of VDR was also observed in TaqI (AG) and BsmI (CT) genotypes, which were more commonly found among T2DM cases. The presence of HLA-DRB*04 with such VDR SNPs increased T2DM susceptibility among Saudi patients [117]. The CT genotype and C allele of FokI were correlated with reduced diabetes susceptibility among Saudi subjects [118]. There was a positive correlation between T1DM and BsmI and FokI polymorphisms in Saudi children [119]. VDR gene FokI SNPs were correlated with GDM among Turkish pregnant women independently. The prevalence of the VDR gene FokI CT and TT genotype was higher among individuals with GDM than the non-GDM controls [120]. VDR gene FokI polymorphism was significantly correlated with T1DM among Kuwaiti Arab children. There was also a positive correlation between T1DM and the C allele TaqI polymorphism was found [121]. Low serum levels of 1,25(OH)2D3 and 25(OH)D3 are associated with impaired function of immune system and T1D susceptibility [122]. The CYP2R1 catalyzes vitamin D3 to D 25-hydroxyvitamin D3 (25(OH) D3). CYP27B1 catalyzes the 25(OH)D3 to 1,25(OH)2D3 in renal cells [123]. It has been reported that CYP2R1 GG or CYP27B1 CC genotype carriers were associated with the increased type 1 diabetes progression. There was increased risk of type 1 diabetes for the GG genotype of CYP2R1 among subjects with CC genotype of CYP27B1. There was higher frequency of CYP2R1 GG+CYP27B1 CC among patients compared with healthy controls. The frequency of CYP2R1 GG carriers was also lower among CA/AA patients compared with CYP27B1 CC patients [124].

Sex hormones may significantly be associated with diabetes mellitus. It has been reported that estrogen can regulate calcium signals, insulin secretion, and K-ATP channel activity [125, 126]. Estrogens are involved in the stimulation of insulin synthesis in pancreas β-cells, prevention of β-cell apoptosis, increasing hepatic insulin sensitivity, and improvement of insulin action in skeletal muscles [127]. Estrogen functions via estrogen receptor (ER) in which estrogen binding with ERs regulate the expression of target genes [128]. A study was done to discover the correlation between PvuII and XbaI polymorphisms and T2DM among Iranian cases. It has been reported that there was a remarkable correlation between both PvuII and XbaI polymorphisms of ERα and T2DM susceptibility. PvuII and XbaI polymorphisms in ERα were also increased with aging [129]. There was also a correlation between the PvuII and XbaI variants and T2D among Iranian males. The frequencies of T allele of PvuII and A allele of XbaI polymorphisms were remarkably higher in male T2D cases compared with controls. Moreover, normal males carrying the AA genotype of PvuII polymorphism had increased levels of fasting glucose [130]. ESR1 positively influences GLUT4 expression and insulin signaling in skeletal muscle. It is suggested that stimulation of estrogen receptor with propylpyrazoletriyl (an agonist of the receptor) in skeletal muscles leads to a higher insulin-stimulated glucose uptake [131]. There was a correlation between ESR1 PvuII variant and T2DM susceptibility in Palestinian cases [132]. Sex hormone-binding globulin (SHBG) has been considered as one of the environmental and genetic factors that have a role in the pathophysiology of type 2 diabetes [133]. It is negatively correlated with insulin levels that cause T2DM progression. It has been reported that SHBG down-regulation increased the estradiol to regulate glucose metabolism among Egyptian T2DM cases. The rs6257 allele carriers were correlated with SHBG down-regulation, while the SHBG up-regulation was observed in rs6259 allele carriers [134].

Peroxisome proliferator-activated receptor-γ (PPAR-γ) belongs to the nuclear receptor protein family associated with regulation of metabolic processes [135, 136]. It regulates adiponectin and leptin expressions that have pivotal roles in insulin sensitivity of skeletal muscles [137,138,139]. Association between Pro12Ala PPAR-γ-2 variant and insulin resistance was assessed in a sample of Iranian cases. There was lower frequency of Ala allele in diabetic patients compared with controls. There were also reduced fasting insulin levels in Ala/Ala and Pro/Ala compared with in Pro/Pro carriers in control cases [140]. PGC-1α encodes an inducible transcriptional co-activator that interacts with PPAR-γ to elevate glucose uptake in muscle cells and also regulates T2D-associated metabolic processes, including hepatic gluconeogenesis and insulin release by the beta cells [141]. It has been shown that there were significant different frequencies of A allele of Thr528Thr and Gly482Ser variants between patients and healthy controls. 394-GG/482-GA/528-GG haplotypes of PGC-1alpha were also remarkably correlated with a higher risk of T2D in a subpopulation of Iranian cases [142]. PPAR-c is involved in subcellular metabolism of arterial wall macrophage and formation of adipose tissue [143, 144]. Moreover, it regulates the insulin sensitivity and induces the transcription of adipocyte-specific genes which are involved in the fatty acid uptake, glucose uptake, and insulin signaling [143]. PPAR-c Pro12Ala polymorphism (rs1801282) was more prevalent among Egyptian diabetic patients suffering from coronary artery disease (CAD) complications compared with patients without any complications. This finding suggested an increased risk of CAD in diabetic patients with PPAR-c Pro12Ala polymorphism. Moreover, diabetic patients with PPAR-c Pro12Ala polymorphism who suffered from CAD complications had higher cholesterol and LDL levels compared with others [145].

Stress response and detoxification

Glutathione S-transferases (GST) are a family of phase II metabolic enzymes which protect cells from oxidative damage through detoxification of carcinogenic and toxic compounds by glutathione conjugation [146,147,148,149,150]. GDM progression and its complications are associated with oxidation and antioxidant imbalance which is caused by increased levels of circulating reactive oxygen species (ROS) and deregulation of anti-oxidative enzymes [151]. A study was done to examine the correlation between GSTM1 and GSTT1 polymorphisms and GDM susceptibility in a sample of Iranian cases. GSTM1 null genotype was involved in increased GDM susceptibility [152]. A significant increased frequency of GSTM1-null genotype was reported in Iranian T2DM subjects compared with controls [153, 154]. A higher frequency of GSTT1 null genotype was also observed in Egyptian T1DM patients compared with healthy controls [155]. There were significant higher frequencies of GSTT1 and GSTM1 polymorphisms in Egyptian T2DM cases compared with controls [156]. Role of GST-P1 (Ile105Val) polymorphism was assessed in Egyptian T2DM cases and controls. There was higher G allele frequency in T2DM patients compared with healthy controls. There were also significant different frequencies of the Ile/Val genotype between patients and the controls [157]. It has been shown that GSTT1 rs17856199-C was significantly correlated with T2DM risk among Egyptian cases. CC homozygote carriers had higher risk of T2DM progression compared with non-carriers [158]. About 15% of liver transplant recipients may reveal signs of post-transplant diabetes mellitus or New-onset diabetes mellitus (NODM) which is a metabolic disease without any previous history of hyperglycemia [159, 160]. Increased plasma glucose and FFA oxidation and also ROS generation through the respiratory electron transport chain are as a result of elevated plasma free fatty acids (FFAs) and post-transplant hyperglycemia [161, 162]. It has been reported that GSTP1 genotypes were significantly associated with risk of NODM progression. The heterozygous (AG) genotype was more frequent in liver transplant cases with NODM compared with non-NODM cases. AG allele of the GSTP1 (A313G) increased risk of NODM in a subpopulation of Iranian cases [163]. A study evaluated the genotype frequencies of the GSTP1, GSTT1, and GSTM1 polymorphisms in order to find the probable correlation of the GST polymorphisms with susceptibility to DM among the Turkish individuals. There was a significant different frequency of the GSTM1 null mutations between diabetics and the controls. Susceptibility to DM was higher 4 times in patients with a combination of the GSTT1 positive genotype and GSTM1 null genotype and the GSTP1 Val allele [164]. Base excision repair (BER) is involved in DNA repair of oxidized bases [165]. The first stage of the BER pathway is the identification and removal of the altered base (8-OHdG) with the help of OGG1. This enzyme is involved in cleavage of the glycosylic bond between the sugar moiety and the modified base, which leads to an apurinic/apyrimidinic (AP) site in DNA. It has been reported that OGG1 (H+M) and GSTT1 null genotypes significantly increased the T2DM susceptibility among Turkish cases. Four times higher risk of having T2DM was identified among subjects who were carriers of the combined GSTT1 null, GSTM1 null, and GSTP1 (H+M) genotypes [166].

Superoxide dismutase (SOD) catalyzes the conversion of superoxide radical into oxygen and hydrogen peroxide. Hydrogen peroxide is also degraded by catalase. Therefore, SOD and catalase are pivotal antioxidant agents in living cells exposed to oxygen. A research among Egyptian population has showed the correlation between SOD + 35A/C and CAT 1167C/T polymorphisms and T2DM. They revealed the association of CAT-C1167T polymorphism with diabetes susceptibility in which the heterozygote CT genotype was significantly more frequent in patients compared with healthy individuals. There was significant increased T allele frequency in patients compared with healthy controls. Considering the polymorphism of + 35A/C SOD1, homozygote CC genotype carriers had higher T2DM susceptibility compared with AA genotype carriers [167]. Microsomal epoxide hydrolase (mEPHX) has important roles in epoxide metabolism. Microsomal (EPHX1) and soluble (EPHX2) epoxide hydrolases are involved in regulation of the oxidation status of lipid- and xenobiotic-derived substrates. A research among Egyptians has been suggested the relation of mEPHX1 (rs1051740) polymorphism with T2DM susceptibility. The Tyr113/Tyr113 was the most frequent genotype in the healthy controls compared with patients. There was decreased risk of T2DM among individuals with homozygous wild genotype. Lower insulin sensitivity and higher fasting insulin levels were also observed among the His139/His139 genotype carriers comparing with Arg139 allele carriers [168]. It has been also reported that EPHX2 rs751141 A allele was protective against diabetic nephropathy among Egyptian T2DM cases [169].

Heat-shock proteins (HSPs) are chaperones produced during ischemia, heat shock, and stressful conditions. JAK/STAT pathway is involved in oxidative stress adaptation via HSP70 regulation [170]. There were significant increased frequencies of CC, AC, and AA genotypes (− 110 A/C HSP 70) in nephropathic T2DM, non-nephropathic T2DM, and control groups, respectively. The C allele of (− 110 A/C HSP 70-1) polymorphism was involved in nephropathy in diabetic patients. There were significant different prevalence of CGGT, CCGT, AGGT, and AGAT haplotypes between diabetic patients suffering from nephropathy and the control group [171]. N-acetyltransferase 1 (NAT1) and NAT2 are two families of enzymes involved in catalyzing the acetylation of several heterocyclic and aromatic amine carcinogens as well as several hydrazine and aromatic drugs [172, 173]. NAT2 is capable of O-acetylation and N-acetylation that are involved in xenobiotics detoxification [174]. The rs1799931 G>A polymorphism of NAT was significantly different between the Saudi T2DM patients and healthy controls [175].

Enzymatic antioxidants including paraoxonase 1 (PON1), catalase (CAT), SOD, and glutathione peroxidase (GPx) are the main components of the antioxidant system [176, 177]. PON1 is a glycoprotein belongs to the hydrolase family that is involved in inhibition of LDL oxidation and peroxidation [178]. There was a remarkable correlation between PON1 activity and polymorphism − 108C>T in Iranian T2D subjects in which TT genotype carriers had the lowest PON1 activity [179, 180]. There was a significant correlation between PON1 promoter polymorphism (− 108C>T) and its Arylesterase-based activity in Iranian T2DM cases compared with controls [181]. There were correlations between L55M and PON1 Q192R polymorphisms and T2DM among Egyptian cases. Diabetic patients had significant lower serum concentration of the PON1 enzyme compared with controls in which the lowest concentrations were related to the 192R allele [182]. R allele of PON1 Q192R polymorphism also increased GDM susceptibility among Saudi individuals [183]. The correlation between PON1 55 leucine (L)/ methionine (M) and CAT-262 cysteine (C)/threonine (T) genetic polymorphisms and the level of malondialdehyde were assessed among Turkish T2DM cases. CAT antioxidant enzyme activity was significantly lower in carriers of TT genotype compared with the CT genotype among diabetic patients. The activity of PON1 was lower in carriers of MM genotype comparing with carriers of LL genotype among diabetic patients and controls [184]. Myeloperoxidase (MPO) belongs to the heme peroxidase superfamily that produces various diffusible radical species and reactive oxidants to initiate peroxidation of lipids [185,186,187]. A study evaluated the associations between T2DM and MPO-463G/A polymorphism among Turkish cases. GG genotype was more frequent among patients than the controls. However, the rate of carrying the A allele and the AA genotype for non-diabetic individuals was higher compared with diabetic patients [188].

Insulin signaling and transporters

Insulin promotes a wide range of growth and metabolic effects through insulin receptor binding and tyrosine kinase activation that phosphorylates insulin receptor substrate protein 1 (IRS1) (189). It has been reported that the A allele of IRS1‐rs10498210 G/A polymorphism induced risk of type 2 diabetes among Iranians [190, 191]. There were significant higher frequencies of D allele (IRS-2 Gly1057Asp) and of R allele (IRS-1 Gly972Arg) polymorphisms in Iranian T2DM cases compared with controls. Normal cases carrying the GD+DD genotypes of IRS-2 Gly1057Asp had remarkably increased fasting plasma glucose and cholesterol in comparison with GG genotype carriers [192]. It has been observed that the IRS-1(Gly972Arg) AA and GA were the most frequent genotypes in Egyptian T2DM patients. Arg 972 IRS-1 polymorphism was involved in inhibiting of IRS-1/PI3-kinase/Akt axis. A allele and GA, GA+AA genotypes had significant higher frequencies in T2DM compared control cases. IRS1 (r.2963G>A) polymorphism was an efficient determinant for insulin resistance in T2DM patients [193]. IRS-2 DD genotype of G1057D polymorphism had a higher prevalence among Turkish GDM patients compared with control group. IRS-2 DD genotype was accompanied by a 2.97-fold risk for GDM. Carriers of the D allele had also a significant higher risk for GDM [194]. The association of IRS-1 G972R polymorphism and GDM was assessed among the Saudi women population. There was significant correlation between allele Arg972 of the IRS-1 and GDM. G972R homozygosity also increased risk of GDM among Saudi women [195]. IGF2BP2 is an mRNA-binding protein involved in regulation of IGF2 protein modifications [196]. It has been revealed that both rs4402960 minor (T) allele containing haplotypes (TA and TC) of IGF2BP2 were correlated with T2DM susceptibility in a sample of Lebanese cases [197]. Src-homology-2 B adaptor protein 1 (SH2B1) is a positive regulator of insulin receptor [198, 199]. A study revealed that the rs4788102 of SH2B1 was significantly correlated with GDM among Saudi cases [200].

The insulin secretion pathway begins with the prevention of ATP-sensitive potassium channels by glucose, β-cell membrane depolarization, and increased intracellular calcium concentration that stimulate exocytosis of insulin-containing granules. This channel includes ABCC8 and KCNJ11 subunits [201]. The KCNJ11 (rs5219) was examined to explore the correlation between E23K polymorphism and T2DM susceptibility among Iranian cases. There was a correlation between E23K polymorphism and T2DM in which K allele carriers had higher risk of disease [202]. It has been shown that the KCNJ11 rs5219 polymorphism was a risk factor for T2DM among Syrian cases [203]. Alfa2-Heremans-Schmid glycoprotein (AHSG) is a serum glycoprotein involved in immune response, bone metabolism, and insulin resistance [204,205,206,207]. It has a role in insulin resistance by inhibition of insulin receptor phosphorylation [208]. A study evaluated the association between 767G>C polymorphism of AHSG and GDM susceptibility among Turkish population that showed the homozygous GG variant might have protective effects against GDM [209]. Selenoprotein P (SEPP1) is mainly produced by liver and is involved in the transport of Selenium from the liver to other organs [210]. The rs13154178 polymorphism was more frequent among Turkish GDM group compared with the controls [211]. Glut1 encoded by SLC2A1 is a carrier protein that preserves the normal glucose concentration and uptake required to maintain respiration in all cells [212]. SLC2A1 HaeIII polymorphism was examined in a subpopulation of Iranian T2DM cases in which CC was detected to be the most common genotype for SLC2A1 HaeIII polymorphism. The frequency of CC genotype was also higher in the DN group, and this genotype was significantly associated with the risk of DN. Therefore, C allele of HaeIII was proposed to be a strong risk factor for the T2DM-related DN progression [213]. The correlation between SLC30A8 rs13266634 polymorphism and T2D was examined in a subpopulation of Iranian patients. There was a significant correlation between rs13266634 polymorphism and T2D in which cases with TT genotype had lower OR compared with CC and CT genotypes. The cases with C allele had higher OR compared to those with allele T [214]. SLC30A8 encodes a zinc transporter which is essential for insulin’s storage, secretion, and stability in the beta cells [215]. It regulates the entry of zinc ions into insulin secretory vesicles from the cytoplasm, where zinc ions prevent insulin degradation by stabilizing insulin hexamers [216]. It has been reported that CC genotype of SLC30A8-rs13266634 polymorphism was significantly associated with the diabetic group in a subpopulation of Jordanian cases [217]. The rs13266634 polymorphism of SLC30A8 was significantly correlated with an increased risk of T2DM in Saudi cases [218].

Organic cation transporters (OCTs) are involved in Metformin transportation. OCT3 regulates the neurotransmission and homeostasis in the central nervous system [219]. It has been reported that the minor allele of OCT3 rs3088442GOA variant was protective toward T2D among Iranian cases. In contrast, rs2292334GOA variant increased risk of T2D. A allele carriers of rs2292334GOA had elevated risk of T2D in obese cases in comparison with non-obese cases [220]. As an endoplasmic reticulum (ER) glycoprotein, Wolferamin (WSF1) is involved in calcium transportation in ER [221, 222]. ER in beta cells had significant influences on the production and secretion of insulin [223,224,225,226]. The pathogenic WSF1 variants and epigenetic modifications result in glucose intolerance, and insulin deficiency that causes ER stress and beta cells apoptosis [222, 227, 228]. There was a significant association between rs1801214 and T2DM in a sample of Iranian cases. T allele of rs1801214 and G allele of rs1046320 reduced T2DM susceptibility [229]. Uncoupling protein 2 (UCP2) is an anion carrier protein in inner mitochondrial membrane, involved in energy homeostasis, insulin secretion, and metabolism of lipids [230, 231]. There was a correlation between UCP2-45 bp I/I polymorphism and increased T2DM risk in a sample of Iranian cases [232]. NPC1 encodes a protein with vital roles in the intracellular trafficking of sterols. This large multi-domain protein is located in lysosomes and endosomes and its function is to transport lipids to several cellular compartments [233]. According to its role in the transport of cholesterol, this protein plays a vital role in the metabolism of lipids [233]. A statistically significant correlation was found between T2D and rs1788799 among Saudi cases [234].

Glucose and insulin metabolism

Incretins are protein hormones secreted by gastrointestinal tract (GIT) due to the food ingestion which are involved in regulation of insulin response [235]. They promote insulin secretion while inhibiting glucagon secretion. Glucose‐dependent insulinotropic polypeptide (GIP) and Glucagon-like peptide-1 (GLP-1) have similar roles like incretins. GLP-1 and GIP bind to particular receptors to activate adenylate cyclase and the subsequent increased level of intracellular cAMP [236]. A correlation between T2DM and GIPR rs2302382 polymorphism has been shown among Egyptian population. There was a correlation between susceptibility to T2DM and A (rs2302382) C (rs1800437) haplotype, while the C (rs2302382) G (rs1800437) haplotype was protective [237].

MicroRNAs (miRNAs) as the pivotal regulators of glucose metabolism and homeostasis are involved in T2DM pathogenesis [238]. Many studies showed that miRNAs are significantly correlated with pancreatic islet development, insulin secretion, and insulin resistance [239]. LncRNAs such as MEG3 and H19 were suggested to adjust β cell function and glucose homeostasis [240,241,242]. H19 down-regulation was reported in the muscle of both insulin-resistant mice and human diabetic patients [241]. MEG3 was proposed to be associated with the pathogenesis of T2D and its micro vascular complications [243]. H19 rs217727- TT and the AA genotype of MEG3 rs7158663 were reported to be correlated with a significant increased risk of T2D among Iranians [244]. A case–control study was conducted to examine the impact of rs895819 (T/C) miR-27a on T2DM susceptibility among Iranian subjects. The C allele was significantly protective in which CC carriers had decreased T2DM risk compared with TT homozygotes and CT heterozygotes [245].

Lipid and cholesterol homeostasis and metabolism

Angiopoietin-like proteins (ANGPTLs) have vital roles in lipid metabolism and trafficking. The activity of lipoprotein lipase (LPL) is regulated by ANGPTL8, which is modulated by insulin [246]. ANGPTL8 belongs to the angiopoietin‐like protein family that is mostly expressed in the liver and fat tissue [247]. It promotes β-cell proliferation that subsequently increases islet size and glucose metabolism [248, 249]. ANGPTL8 is associated with T2DM progression, lipid metabolism, and insulin resistance [250, 251]. Cholesteryl ester transfer protein (CETP) has a vital role in HDL-C metabolism. CETP is involved in transferring cholesteryl esters from HDL-C to LDL and VLDL that reduces HDL-C concentration and changes susceptibility to atherosclerotic vascular disorders [252,253,254]. It has been reported that CETP rs708272 and ANGPTL8 rs2278426 variants were correlated with increased risk of T2DM. T allele was protective against CVD progression, while C allele increased risk of CVD in T2DM patients. The risk of T2DM was increased in homozygous B1 allele carriers in Egyptian T2DM cases [255]. It has been reported that there was a significant different genotype and allele frequencies of ANGPTL8 rs2278426 (C/T) variant between T2DM patients and controls. CT genotype was more susceptible to develop T2D. There were significant higher insulin resistance in CT genotype carriers compared with CC and TT genotype carriers [256]. LPL is a pivotal regulator of body fat saving through eliminating triglycerides (TGs) from blood and transferring to the fat cells. The correlation between LPL rs13702 C/T polymorphism and T2DM was explored in a sample of Iranian population. CC genotype was considerably related to the chance of T2DM. CT genotype was protective against T2DM. The rs13702 C allele damaged the binding sequence of miR-410 and up-regulated LPL which reduced serum triglyceride level and relocates FFA to peripheral tissues to cause insulin resistance [257].

The lipid profile is affected by diet and Fatty acid desaturase 1 (FADS1) and FADS2 alleles [258]. Higher susceptibility to specific metabolic disorders in adulthood is influenced by the amount of total cholesterol, LDL, HDL, and TGs in childhood which is influenced by FADS1 and FADS2 [259]. It has been reported that FADS1 (rs174537) polymorphism had a remarkable correlation with diabetes type 2 among Iranian cases [260]. Low-density lipoprotein receptor (LDLR) is down-regulated by PCSK9, which induces lysosomal degradation of LDLR in both pancreatic and liver cells. PCSK9 down-regulation increases the LDL-C clearance that results in hypocholesterolemia [261]. It has been reported that cell survival, insulin production, and secretion might be impaired by LDLR-mediated entry of excess extracellular LDL-C in beta cells [262,263,264]. A study in a Saudi Arabia samples has been investigated the prevalence of four common PCSK9 polymorphisms. They showed a prevalence of 29.59% and 35.71% for the E670G and I474V variations, respectively, which were the most common variations. Both E670G and I474V variations were observed in approximately 60% of patients. There was also a correlation between L10ins/ A56V variations and lower plasma cholesterol level [265]. Perilipin (PLIN) is a phosphoprotein target of protein kinase A (PKA). Lipolysis of TAG’s in lipid droplets is mediated through the activation or inhibition of hormone-sensitive lipase (HSL) by phosphorylated and non-phosphorylated perilipin, respectively [266, 267]. There was a correlation between PLIN (rs1052700) polymorphism and T2D in a sample of Iranian cases [268]. Sterol regulatory element-binding transcription factor-2 (SREBF-2) is involved in regulation of cholesterol hemostasis [269]. There was a significant correlation between SREBF-2 rs2267439C/T variant and T2D susceptibility in a subpopulation of Iranian cases [270]. Diabetic nephropathy (DN) is one of the leading causes of morbidity and death in T2D patients and has become a serious health problem [271]. About 30–40 percent of diabetic patients are affected by DN which is a prevalent and important micro vascular diabetic complication [272]. DN is the main reason for end-stage renal disease that is hardly identified with elevated creatinine and proteinuria levels, while reduced glomerular filtration rate. New approaches are needed to develop the diagnosis of devastating complications of diabetes [271]. APOE belongs to the apolipoprotein family of polymorphic glycoproteins involved in cholesterol transport [273]. Apolipoprotein A5 (APOA5) has a pivotal role in TG metabolism [274]. APOA5 up-regulation is associated with reduced TG plasma levels [274]. Correlation between APOA5 (rs662799) variants and lipid profile levels were investigated in case–control study on Iranian T2D patients. Higher TG levels were observed in CC carriers in DN+, DN−, and control groups [275]. APOE e2 and e4 alleles were correlated with the higher risk of T2DM, while e3 was protective against diabetes among the Saudi population [276]. ApoC3, as a natural inhibitor of lipoprotein lipase, is involved in the modulation of the metabolism of triglyceride-rich lipoproteins [277, 278]. The levels of ApoC3 are positively associated with the levels of plasma triglyceride, which might be due to its inhibitory effect on lipoprotein lipase [279,280,281]. A significant correlation was observed between 3238C>G polymorphism of ApoC3 and susceptibility to T2DM among the Saudi population [282]. It has been revealed that the e3, e4, and e2 alleles were the first three most prevalent alleles of Apo E polymorphism among Turkish diabetic cases. The prevalence of the Apo E4 genotype was lower in normal controls compared with the diabetics with nephropathy [283].

Nitric oxide

Nitric oxide (NO) is a pivotal regulator of endothelial action and homeostasis that is derived from L-arginine by nitric oxide synthases (NOSs) which are necessary for cellular signaling and insulin secretion. It has been reported that NOS2 rs2779248T/C and rs1137933C/T gene polymorphisms significantly increased T2D risk in a sample of Iranian cases. T allele and CT genotype of NOS2 rs1137933C/T and CC genotype of NOS2 rs2779248T/C were remarkably correlated with increased risk of T2D, while TC genotype of NOS2 rs277 was remarkably protective for T2D [284]. A positive correlation was also observed between the rs1800779 (A/G) polymorphism of NOS3 and T2D in dominant (AG+GG vs. AA) and codominant (AG vs. AA) patterns among Iranian subjects [285]. Endothelial-derived NO is produced by eNOS that is involved in vascular action in insulin and glucose transfer to the skeletal muscles [286]. eNOS regulates insulin secretion and glucose metabolism that can be associated with T2D progression [287]. A remarkable different allele and genotype frequency of eNOS VNTR polymorphism was reported among Iranian diabetic cases. There was a significant correlation between this polymorphism and cases with diabetic neuropathy [288]. The presence of eNOS variants may also cause nephropathy and endothelial disorder via diminished production of NO [289, 290]. The eNOS 4a or 894 T allele increased DN progression in a sample of Iranian T2DM cases [291]. The correlation of type 2 diabetes with TT genotype of eNOS G894T variant was also found among a sample of Egyptian cases [292]. End-stage renal disease (ESRD) is mainly caused by DN. Pathophysiological specifications of DN are an early phase with hyper filtration, glomerular hypertrophy, and microalbuminuria which leads to an advanced phase with proteinuria progressive glomerulosclerosis, and reduced renal function [293]. It has been reported that eNOS polymorphism was involved in ESRD among Egyptian T2D patients in which TT genotype highly increased the ESRD susceptibility. There was significant reduced plasma nitrate/nitrite level and serum NOS activity in TT genotype carriers compared with GG and GT genotypes, mentioning the Glu298Asp polymorphism as an important risk factor of DN to ESRD progression via NO levels reduction [294]. It has been suggested that the T allele and the TT genotype of eNOS 894G>T polymorphism, and the C allele and the CC genotype of − 786 T>C SNP, were significantly more prevalent among Egyptian diabetic patients suffering from nephropathy than those without nephropathy. Serum levels of NO were also significantly reduced in (− 786 T/C) CC and TC genotypes compared with TT genotype, and also 894G>T TT and GT genotypes compared with GG genotype among patients with diabetic nephropathy and patients without diabetic nephropathy [295].

Signaling pathways

WNT is a pivotal signaling pathway that is involved in regulation of various physiological and pathophysiological processes such as cell cycle, metabolism, apoptosis, immune response, and tumorigenesis [296,297,298,299]. Transcription factor 7-like 2 (TCF7L2) belongs to the high mobility group box transcription factors involved in WNT signaling pathway. It regulates cortisol/aldosterone secretion, pancreatic β-cell function, inflammatory status, and preadipocyte differentiation [300]. TCF7L2 is associated with Wnt signaling pathway via regulation of GLP-1, which is involved in blood glucose homeostasis [301, 302]. Deregulation of Wnt signaling has a pivotal role in insulin resistance [303]. T allele of TCF7L2 (rs7903146C/T) polymorphism was considered as a risk allele in diabetes among Iranian cases [304,305,306]. The correlation between rs12255372, rs7903146, and rs290487 polymorphisms of TCF7L2 and T2DM was investigated among Iranian cases. There were correlations between T allele and genotypes of these variants and T2DM. Normal cases carrying the GT+TT genotypes of the rs12255372 variation had a remarkably higher WHR compared with GG genotype carriers [307]. The correlation between T2DM and TCF7L2 rs12255372 variant was assessed in a subpopulation of Iranian cases in which the minor T allele of TCF7L2 rs12255372 significantly elevated the T2DM risk. There was significant different frequency of TT genotypes in T2DM cases compared with controls [308]. TCF7L2 rs7903146 and rs12255372 were also correlated with T2DM susceptibility among Egyptian population [309]. The rs7903146 variant of TCF7L2 was significantly correlated with T2DM among Palestinian individuals [310]. The rs12255372 G/T substitution and the rs7903146 C/T substitution were considerably correlated with T2DM. The TTTCTT haplotype for rs11196213, rs11196205, rs12255372, rs3814573, rs7901695, and rs7903146 was a risk factor for the occurrence of T2DM among Turkish populations [311]. There were significant correlations between TCF7L2 rs12255372 polymorphism and T2DM in among Emirati cases in which “TT” genotype increased the T2DM risk [312, 313]. Adropin is involved in insulin resistance and glucose oxidation. In a case control study, the serum levels of adropin and rs7903146 polymorphism were examined in Iranian T2DM subjects. Remarkable different frequency of adropin genotypes was observed between subjects and control groups. TT genotype carriers had the highest adropin serum level whereas healthy people with CC genotype had the lowest adropin serum level. The rs7903146T/T and rs7903146C/T genotypes also increased the risk of T2DM [314].

Hematopoietically expressed homeobox (HHEX) is a transcription factor involved in regulation of WNT signaling that has pivotal roles during pancreas development [315, 316]. HHEX variants have been proved to be associated with T2D [316]. The correlation between rs1111875G/A and rs5015480C/T polymorphisms of HHEX and risk of T2D was investigated among Iranian diabetic cases. GA and AA genotypes of rs1111875G/A increased risk of T2D. CT genotype of rs5015480C/T was also significantly associated with T2D progression [317]. It has been found that GG genotype of HHEX rs1111875 A/G polymorphism had an important relationship with T2DM susceptibility among Iranians. GA genotype was also significantly protective in T2DM [318].

MAPK signaling pathway is involved in signal transduction of hyperglycemia [319]. Deregulation of MAPK pathway and related impact on insulin pathway was reported in T2DM patients [320,321,322,323]. It has been observed that there was a significant correlation between MAP3K1 (rs10461617) polymorphism and T2DM in a sample of Iranian subjects. The homozygous AA genotype had higher T2DM risk compared with heterozygous AG genotype [324]. Transforming growth factor-b (TGF-b) is a member of growth factors family, which have important regulatory impacts on many physiological processes [325]. TGF-b/Smad3 signaling is a pivotal regulator of insulin expression that can be deregulated in diabetes [326]. It has been observed that TGF-b1 (T869C) C and T alleles increased and reduced T2D susceptibility among a sample of Egyptian patients, respectively [327].

Structural proteins

The function and structure of many cell types are associated with the extracellular matrix that is involved in cell adhesion, cellular differentiation, proliferation, and migration [328]. Noticeable modifications in the structure and synthesis of the extracellular matrix have been reported in diabetes mellitus. Hyperglycemia and insulin resistance were reported to be correlated with collagen IV levels [329]. Zinc-dependent endopeptidases are called matrix metalloproteinases (MMP) that affect matrix and non-matrix proteins [330]. A study was done in an Iranian population to examine the probable correlation between COL4A3 (rs55703767, G/T) and MMP-9 (rs17576, A/G) polymorphisms and T2D. T allele of COL4A3 (G/T) had a protective role, whereas A allele of MMP-9 (A/G) appeared to be a risk factor of T2D [331]. Serine protease inhibitor B1 (SerpinB1) acts as a neutrophil elastase inhibitor, which is correlated with improved insulin sensitivity [332, 333]. It also inhibits cell migration by MMP-2 down-regulation [334]. Diabetic cases with rs15286 AA genotype had higher HOMA2-β levels and lower FPG and HbA1C levels, compared with other genotypes. There was also a significant correlation between AA genotype and good glycemic control among Egyptian patients. Moreover, there was a direct correlation between G allele and prediction of poor glycemic control [335]. Calpains are cysteine proteases involved in cell proliferation, signal transduction, apoptosis, membrane fusion, and platelet activation [336, 337]. Calpain 10 (CAPN10) regulates the reorganization of actin which is vital for insulin-stimulated translocation of GLUT4 to the plasma membrane of adipocytes [338]. There was a significant correlation between allele 2 (C) of CAPN10 (SNP-44) and increased risk of T2DM in a sample of Palestinian cases [339]. There was also a correlation between SNP-44 polymorphism and T2DM in a sample of Turkish cases in which T allele had lower frequency among patients compared with control group [340].

Engulfment And Cell Motility 1 (ELMO1) is involved in cell movement and phagocytosis [341]. Correlation between the re1345365, rs741301 variants, and DN were assessed in an Iranian subpopulation. There was an association between allelic and genotypic frequencies of the rs741301 variant and DN. G alleles and GG genotype carriers had higher DN susceptibility. The rs1345365A/rs741301G was considered as a risk haplotype for DN progression in T2DM patients [342]. There was also a significant correlation between ELMO1 gene (rs741301) polymorphism and DN in a sample of Egyptian subjects. DN patients with GG genotype and G allele were more than twice as likely to develop DN. The ELMO1 (rs741301) polymorphism increased the DN susceptibility among T2D patients [343]. SNARE protein family including VAMP2 and SNAP25 are structural proteins involved in insulin secretion through the vesicle fusion. It has been shown that SNAP25 polymorphisms were associated with the concentration of HbA1c, fasting glycemia, and insulinemia in T2DM patients. There were also significant increased levels of HbA1c and fasting glucose among diabetic patients who were carriers of the rs363050 (AG/GG) compared with (AA) genotype. Insulin levels were significantly higher in carriers of the (AA) genotype compared with (AG/GG) [344].

ERBB receptor feedback inhibitor 1 (ERRFI1) is an adapter protein involved in regulation of tyrosine kinase receptors [345,346,347]. Over its antagonistic role in the EGFR signaling pathway, ERRFI1 appears to decrease the mass of beta cells [348, 349]. A study was done in a group of Iranian diabetic cases to examine the correlation between + 808 (T/G) polymorphism and DN. There was a remarkable correlation between + 808 T/G variant and diabetes. T allele of this polymorphism had a protective role against diabetes [350].

Renin–angiotensin system

The renin–angiotensin system (RAS) includes a series of cellular processes that lead to the generation of angiotensin II. The activation of this system has a pivotal role in CAD and hypertension [351, 352]. The correlation between AT1R A11166C polymorphism and DM was assessed in a group of Iranian subjects with CAD. There was a significant higher frequency of polymorphic genotypes (AC and CC) and the 1166 C allele in the diabetic group compared with non-diabetic cases [353]. The angiotensin-converting enzyme (ACE), which is a vital part of the RAS, is involved in the homeostasis of renal electrolytes and regulation of systemic blood pressure [354, 355]. There was significant correlation between DD genotype and D allele of ACE and increased T2DM progression among Egyptian and Saudi Arabian cases [356, 357]. There were also high frequencies of D allele and DD genotypes of ACE I/D polymorphism among Kuwaiti T2DM patients [358].

Conclusions

Diabetes is a chronic disorder that often lacks any significant clinical symptoms in the early stages. Therefore, late diagnosis can be associated with tissue damages in various organs such as kidney and cardiovascular systems that leads in diabetic complications. SNPs are pivotal factors involved in diabetic susceptibility that can be used for the early detection and better disease management. Given the high prevalence of diabetes in Middle East, in the present review we assessed the role of SNPs in diabetes susceptibility and prevalence in this region. It has been shown that the diabetes-related SNPs were mainly observed in genes which were associated with immune system, nuclear receptors, and insulin signaling pathway. Since, various SNPs have been reported in different Middle East countries, it is difficult to introduce an efficient general SNP-based diagnostic panel marker in this region. However, based on the number of studied patients in this region, it seems that a general panel of NOS, TCF7L2, VDR, and PON1 polymorphisms can be used as diagnostic panel markers to identify the susceptible cases to diabetes in Middle East population. Moreover, we can also introduce TNF-α (-308G/A), NPC1(rs1805081 and rs1788799), MPO (-463G/A), TCF7L2 (rs4506565 and rs12255372), KCNJ11 (rs5219), IGF2BP2 (rs4402960 and rs1470579), VDR (rs10735810, rs731236, rs7975232, and rs1544410), TCF7L2 (rs7903146), eNOS (T786C and G894T), and ACE (C677T and I/D) polymorphisms as the candidates for the screening of the diabetes susceptibility among Iranian, Saudi Arabia, Turkish, Emirati, Syrian, Lebanese, Kuwaiti, Palestinian, Jordanian, and Bahraini populations, respectively. Regarding the high racial diversity in the Middle East countries, the present review can be considered as a suitable model to investigate the role of SNPs in other races and countries to pave the way of introducing a global SNP-based diagnostic panel marker for diabetes.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

SNPs:

Single-nucleotide polymorphisms

GDM:

Gestational diabetes mellitus

T1D:

Type 1 diabetes

T2D:

Type 2 diabetes mellitus

ADIPOQ:

Adiponectin

MIF:

Macrophage migration inhibitory factor

HLA-G:

Human leukocyte antigen-G

VDR:

Vitamin D receptor

ER:

Estrogen receptor

SHBG:

Sex hormone-binding globulin

PPAR-γ:

Peroxisome proliferator-activated receptor-γ

GST:

Glutathione S-transferases

ROS:

Reactive oxygen species

NODM:

New-onset diabetes mellitus

FFAs:

Free fatty acids

SOD:

Superoxide dismutase

mEPHX:

Microsomal epoxide hydrolase

HSPs:

Heat-shock proteins

NAT1:

N-acetyltransferase 1

PON1:

Paraoxonase 1

CAT:

Catalase

GPx:

Glutathione peroxidase

MPO:

Myeloperoxidase

IRS1:

Insulin receptor substrate protein 1

SH2B1:

Src-homology-2 B adaptor protein 1

AHSG:

Alfa2-Heremans-Schmid glycoprotein

SEPP1:

Selenoprotein P

OCTs:

Organic cation transporters

ER:

Endoplasmic reticulum

UCP2:

Uncoupling protein 2

GIT:

Gastrointestinal tract

GIP:

Glucose‐dependent insulinotropic polypeptide

GLP-1:

Glucagon-like peptide-1

miRNAs:

MicroRNAs

ANGPTLs:

Angiopoietin-like proteins

CETP:

Cholesteryl ester transfer protein

FADS1:

Fatty acid desaturase 1

PLIN:

Perilipin

PKA:

Protein kinase A

HSL:

Hormone-sensitive lipase

DN:

Diabetic nephropathy

APOA5:

Apolipoprotein A5

NO:

Nitric oxide

NOSs:

Nitric oxide synthases

ESRD:

End-stage renal disease

TCF7L2:

Transcription factor 7-like 2

HHEX:

Hematopoietically expressed homeobox

TGF-b:

Transforming growth factor-b

MMP:

Matrix metalloproteinases

SerpinB1:

Serine protease inhibitor B1

CAPN10:

Calpain 10

ELMO1:

Engulfment and Cell Motility 1

ERRFI1:

ERBB receptor feedback inhibitor 1

RAS:

Renin–angiotensin system

CAD:

Coronary artery disease

ACE:

Angiotensin-converting enzyme

References

  1. Crafa A, Calogero AE, Cannarella R, Mongioi LM, Condorelli RA, Greco EA, et al. The burden of hormonal disorders: a worldwide overview with a particular look in Italy. Front Endocrinol. 2021;12:745.

    Google Scholar 

  2. Association AD. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2014;37(Supplement 1):S81–90.

    Google Scholar 

  3. Association AD. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2010;33(Supplement 1):S62–9.

    Google Scholar 

  4. Chentoufi A, Binder N, Berka N, Abunadi T, Polychronakos C. Advances in type I diabetes associated tolerance mechanisms. Scand J Immunol. 2008;68(1):1–11.

    CAS  PubMed  Google Scholar 

  5. Mobasseri M, Shirmohammadi M, Amiri T, Vahed N, Fard HH, Ghojazadeh M. Prevalence and incidence of type 1 diabetes in the world: a systematic review and meta-analysis. Health Promot Perspect. 2020;10(2):98.

    PubMed  PubMed Central  Google Scholar 

  6. Noble D, Mathur R, Dent T, Meads C, Greenhalgh T. Risk models and scores for type 2 diabetes: systematic review. BMJ. 2011;343:d7163.

    PubMed  PubMed Central  Google Scholar 

  7. Association AD. Gestational diabetes mellitus. Diabetes Care. 2004;27:S88.

    Google Scholar 

  8. Khawandanah J. Double or hybrid diabetes: a systematic review on disease prevalence, characteristics and risk factors. Nutr Diabetes. 2019;9(1):1–9.

    Google Scholar 

  9. Organization WH. Global report on diabetes [Internet]. 2016. Disponible sur. 2017.

  10. Saeedi P, Salpea P, Karuranga S, Petersohn I, Malanda B, Gregg EW, et al. Mortality attributable to diabetes in 20–79 years old adults, 2019 estimates: results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res Clin Pract. 2020;162:108086.

    PubMed  Google Scholar 

  11. El-Kebbi IM, Bidikian NH, Hneiny L, Nasrallah MP. Epidemiology of type 2 diabetes in the Middle East and North Africa: challenges and call for action. World J Diabetes. 2021;12(9):1401–25.

    PubMed  PubMed Central  Google Scholar 

  12. Esteghamati A, Larijani B, Aghajani MH, Ghaemi F, Kermanchi J, Shahrami A, et al. Diabetes in Iran: prospective analysis from first nationwide diabetes report of National Program for Prevention and Control of Diabetes (NPPCD-2016). Sci Rep. 2017;7(1):1–10.

    CAS  Google Scholar 

  13. Azizi F, Hadaegh F, Hosseinpanah F, Mirmiran P, Amouzegar A, Abdi H, et al. Metabolic health in the Middle East and north Africa. Lancet Diabetes Endocrinol. 2019;7(11):866–79.

    PubMed  Google Scholar 

  14. Abuhendi N, Qush A, Naji F, Abunada H, Al Buainain R, Shi Z, et al. Genetic polymorphisms associated with type 2 diabetes in the Arab world: a systematic review and meta-analysis. Diabetes Res Clin Pract. 2019;151:198–208.

    CAS  PubMed  Google Scholar 

  15. Musambil M, Siddiqui K. Genetics and genomics studies in type 2 diabetes: a brief review of the current scenario in the Arab region. Diabetes Metab Syndr. 2019;13(2):1629–32.

    PubMed  Google Scholar 

  16. Staiger H, Machicao F, Fritsche A, Häring H-U. Pathomechanisms of type 2 diabetes genes. Endocr Rev. 2009;30(6):557–85.

    CAS  PubMed  Google Scholar 

  17. Kharroubi AT, Darwish HM. Diabetes mellitus: the epidemic of the century. World J Diabetes. 2015;6(6):850.

    PubMed  PubMed Central  Google Scholar 

  18. Kazemi AM. Interleukin-4 gene polymorphisms in type 2 diabetic patients with nephropathy. 2010.

  19. Imran M, Laddha N, Dwivedi M, Mansuri M, Singh J, Rani R, et al. Interleukin-4 genetic variants correlate with its transcript and protein levels in patients with vitiligo. Br J Dermatol. 2012;167(2):314–23.

    CAS  PubMed  Google Scholar 

  20. Sobti R, Maithil N, Thakur H, Sharma Y, Talwar K. VEGF and IL-4 gene variability and its association with the risk of coronary heart disease in north Indian population. Mol Cell Biochem. 2010;341(1):139–48.

    CAS  PubMed  Google Scholar 

  21. Ichinose K, Kawasaki E, Eguchi K. Recent advancement of understanding pathogenesis of type 1 diabetes and potential relevance to diabetic nephropathy. Am J Nephrol. 2007;27(6):554–64.

    CAS  PubMed  Google Scholar 

  22. Yoon J-W, Jun H-S. Autoimmune destruction of pancreatic β cells. Am J Ther. 2005;12(6):580–91.

    PubMed  Google Scholar 

  23. Mandrup-Poulsen T. Interleukin-1 antagonists and other cytokine blockade strategies for type 1 diabetes. Rev Diabet Stud RDS. 2012;9(4):338–47.

    PubMed  Google Scholar 

  24. Ali RA, Saber LM, Al-Harbi AM. A novel association between IL1-Ra (receptor antagonist) gene polymorphism and T1DM in Al-Madina Al-Mounawra. Eur Rev Med Pharmacol Sci. 2015;19(19):3701–8.

    CAS  PubMed  Google Scholar 

  25. Ueta M, Sotozono C, Inatomi T, Kojima K, Hamuro J, Kinoshita S. Association of combined IL-13/IL-4R signaling pathway gene polymorphism with Stevens-Johnson syndrome accompanied by ocular surface complications. Invest Ophthalmol Vis Sci. 2008;49(5):1809–13.

    PubMed  Google Scholar 

  26. Alsaid A, El-Missiry M, el Hatata S, Tarabay M, Settin A. Association of IL-4-590 C>T and IL-13-1112 C>T gene polymorphisms with the susceptibility to type 2 diabetes mellitus. Dis Markers. 2013;35(4):243–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Ali R, El-Said A, El-Baz H, Settin A. Ethnic variation of IL-4 intron 3 VNTR gene polymorphism; its association with type 2 diabetes mellitus and its complication (neuropathy) in Egyptian subjects. Am J Med Genet B Neuropsychiatr Genet. 2018;177(7):635–40.

    CAS  PubMed  Google Scholar 

  28. Skopiński P, Rogala E, Duda-Król B, Lipińska A, Sommer E, Chorostowska-Wynimko J, et al. Increased interleukin-18 content and angiogenic activity of sera from diabetic (Type 2) patients with background retinopathy. J Diabetes Complic. 2005;19(6):335–8.

    Google Scholar 

  29. Pickup JC, Chusney GD, Thomas SM, Burt D. Plasma interleukin-6, tumour necrosis factor alpha and blood cytokine production in type 2 diabetes. Life Sci. 2000;67(3):291–300.

    CAS  PubMed  Google Scholar 

  30. Arababadi MK, Nosratabadi R, Hassanshahi G, Yaghini N, Pooladvand V, Shamsizadeh A, et al. Nephropathic complication of type-2 diabetes is following pattern of autoimmune diseases? Diabetes Res Clin Pract. 2010;87(1):33–7.

    PubMed  Google Scholar 

  31. Kazemi AM. Interleukin-4 gene polymorphisms in type 2 diabetic patients with nephropathy. Iran J Kidney Dis. 2010;4(4):302–6.

    Google Scholar 

  32. Sanjabi S, Zenewicz LA, Kamanaka M, Flavell RA. Anti-inflammatory and pro-inflammatory roles of TGF-beta, IL-10, and IL-22 in immunity and autoimmunity. Curr Opin Pharmacol. 2009;9(4):447–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Arababadi MK, Reza Mirzaei M, Ali Sajadi SM, Hassanshahi G, Ahmadabadi BN, Salehabadi VA, et al. Interleukin (IL)-10 gene polymorphisms are associated with type 2 diabetes with and without nephropathy: a study of patients from the southeast region of Iran. Inflammation. 2012;35(3):797–802.

    PubMed  Google Scholar 

  34. Erdogan M, Cetinkalp S, Ozgen AG, Saygili F, Berdeli A, Yilmaz C. Interleukin-10 (-1082G/A) gene polymorphism in patients with type 2 diabetes with and without nephropathy. Genet Test Mol Biomarkers. 2012;16(2):91–4.

    CAS  PubMed  Google Scholar 

  35. Yaghini N, Mahmoodi M, Hassanshahi G, Asadikaram G, Arababadi MK, Rezaeian M, et al. Genetic variation of IL-12B (+1188 region) is associated with its decreased circulating levels and susceptibility to Type 2 diabetes. Biomark Med. 2012;6(1):89–95.

    CAS  PubMed  Google Scholar 

  36. Nakanishi K, Yoshimoto T, Tsutsui H, Okamura H. Interleukin-18 is a unique cytokine that stimulates both Th1 and Th2 responses depending on its cytokine milieu. Cytokine Growth Factor Rev. 2001;12(1):53–72.

    CAS  PubMed  Google Scholar 

  37. André-Schmutz I, Hindelang C, Benoist C, Mathis D. Cellular and molecular changes accompanying the progression from insulitis to diabetes. Eur J Immunol. 1999;29(1):245–55.

    PubMed  Google Scholar 

  38. Mojtahedi Z, Naeimi S, Farjadian S, Omrani GR, Ghaderi A. Association of IL-18 promoter polymorphisms with predisposition to Type 1 diabetes. Diabet Med J Br Diabet Assoc. 2006;23(3):235–9.

    CAS  Google Scholar 

  39. Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP, et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science. 1995;270(5238):985–8.

    CAS  PubMed  Google Scholar 

  40. Ranjouri MR, Aob P, Mansoori Derakhshan S, Shekari Khaniani M, Chiti H, Ramazani A. Association study of IL2RA and CTLA4 gene variants with Type I diabetes mellitus in children in the northwest of Iran. Bioimpacts. 2016;6(4):187–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Mojtahedi Z, Omrani GR, Doroudchi M, Ghaderi A. CTLA-4 +49 A/G polymorphism is associated with predisposition to type 1 diabetes in Iranians. Diabetes Res Clin Pract. 2005;68(2):111–6.

    CAS  PubMed  Google Scholar 

  42. Kiani J, Khadempar S, Hajilooi M, Rezaei H, Keshavarzi F, Solgi G. Cytotoxic T lymphocyte antigen-4 gene variants in Type 2 diabetic patients with or without neuropathy. Iran J Allergy Asthma Immunol. 2016;15(3):220–8.

    PubMed  Google Scholar 

  43. Wafai RJE, Chmaisse HN, Makki RF, Fakhoury H. Association of HLA class II alleles and CTLA-4 polymorphism with type 1 diabetes. Saudi J Kidney Dis Transplant. 2011;22(2):273.

    Google Scholar 

  44. Chen Y, Qiao Y, Xu Y, Ling W, Pan Y, Huang Y, et al. Serum TNF-α concentrations in type 2 diabetes mellitus patients and diabetic nephropathy patients: a systematic review and meta-analysis. Immunol Lett. 2017;186:52–8.

    CAS  PubMed  Google Scholar 

  45. Gustafson B. Adipose tissue, inflammation and atherosclerosis. J Atheroscler Thromb. 2010;17(4):332–41.

    CAS  PubMed  Google Scholar 

  46. Gillespie KM, Nolsøe R, Betin VM, Kristiansen OP, Bingley PJ, Mandrup-Poulsen T, et al. Is puberty an accelerator of type 1 diabetes in IL6-174CC females? Diabetes. 2005;54(4):1245–8.

    CAS  PubMed  Google Scholar 

  47. Settin A, Ismail A, El-Magd MA, El-Baz R, Kazamel A. Gene polymorphisms of TNF-alpha-308 (G/A), IL-10(-1082) (G/A), IL-6(-174) (G/C) and IL-1Ra (VNTR) in Egyptian cases with type 1 diabetes mellitus. Autoimmunity. 2009;42(1):50–5.

    CAS  PubMed  Google Scholar 

  48. Golshani H, Haghani K, Dousti M, Bakhtiyari S. Association of TNF-α 308 G/A polymorphism with Type 2 diabetes: a case-control study in the Iranian Kurdish Ethnic Group. Osong Public Health Res Perspect. 2015;6(2):94–9.

    PubMed  PubMed Central  Google Scholar 

  49. Allam G, Nasr A, Talaat IM, Abuelsaad ASA, Bakheit AM, Nemenqani D, et al. Association between cytokine genes polymorphisms and type 1 diabetes: a case-control study on Saudi population. Immunol Invest. 2018;47(3):229–40.

    CAS  PubMed  Google Scholar 

  50. Emara M, El-Edel R, Fathy WM, Aboelkhair NT, Watany MM, Abou-Elela DH. Study the association of tumor necrosis factor promoter polymorphism with Type 2 diabetic nephropathy. Mediators Inflamm. 2020;2020:1498278.

    PubMed  PubMed Central  Google Scholar 

  51. Al-Azzam SI, Khabour OF, Alzoubi KH, Ghanma MW, Alhasan AY. The role of TNF-α G-308A promoter polymorphism in glycemic control in Type 2 diabetes patients. J Endocrinol Invest. 2014;37(2):113–8.

    CAS  PubMed  Google Scholar 

  52. Burn GL, Svensson L, Sanchez-Blanco C, Saini M, Cope AP. Why is PTPN22 a good candidate susceptibility gene for autoimmune disease? FEBS Lett. 2011;585(23):3689–98.

    CAS  PubMed  Google Scholar 

  53. Hasegawa K, Martin F, Huang G, Tumas D, Diehl L, Chan AC. PEST domain-enriched tyrosine phosphatase (PEP) regulation of effector/memory T cells. Science (New York, NY). 2004;303(5658):685–9.

    CAS  Google Scholar 

  54. Alswat KA, Nasr A, Al Dubayee MS, Talaat IM, Alsulaimani AA, Mohamed IAA, et al. The potential role of PTPN-22 C1858T Gene polymorphism in the pathogenesis of Type 1 diabetes in Saudi population. Immunol Invest. 2018;47(5):521–33.

    CAS  PubMed  Google Scholar 

  55. Abbasi F, Soltani S, Saghazadeh A, Soltaninejad E, Rezaei A, Zare Bidoki A, et al. PTPN22 single-nucleotide polymorphisms in iranian patients with Type 1 diabetes mellitus. Immunol Invest. 2017;46(4):409–18.

    CAS  PubMed  Google Scholar 

  56. Kobayashi M, Abiru N, Arakawa T, Fukushima K, Zhou H, Kawasaki E, et al. Altered B: 9–23 insulin, when administered intranasally with cholera toxin adjuvant, suppresses the expression of insulin autoantibodies and prevents diabetes. J Immunol. 2007;179(4):2082–8.

    CAS  PubMed  Google Scholar 

  57. Abdelrahman HM, Sherief LM, Abd Elrahman DM, Alghobashy A, Elsaadani HF, Mohamed RH. The association of PTPN22 (rs2476601) and IL2RA (rs11594656) polymorphisms with T1D in Egyptian children. Hum Immunol. 2016;77(8):682–6.

    CAS  PubMed  Google Scholar 

  58. Sahin-Efe A, Katsikeris F. Advances in adipokines. Metab Clin Exp. 2012;61(12):1659–65.

    CAS  PubMed  Google Scholar 

  59. Raucci R, Rusolo F, Sharma A, Colonna G, Castello G, Costantini S. Functional and structural features of adipokine family. Cytokine. 2013;61(1):1–14.

    CAS  PubMed  Google Scholar 

  60. Hopkins TA, Ouchi N, Shibata R, Walsh K. Adiponectin actions in the cardiovascular system. Cardiovasc Res. 2007;74(1):11–8.

    CAS  PubMed  Google Scholar 

  61. Karimi H, Nezhadali M, Hedayati M. Association between adiponectin rs17300539 and rs266729 gene polymorphisms with serum adiponectin level in an Iranian diabetic/pre-diabetic population. Endocr Regul. 2018;52(4):176–84.

    PubMed  Google Scholar 

  62. Nomani H, Hesami O, Vaisi-Raygani A, Tanhapour M, Bahrehmand F, Rahimi Z, et al. Association between the -11377 C/G and -11391 G/A polymorphisms of adiponectin gene and adiponectin levels with susceptibility to type 1 and type 2 diabetes mellitus in population from the west of Iran, correlation with lipid profile. J Cell Biochem. 2019;120(3):3574–82.

    CAS  PubMed  Google Scholar 

  63. Mohammadzadeh G, Zarghami N. Associations between single-nucleotide polymorphisms of the adiponectin gene, serum adiponectin levels and increased risk of type 2 diabetes mellitus in Iranian obese individuals. Scand J Clin Lab Invest. 2009;69(7):764–71.

    CAS  PubMed  Google Scholar 

  64. Takhshid MA, Haem Z, Aboualizadeh F. The association of circulating adiponectin and + 45 T/G polymorphism of adiponectin gene with gestational diabetes mellitus in Iranian population. J Diabetes Metab Disord. 2015;14:30.

    PubMed  PubMed Central  Google Scholar 

  65. El-Shal AS, Zidan HE, Rashad NM. Adiponectin gene polymorphisms in Egyptian type 2 diabetes mellitus patients with and without diabetic nephropathy. Mol Biol Rep. 2014;41(4):2287–98.

    CAS  PubMed  Google Scholar 

  66. Park HK, Ahima RSJD. Resistin in rodents and humans. Diabetes Metab J. 2013;37(6):404–14.

    PubMed  PubMed Central  Google Scholar 

  67. Takhshid MA, Zare Z. Resistin - 420 C/G polymorphism and serum resistin level in Iranian patients with gestational diabetes mellitus. J Diabetes Metab Disord. 2015;14:37.

    PubMed  PubMed Central  Google Scholar 

  68. El-Shal AS, Pasha HF, Rashad NM. Association of resistin gene polymorphisms with insulin resistance in Egyptian obese patients. Gene. 2013;515(1):233–8.

    CAS  PubMed  Google Scholar 

  69. Motawi TM, Shaker OG, El-Sawalhi MM, Abdel-Nasser ZM. Visfatin -948G/T and resistin -420C/G polymorphisms in Egyptian type 2 diabetic patients with and without cardiovascular diseases. Genome. 2014;57(5):259–66.

    CAS  PubMed  Google Scholar 

  70. Roh SG, Song SH, Choi KC, Katoh K, Wittamer V, Parmentier M, et al. Chemerin—a new adipokine that modulates adipogenesis via its own receptor. Biochem Biophys Res Commun. 2007;362(4):1013–8.

    CAS  PubMed  Google Scholar 

  71. Roman AA, Parlee SD, Sinal CJ. Chemerin: a potential endocrine link between obesity and type 2 diabetes. Endocrine. 2012;42(2):243–51.

    CAS  PubMed  Google Scholar 

  72. Hasanvand Z, Sadeghi A, Rezvanfar MR, Goodarzi MT, Rahmannezhad G, Mashayekhi FJ. Association between chemerin rs17173608 and rs4721 gene polymorphisms and gestational diabetes mellitus in Iranian pregnant women. Gene. 2018;649:87–92.

    CAS  PubMed  Google Scholar 

  73. Yang RZ, Lee MJ, Hu H, Pray J, Wu HB, Hansen BC, et al. Identification of omentin as a novel depot-specific adipokine in human adipose tissue: possible role in modulating insulin action. Am J Physiol Endocrinol Metab. 2006;290(6):E1253–61.

    CAS  PubMed  Google Scholar 

  74. Khoshi A, Bajestani MK, Shakeri H, Goodarzi G, Azizi F. Association of Omentin rs2274907 and FTO rs9939609 gene polymorphisms with insulin resistance in Iranian individuals with newly diagnosed type 2 diabetes. Lipids Health Dis. 2019;18(1):142.

    PubMed  PubMed Central  Google Scholar 

  75. Chen J. Integration to continuous success. Wiley Online Library; 2015.

  76. Huh JY, Panagiotou G, Mougios V, Brinkoetter M, Vamvini MT, Schneider BE, et al. FNDC5 and Irisin in humans: I—predictors of circulating concentrations in serum and plasma and II—mRNA expression and circulating concentrations in response to weight loss and exercise. Metab Clin Exp. 2012;61(12):1725–38.

    CAS  PubMed  Google Scholar 

  77. Khidr EG, Ali SS, Elshafey MM, Fawzy OA. Association of irisin and FNDC5 rs16835198 G> T gene polymorphism with type 2 diabetes mellitus and diabetic nephropathy. Egypt Pilot Study Gene. 2017;626:26–31.

    CAS  PubMed  Google Scholar 

  78. Sánchez-Zamora YI, Rodriguez-Sosa MJ. The role of MIF in type 1 and type 2 diabetes mellitus. J Diabetes Res. 2014;2014:1.

    Google Scholar 

  79. Hamidi AK, Arzaghi SM, Qorbani M, Khatami F, Ebrahimi M, Bandarian F, et al. MIF 173 G>C variation was associated with depressive disorder in type 2 diabetes in an Iranian population. Psychoneuroendocrinology. 2019;104:243–8.

    CAS  PubMed  Google Scholar 

  80. Shibuya A, Campbell D, Hannum C, Yssel H, Franz-Bacon K, McClanahan T, et al. DNAM-1, a novel adhesion molecule involved in the cytolytic function of T lymphocytes. Immunity. 1996;4(6):573–81.

    CAS  PubMed  Google Scholar 

  81. Shibuya K, Shirakawa J, Kameyama T, Honda S, Tahara-Hanaoka S, Miyamoto A, et al. CD226 (DNAM-1) is involved in lymphocyte function–associated antigen 1 costimulatory signal for naive T cell differentiation and proliferation. J Exp Med. 2003;198(12):1829–39.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Abu El-Ella SS, Khattab E, El-Mekkawy MS, El-Shamy AA. CD226 gene polymorphism (rs763361 C>T) is associated with susceptibility to type 1 diabetes mellitus among Egyptian children. Archiv Pediatrie Organe Off Soc Franc Pediatrie. 2018;25(6):378–82.

    CAS  Google Scholar 

  83. Rizzo R, Bortolotti D, Bolzani S, Fainardi E. HLA-G molecules in autoimmune diseases and infections. Front Immunol. 2014;5:592.

    PubMed  PubMed Central  Google Scholar 

  84. Morandi F, Rizzo R, Fainardi E, Rouas-Freiss N, Pistoia V. Recent advances in our understanding of HLA-G biology: lessons from a wide spectrum of human diseases. J Immunol Res. 2016;2016:4326495.

    PubMed  PubMed Central  Google Scholar 

  85. Laaribi AB, Zidi I, Hannachi N, Ben Yahia H, Chaouch H, Bortolotti D, et al. Association of an HLA-G 14-bp insertion/deletion polymorphism with high HBV replication in chronic hepatitis. J Viral Hepatitis. 2015;22(10):835–41.

    CAS  Google Scholar 

  86. Deschaseaux F, Delgado D, Pistoia V, Giuliani M, Morandi F, Durrbach A. HLA-G in organ transplantation: towards clinical applications. Cell Mol Life Sci CMLS. 2011;68(3):397–404.

    CAS  PubMed  Google Scholar 

  87. Silva HP, Ururahy MA, Souza KS, Loureiro MB, Oliveira YM, Oliveira GH, et al. The association between the HLA-G 14-bp insertion/deletion polymorphism and type 1 diabetes. Genes Immun. 2016;17(1):13–8.

    CAS  PubMed  Google Scholar 

  88. Gerasimou P, Skordis N, Picolos M, Spyridonidis A, Costeas P. HLA-G 14-bp polymorphism affects the age of onset in Type I diabetes mellitus. Int J Immunogenet. 2016;43(3):135–42.

    CAS  PubMed  Google Scholar 

  89. Rezaei F, Zareei N, Razmi N, Nikeghbalian S, Azarpira N. Genetic polymorphism of HLA-G 14-bp insertion/deletion in pancreas transplant recipients and its association with Type 1 diabetes mellitus. Exp Clin Transplant Off J Middle East Soc Organ Transplant. 2021;19(2):154–9.

    Google Scholar 

  90. Cerna M, Novota P, Kolostova K, Cejkova P, Zdarsky E, Novakova D, et al. HLA in Czech adult patients with autoimmune diabetes mellitus: comparison with Czech children with type 1 diabetes and patients with type 2 diabetes. Eur J Immunogenet Off J Br Soc Histocompat Immunogenet. 2003;30(6):401–7.

    CAS  Google Scholar 

  91. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2008;31(Suppl 1): S55–60.

  92. Mansoori Derakhshan S, Zeinali Sehrig F, Sohrabi N, Shiva S, Baradaran B, Shekari KM. The association between human leukocyte antigen class II DR3-DQ2 haplotype and type 1 diabetes in children of the East Azerbaijan state of Iran. Iran Red Crescent Med J. 2015;17(9):e28380.

    PubMed  PubMed Central  Google Scholar 

  93. Bener A, Al-Ali M, Hoffmann G. High prevalence of vitamin D deficiency in young children in a highly sunny humid country: a global health problem. Minerva Pediatr. 2009;61(1):15–22.

    CAS  PubMed  Google Scholar 

  94. Gordon CM, Feldman HA, Sinclair L, Williams AL, Kleinman PK, Perez-Rossello J, et al. Prevalence of vitamin D deficiency among healthy infants and toddlers. Arch Pediatr Adolesc Med. 2008;162(6):505–12.

    PubMed  PubMed Central  Google Scholar 

  95. Jabbar Z, Aggarwal PK, Chandel N, Kohli HS, Gupta KL, Sakhuja V, et al. High prevalence of vitamin D deficiency in north Indian adults is exacerbated in those with chronic kidney disease. Nephrology. 2009;14(3):345–9.

    CAS  PubMed  Google Scholar 

  96. Rovner AJ, O’Brien KO. Hypovitaminosis D among healthy children in the United States: a review of the current evidence. Arch Pediatr Adolesc Med. 2008;162(6):513–9.

    PubMed  Google Scholar 

  97. Rasoul MA, Al-Mahdi M, Al-Kandari H, Dhaunsi GS, Haider MZ. Low serum vitamin-D status is associated with high prevalence and early onset of type-1 diabetes mellitus in Kuwaiti children. BMC Pediatr. 2016;16:95.

    PubMed  PubMed Central  Google Scholar 

  98. Basit S. Vitamin D in health and disease: a literature review. Br J Biomed Sci. 2013;70(4):161–72.

    CAS  PubMed  Google Scholar 

  99. Khashayar P, Aghaei Meybodi HR, Rezai Hemami M, Keshtkar A, Dimai HP, Larijani B. Vitamin D status and its relationship with bone mineral density in a healthy Iranian population. Rev Bras Ortopedia. 2016;51(4):454–8.

    Google Scholar 

  100. Kelishadi R, Ardalan G, Motlagh ME, Shariatinejad K, Heshmat R, Poursafa P, et al. National report on the association of serum vitamin D with cardiometabolic risk factors in the pediatric population of the Middle East and North Africa (MENA): the CASPIAN-III Study. Nutrition (Burbank, Los Angeles County, Calif). 2014;30(1):33–8.

    CAS  Google Scholar 

  101. Jari M, Qorbani M, Moafi M, Motlagh ME, Keikha M, Ardalan G, et al. Association of 25-hydroxy Vitamin D levels with indexes of general and abdominal obesity in Iranian adolescents: The CASPIAN-III study. J Res Med Sci. 2015;20(2):122–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Hossein-Nezhad A, Khoshniat N, Maghbooli M, Karimi Z, Mirzaei F, Hosseini A, et al. Relationship between serum vitamin D concentration and metabolic syndrome among Iranian adults population. DARU J Pharm Sci. 2015;2015(1):1–5.

    Google Scholar 

  103. Heshmat R, Tabatabaei-Malazy O, Abbaszadeh-Ahranjani S, Shahbazi S, Khooshehchin G, Bandarian F, et al. Effect of vitamin D on insulin resistance and anthropometric parameters in Type 2 diabetes; a randomized double-blind clinical trial. Daru J Faculty Pharmacy Tehran Univ Med Sci. 2012;20(1):10.

    CAS  Google Scholar 

  104. Lemire J. 1,25-Dihydroxyvitamin D3–a hormone with immunomodulatory properties. Z Rheumatol. 2000;59(Suppl 1):24–7.

    CAS  PubMed  Google Scholar 

  105. Mathieu C, van Etten E, Decallonne B, Guilietti A, Gysemans C, Bouillon R, et al. Vitamin D and 1,25-dihydroxyvitamin D3 as modulators in the immune system. J Steroid Biochem Mol Biol. 2004;89–90(1–5):449–52.

    PubMed  Google Scholar 

  106. Fan LY, Tu XQ, Zhu Y, Pfeiffer T, Feltens R, Stoecker W, et al. Genetic association of cytokines polymorphisms with autoimmune hepatitis and primary biliary cirrhosis in the Chinese. World J Gastroenterol. 2005;11(18):2768–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Lemire JM. Immunomodulatory actions of 1,25-dihydroxyvitamin D3. J Steroid Biochem Mol Biol. 1995;53(1–6):599–602.

    CAS  PubMed  Google Scholar 

  108. Trembleau S, Germann T, Gately MK, Adorini L. The role of IL-12 in the induction of organ-specific autoimmune diseases. Immunol Today. 1995;16(8):383–6.

    CAS  PubMed  Google Scholar 

  109. Habibian N, Amoli MM, Abbasi F, Rabbani A, Alipour A, Sayarifard F, et al. Role of vitamin D and vitamin D receptor gene polymorphisms on residual beta cell function in children with type 1 diabetes mellitus. Pharmacol Rep PR. 2019;71(2):282–8.

    CAS  PubMed  Google Scholar 

  110. Mohammadnejad Z, Ghanbari M, Ganjali R, Afshari JT, Heydarpour M, Taghavi SM, et al. Association between vitamin D receptor gene polymorphisms and type 1 diabetes mellitus in Iranian population. Mol Biol Rep. 2012;39(2):831–7.

    CAS  PubMed  Google Scholar 

  111. Rahmannezhad G, Mashayekhi FJ, Goodarzi MT, Rezvanfar MR, Sadeghi A. Association between vitamin D receptor ApaI and TaqI gene polymorphisms and gestational diabetes mellitus in an Iranian pregnant women population. Gene. 2016;581(1):43–7.

    CAS  PubMed  Google Scholar 

  112. Razi F, Meshkani MA, Zarrabi F, Sadr M, Asgarbeik S, Bandarian F, et al. Haplotypes in vitamin D receptor gene encode risk in diabetic nephropathy. Gene. 2019;683:149–52.

    CAS  PubMed  Google Scholar 

  113. Aslani S, Hossein-Nezhad A, Mirzaei K, Maghbooli Z, Afshar AN, Karimi F. VDR FokI polymorphism and its potential role in the pathogenesis of gestational diabetes mellitus and its complications. Gynecol Endocrinol Off J Int Soc Gynecol Endocrinol. 2011;27(12):1055–60.

    CAS  Google Scholar 

  114. Abd-Allah SH, Pasha HF, Hagrass HA, Alghobashy AA. Vitamin D status and vitamin D receptor gene polymorphisms and susceptibility to type 1 diabetes in Egyptian children. Gene. 2014;536(2):430–4.

    CAS  PubMed  Google Scholar 

  115. Ahmed AE, Sakhr HM, Hassan MH, El-Amir MI, Ameen HH. Vitamin D receptor rs7975232, rs731236 and rs1544410 single nucleotide polymorphisms, and 25-hydroxyvitamin D levels in Egyptian children with type 1 diabetes mellitus: effect of vitamin D co-therapy. Diabetes Metab Syndr Obes Targets Ther. 2019;12:703–16.

    Google Scholar 

  116. Pfaffl MW, Horgan GW, Dempfle L. Relative expression software tool (REST) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Res. 2002;30(9):e36.

    PubMed  PubMed Central  Google Scholar 

  117. Al-Daghri NM, Al-Attas O, Alokail MS, Alkharfy KM, Draz HM, Agliardi C, et al. Vitamin D receptor gene polymorphisms and HLA DRB1*04 cosegregation in Saudi type 2 diabetes patients. J Immunol. 2012;188(3):1325–32.

    CAS  PubMed  Google Scholar 

  118. Al-Daghri NM, Al-Attas OS, Alkharfy KM, Khan N, Mohammed AK, Vinodson B, et al. Association of VDR-gene variants with factors related to the metabolic syndrome, type 2 diabetes and vitamin D deficiency. Gene. 2014;542(2):129–33.

    CAS  PubMed  Google Scholar 

  119. Ali R, Fawzy I, Mohsen I, Settin A. Evaluation of vitamin D receptor gene polymorphisms (Fok-I and Bsm-I) in T1DM Saudi children. J Clin Lab Anal. 2018;32(5):e22397.

    PubMed  PubMed Central  Google Scholar 

  120. Apaydın M, Beysel S, Eyerci N, Pinarli FA, Ulubay M, Kizilgul M, et al. The VDR gene FokI polymorphism is associated with gestational diabetes mellitus in Turkish women. BMC Med Genet. 2019;20(1):82.

    PubMed  PubMed Central  Google Scholar 

  121. Rasoul MA, Haider MZ, Al-Mahdi M, Al-Kandari H, Dhaunsi GS. Relationship of four vitamin D receptor gene polymorphisms with type 1 diabetes mellitus susceptibility in Kuwaiti children. BMC Pediatr. 2019;19(1):71.

    PubMed  PubMed Central  Google Scholar 

  122. Pozzilli P, Manfrini S, Crinò A, Picardi A, Leomanni C, Cherubini V, et al. Low levels of 25-hydroxyvitamin D3 and 1, 25-dihydroxyvitamin D3 in patients with newly diagnosed type 1 diabetes. Horm Metab Res. 2005;37(11):680–3.

    CAS  PubMed  Google Scholar 

  123. Jones G, Strugnell SA, DeLUCA HF. Current understanding of the molecular actions of vitamin D. Physiol Rev. 1998;78:1193.

    CAS  PubMed  Google Scholar 

  124. Hussein AG, Mohamed RH, Alghobashy AA. Synergism of CYP2R1 and CYP27B1 polymorphisms and susceptibility to type 1 diabetes in Egyptian children. Cell Immunol. 2012;279(1):42–5.

    CAS  PubMed  Google Scholar 

  125. Speer G, Cseh K, Winkler G, Vargha P, Braun E, Takács I, et al. Vitamin D and estrogen receptor gene polymorphisms in type 2 diabetes mellitus and in android type obesity. Eur J Endocrinol. 2001;144(4):385–9.

    CAS  PubMed  Google Scholar 

  126. Zhang Y, Howard BV, Cowan LD, Yeh J, Schaefer CF, Wild RA, et al. The effect of estrogen use on levels of glucose and insulin and the risk of type 2 diabetes in American Indian postmenopausal women : the strong heart study. Diabetes Care. 2002;25(3):500–4.

    CAS  PubMed  Google Scholar 

  127. Meyer MR, Clegg DJ, Prossnitz ER, Barton M. Obesity, insulin resistance and diabetes: sex differences and role of oestrogen receptors. Acta Physiol (Oxf). 2011;203(1):259–69.

    CAS  Google Scholar 

  128. Casazza K, Page GP, Fernandez JR. The association between the rs2234693 and rs9340799 estrogen receptor alpha gene polymorphisms and risk factors for cardiovascular disease: a review. Biol Res Nurs. 2010;12(1):84–97.

    CAS  PubMed  Google Scholar 

  129. Mohammadi F, Pourahmadi M, Mosalanejad M, Jamali H, Ghobadifar MA, Erfanian S. Association of estrogen receptor α genes Pvuii and Xbai polymorphisms with Type 2 diabetes mellitus in the inpatient population of a hospital in Southern Iran. Diabet Metab J. 2013;37(4):270–7.

    Google Scholar 

  130. Meshkani R, Saberi H, MohammadTaghvaei N, Tabatabaiefar MA. Estrogen receptor alpha gene polymorphisms are associated with type 2 diabetes and fasting glucose in male subjects. Mol Cell Biochem. 2012;359(1–2):225–33.

    CAS  PubMed  Google Scholar 

  131. Gorres BK, Bomhoff GL, Morris JK, Geiger PC. In vivo stimulation of oestrogen receptor α increases insulin-stimulated skeletal muscle glucose uptake. J Physiol. 2011;589(Pt 8):2041–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Ereqat S, Cauchi S, Eweidat K, Elqadi M, Nasereddin A. Estrogen receptor 1 gene polymorphisms (PvuII and XbaI) are associated with type 2 diabetes in Palestinian women. PeerJ. 2019;7:e7164.

    PubMed  PubMed Central  Google Scholar 

  133. Le TN, Nestler JE, Strauss JF III, Wickham EP III. Sex hormone-binding globulin and type 2 diabetes mellitus. Trends Endocrinol Metab. 2012;23(1):32–40.

    CAS  PubMed  Google Scholar 

  134. El Tarhouny SA, Zakaria SS, Abdu-Allah AM, Hadhoud KM, Mahmoud MI, Al Nozha OM. Study of sex hormone-binding globulin gene polymorphism and risk of Type 2 diabetes mellitus in Egyptian men. West Indian Med J. 2015;64(4):338–43.

    PubMed  Google Scholar 

  135. Tontonoz P, Hu E, Spiegelman BM. Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell. 1994;79(7):1147–56.

    CAS  PubMed  Google Scholar 

  136. Tontonoz P, Hu E, Graves RA, Budavari AI, Spiegelman BM. mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer. Genes Dev. 1994;8(10):1224–34.

    CAS  PubMed  Google Scholar 

  137. Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, et al. Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab. 2001;86(5):1930–5.

    CAS  PubMed  Google Scholar 

  138. Spiegelman BMJD. PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes. 1998;47(4):507–14.

    CAS  PubMed  Google Scholar 

  139. Kroder G, Bossenmaier B, Kellerer M, Capp E, Stoyanov B, Mühlhöfer A, et al. Tumor necrosis factor-alpha- and hyperglycemia-induced insulin resistance: evidence for different mechanisms and different effects on insulin signaling. J Clin Investig. 1996;97(6):1471–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Meshkani R, Taghikhani M, Larijani B, Bahrami Y, Khatami S, Khoshbin E, et al. Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma2 (PPARgamma-2) gene is associated with greater insulin sensitivity and decreased risk of type 2 diabetes in an Iranian population. Clin Chem Lab Med. 2007;45(4):477–82.

    CAS  PubMed  Google Scholar 

  141. Bhat A, Koul A, Rai E, Sharma S, Dhar MK, Bamezai RN. PGC-1alpha Thr394Thr and Gly482Ser variants are significantly associated with T2DM in two North Indian populations: a replicate case-control study. Hum Genet. 2007;121(5):609–14.

    PubMed  Google Scholar 

  142. Shokouhi S, Haghani K, Borji P, Bakhtiyari S. Association between PGC-1alpha gene polymorphisms and type 2 diabetes risk: a case-control study of an Iranian population. Can J Diabet. 2015;39(1):65–72.

    Google Scholar 

  143. Schoonjans K, Martin G, Staels B, Auwerx J. Peroxisome proliferator-activated receptors, orphans with ligands and functions. Curr Opin Lipidol. 1997;8(3):159–66.

    CAS  PubMed  Google Scholar 

  144. Tontonoz P, Hu E, Spiegelman BM. Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor. Cell. 1994;79(7):1147–56.

    CAS  PubMed  Google Scholar 

  145. Hasan NS, Kamel SA, Hamed M, Awadallah E, Rahman AHA, Musa NI, et al. Peroxisome proliferator-activated receptor-γ polymorphism (rs1801282) is associated with obesity in Egyptian patients with coronary artery disease and type 2 diabetes mellitus. J Genet Eng Biotechnol. 2017;15(2):409–14.

    PubMed  PubMed Central  Google Scholar 

  146. Armstrong RN. Structure, catalytic mechanism, and evolution of the glutathione transferases. Chem Res Toxicol. 1997;10(1):2–18.

    CAS  PubMed  Google Scholar 

  147. Habig WH, Pabst MJ, Jakoby WB. Glutathione S-transferases: the first enzymatic step in mercapturic acid formation. J Biol Chem. 1974;249(22):7130–9.

    CAS  PubMed  Google Scholar 

  148. Jakoby WB, Ziegler DM. The enzymes of detoxication. J Biol Chem. 1990;265(34):20715–8.

    CAS  PubMed  Google Scholar 

  149. Josephy PD. Genetic variations in human glutathione transferase enzymes: significance for pharmacology and toxicology. Hum Genomics Proteomics HGP. 2010;2010:876940.

    PubMed  Google Scholar 

  150. Wilce MC, Parker MW. Structure and function of glutathione S-transferases. Biochem Biophys Acta. 1994;1205(1):1–18.

    CAS  PubMed  Google Scholar 

  151. Karacay O, Sepici-Dincel A, Karcaaltincaba D, Sahin D, Yalvaç S, Akyol M, et al. A quantitative evaluation of total antioxidant status and oxidative stress markers in preeclampsia and gestational diabetic patients in 24–36 weeks of gestation. Diabetes Res Clin Pract. 2010;89(3):231–8.

    CAS  PubMed  Google Scholar 

  152. Montazeri-Najafabady N, Dabbaghmanesh MH, Namavar Jahromi B, Chatrabnous N, Chatrsimin F. The impact of GSTM1 and GSTT1 polymorphisms on susceptibility to gestational diabetes in Iranian population. J Maternal Fetal Neonatal Med Off J Eur Assoc Perinat Med Fed Asia Oceania Perinat Soc Int Soc Perinat Obstet. 2020;35:1–6.

    Google Scholar 

  153. Moasser E, Kazemi-Nezhad SR, Saadat M, Azarpira N. Study of the association between glutathione S-transferase (GSTM1, GSTT1, GSTP1) polymorphisms with type II diabetes mellitus in southern of Iran. Mol Biol Rep. 2012;39(12):10187–92.

    CAS  PubMed  Google Scholar 

  154. Moasser E, Azarpira N, Shirazi B, Saadat M, Geramizadeh B. Genetic polymorphisms of glutathione-s-transferase M1 and T1 genes with risk of diabetic retinopathy in Iranian population. Iran J Basic Med Sci. 2014;17(5):351–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Barseem N, Elsamalehy M. Gene polymorphisms of glutathione S-transferase T1/M1 in Egyptian children and adolescents with Type 1 diabetes mellitus. J Clin Res Pediatr Endocrinol. 2017;9(2):138–43.

    PubMed  PubMed Central  Google Scholar 

  156. Amer MA, Ghattas MH, Abo-Elmatty DM, Abou-El-Ela SH. Influence of glutathione S-transferase polymorphisms on type-2 diabetes mellitus risk. Genetics Mol Res GMR. 2011;10(4):3722–30.

    CAS  PubMed  Google Scholar 

  157. Amer MA, Ghattas MH, Abo-Elmatty DM, Abou-El-Ela SH. Evaluation of glutathione S-transferase P1 genetic variants affecting type-2 diabetes susceptibility and glycemic control. Archiv Med Sci AMS. 2012;8(4):631–6.

    CAS  Google Scholar 

  158. Gusti AMT, Qusti SY, Bahijri SM, Toraih EA, Bokhari S, Attallah SM, et al. Glutathione S-transferase (GSTT1 rs17856199) and nitric oxide synthase (NOS2 rs2297518) genotype combination as potential oxidative stress-related molecular markers for Type 2 diabetes mellitus. Diabet Metab Syndr Obes Targets Ther. 2021;14:1385–403.

    Google Scholar 

  159. Marchetti P. New-onset diabetes after liver transplantation: from pathogenesis to management. Liver Transplant Off Publ Am Assoc Study Liver Dis Int Liver Transplant Soc. 2005;11(6):612–20.

    Google Scholar 

  160. Parvizi Z, Azarpira N, Kohan L, Darai M, Kazemi K, Parvizi MM. Association between E23K variant in KCNJ11 gene and new-onset diabetes after liver transplantation. Mol Biol Rep. 2014;41(9):6063–9.

    CAS  PubMed  Google Scholar 

  161. Jenssen T, Hartmann A. Emerging treatments for post-transplantation diabetes mellitus. Nat Rev Nephrol. 2015;11(8):465–77.

    CAS  PubMed  Google Scholar 

  162. Sharif A, Cohney S. Post-transplantation diabetes-state of the art. Lancet Diabetes Endocrinol. 2016;4(4):337–49.

    PubMed  Google Scholar 

  163. Musavi Z, Moasser E, Zareei N, Azarpira N, Shamsaeefar A. Glutathione S-transferase gene polymorphisms and the development of new-onset diabetes after liver transplant. Exp Clin Transplant Off J Middle East Soc Organ Transplant. 2019;17(3):375–80.

    Google Scholar 

  164. Yalin S, Hatungil R, Tamer L, Ates NA, Dogruer N, Yildirim H, et al. Glutathione S-transferase gene polymorphisms in Turkish patients with diabetes mellitus. Cell Biochem Funct. 2007;25(5):509–13.

    CAS  PubMed  Google Scholar 

  165. Goode EL, Ulrich CM, Potter JD. Polymorphisms in DNA repair genes and associations with cancer risk. Cancer Epidemiol Prevent Biomark. 2002;11(12):1513–30.

    CAS  Google Scholar 

  166. Gönül N, Kadioglu E, Kocabaş NA, Ozkaya M, Karakaya AE, Karahalil B. The role of GSTM1, GSTT1, GSTP1, and OGG1 polymorphisms in type 2 diabetes mellitus risk: a case-control study in a Turkish population. Gene. 2012;505(1):121–7.

    PubMed  Google Scholar 

  167. Ghattas MH, Abo-Elmatty DM. Association of polymorphic markers of the catalase and superoxide dismutase genes with type 2 diabetes mellitus. DNA Cell Biol. 2012;31(11):1598–603.

    CAS  PubMed  Google Scholar 

  168. Ghattas MH, Amer MA. Possible role of microsomal epoxide hydrolase gene polymorphism as a risk factor for developing insulin resistance and type 2 diabetes mellitus. Endocrine. 2012;42(3):577–83.

    CAS  PubMed  Google Scholar 

  169. Habieb MS, Dawood AA, Emara MM, Elhelbawy MG, Elhelbawy NG. The human genetic variants CYP2J2 rs2280275 and EPHX2 rs751141 and risk of diabetic nephropathy in Egyptian Type 2 diabetic patients. Appl Clin Genet. 2020;13:165–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Madamanchi NR, Li S, Patterson C, Runge MS. Reactive oxygen species regulate heat-shock protein 70 via the JAK/STAT pathway. Arterioscler Thromb Vasc Biol. 2001;21(3):321–6.

    CAS  PubMed  Google Scholar 

  171. Elshahed OM, Shaker OG. Heat shock protein 70 gene polymorphism in Egyptian patients with Type 2 diabetes mellitus, with and without nephropathy. Saudi J Kidney Dis Transplant Off Publ Saudi Center Organ Transplant Saudi Arabia. 2020;31(4):787–95.

    Google Scholar 

  172. Butcher N, Boukouvala S, Sim E, Minchin R. Pharmacogenetics of the arylamine N-acetyltransferases. Pharmacogenomics J. 2002;2(1):30–42.

    CAS  PubMed  Google Scholar 

  173. Hein DW, Doll MA, Fretland AJ, Leff MA, Webb SJ, Xiao GH, et al. Molecular genetics and epidemiology of the NAT1 and NAT2 acetylation polymorphisms. Cancer Epidemiol Prevent Biomark. 2000;9(1):29–42.

    CAS  Google Scholar 

  174. Lee M-S, Su L, Christiani DC. Synergistic effects of NAT2 slow and GSTM1 null genotypes on carcinogen DNA damage in the lung. Cancer Epidemiol Prevent Biomark. 2010;19(6):1492–7.

    CAS  Google Scholar 

  175. Al-Shaqha WM, Alkharfy KM, Al-Daghri NM, Mohammed AK. N-acetyltransferase 1 and 2 polymorphisms and risk of diabetes mellitus type 2 in a Saudi population. Ann Saudi Med. 2015;35(3):214–21.

    PubMed  PubMed Central  Google Scholar 

  176. Gispen WH, van Dam P, van Asbeck B, Erkelens D, Marx J, Bravenboer B. The role of oxidative stress in neuropathy and other diabetic complications. Diabet Metab Rev. 1995;11:181–92.

    Google Scholar 

  177. Bullon P, Newman HN, Battino M. Obesity, diabetes mellitus, atherosclerosis and chronic periodontitis: a shared pathology via oxidative stress and mitochondrial dysfunction? Periodontol. 2014;64(1):139–53.

    Google Scholar 

  178. Deakin SP, James RW. Genetic and environmental factors modulating serum concentrations and activities of the antioxidant enzyme paraoxonase-1. Clin Sci. 2004;107(5):435–47.

    CAS  Google Scholar 

  179. Shakeri R, Khajeniazi S, Marjani A. Association between promoter polymorphism (-108C>T) of paraoxonase1 gene and it(')s paraoxonase activity in patients with Type2 diabetes in northern Iran. Clin Chim Acta Int J Clin Chem. 2017;474:34–7.

    CAS  Google Scholar 

  180. Emami A, Tajadini M, Zeinalian M, Keshvari M, Asgary S. Paraoxonase 1 activities and its gene promoter single nucleotide polymorphisms (-108, -126, and -162) in diabetes mellitus. Interv Med Appl Sci. 2018;10(1):27–32.

    PubMed  PubMed Central  Google Scholar 

  181. Khajeniazi S, Shakeri R, Marjani A. Evaluation of relationship between arylesterase-based activity and genetic variants of paraoxonase1 in T2DM patients within golestan province. Indian J Clin Biochem IJCB. 2020;35(2):239–44.

    CAS  PubMed  Google Scholar 

  182. El-Lebedy D, Kafoury M, Abd-El Haleem D, Ibrahim A, Awadallah E, Ashmawy I. Paraoxonase-1 gene Q192R and L55M polymorphisms and risk of cardiovascular disease in Egyptian patients with type 2 diabetes mellitus. J Diabetes Metab Disord. 2014;13(1):124.

    PubMed  PubMed Central  Google Scholar 

  183. Al-Hakeem MM, Abotalib Z, Alharbi KK, Khan IA. Relationship between the paraoxonase 1 gene glutamine 192 to arginine polymorphism and gestational diabetes mellitus in Saudi women. Clin Biochem. 2014;47(15):122–5.

    CAS  PubMed  Google Scholar 

  184. Arpaci A, Yalın S, Ecevit H, Comelekoglu U, Mete T. Enzyme activity and genetic polymorphisms in patients with type II diabetes mellitus. Adv Clin Exp Med Off Organ Wroclaw Med Univ. 2020;29(9):1057–63.

    Google Scholar 

  185. Klebanoff SJ, Waltersdorph AM, Rosen H. [52] Antimicrobial activity of myeloperoxidase. Methods Enzymol. 1984;105:399–403.

    CAS  PubMed  Google Scholar 

  186. Zhang R, Shen Z, Nauseef WM, Hazen SL. Defects in leukocyte-mediated initiation of lipid peroxidation in plasma as studied in myeloperoxidase-deficient subjects: systematic identification of multiple endogenous diffusible substrates for myeloperoxidase in plasma. Blood J Am Soc Hematol. 2002;99(5):1802–10.

    CAS  Google Scholar 

  187. Zhang R, Brennan M-L, Shen Z, MacPherson JC, Schmitt D, Molenda CE, et al. Myeloperoxidase functions as a major enzymatic catalyst for initiation of lipid peroxidation at sites of inflammation. J Biol Chem. 2002;277(48):46116–22.

    CAS  PubMed  Google Scholar 

  188. Ergen A, Karagedik H, Karaali ZE, Isbir T. An association between MPO -463 G/A polymorphism and type 2 diabetes. Folia Biol. 2014;60(3):108–12.

    CAS  Google Scholar 

  189. White MF. The insulin signalling system and the IRS proteins. Diabetologia. 1997;40(Suppl 2):S2-17.

    CAS  PubMed  Google Scholar 

  190. Keshavarzi F, Golsheh S. IRS1- rs10498210 G/A and CCR5–59029 A/G polymorphisms in patients with type 2 diabetes in Kurdistan. Mol Genet Genomic Med. 2019;7(5):e631.

    PubMed  PubMed Central  Google Scholar 

  191. Golsheh S, Keshavarzi F. Genetic variants linked to T2DM risk in Kurdish populations. Diabet Metab Syndr Obes Targets Ther. 2019;12:431–7.

    CAS  Google Scholar 

  192. Haghani K, Bakhtiyari S. The study on the relationship between IRS-1 Gly972Arg and IRS-2 Gly1057Asp polymorphisms and type 2 diabetes in the Kurdish ethnic group in West Iran. Genet Test Mol Biomark. 2012;16(11):1270–6.

    CAS  Google Scholar 

  193. Yousef AA, Behiry EG, Allah WMA, Hussien AM, Abdelmoneam AA, Imam MH, et al. IRS-1 genetic polymorphism (r.2963G>A) in type 2 diabetes mellitus patients associated with insulin resistance. Appl Clin Genetics. 2018;11:99–106.

    CAS  Google Scholar 

  194. Ayaz L, Karakaş Çelik S, Cayan F. The G1057D polymorphism of insulin receptor substrate-2 associated with gestational diabetes mellitus. Gynecol Endocrinol Off J Int Soc Gynecol Endocrinol. 2014;30(2):165–8.

    CAS  Google Scholar 

  195. Alharbi KK, Khan IA, Abotalib Z, Al-Hakeem MM. Insulin receptor substrate-1 (IRS-1) Gly927Arg: correlation with gestational diabetes mellitus in Saudi women. BioMed Res Int. 2014;2014:1.

    Google Scholar 

  196. Christiansen J, Kolte AM, Hansen T, Nielsen FC. IGF2 mRNA-binding protein 2: biological function and putative role in type 2 diabetes. J Mol Endocrinol. 2009;43(5):187–95.

    CAS  PubMed  Google Scholar 

  197. Nemr R, Echtay A, Dashti EA, Almawi AW, Al-Busaidi AS, Keleshian SH, et al. Strong association of common variants in the IGF2BP2 gene with type 2 diabetes in Lebanese Arabs. Diabet Res Clin Pract. 2012;96(2):225–9.

    CAS  Google Scholar 

  198. Federici M, Pandolfi A, De Filippis EA, Pellegrini G, Menghini R, Lauro D, et al. G972R IRS-1 variant impairs insulin regulation of endothelial nitric oxide synthase in cultured human endothelial cells. Circulation. 2004;109(3):399–405.

    CAS  PubMed  Google Scholar 

  199. Gorfien S, Spector A, DeLuca D, Weiss S. Growth and physiological functions of vascular endothelial cells in a new serum-free medium (SFM). Exp Cell Res. 1993;206(2):291–301.

    CAS  PubMed  Google Scholar 

  200. Al-Hakeem MM. Implication of SH2B1 gene polymorphism studies in gestational diabetes mellitus in Saudi pregnant women. Saudi J Biol Sci. 2014;21(6):610–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  201. Dean L, McEntyre J. The genetic landscape of diabetes: NCBI; 2004.

  202. Rastegari A, Rabbani M, Sadeghi HM, Imani EF, Hasanzadeh A, Moazen F. Association of KCNJ11 (E23K) gene polymorphism with susceptibility to type 2 diabetes in Iranian patients. Adv Biomed Res. 2015;4:1.

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Makhzoom O, Kabalan Y, Al-Quobaili F. Association of KCNJ11 rs5219 gene polymorphism with type 2 diabetes mellitus in a population of Syria: a case-control study. BMC Med Genet. 2019;20(1):107.

    PubMed  PubMed Central  Google Scholar 

  204. Dickson I, Poole A, Veis A. Localisation of plasma α 2 HS glycoprotein in mineralising human bone. Nature. 1975;256(5516):430–2.

    CAS  PubMed  Google Scholar 

  205. Arnaud P, Miribel L, Emerson D. [39] α2-HS glycoprotein. Methods Enzymol. 1988;163:431–41.

    CAS  PubMed  Google Scholar 

  206. Kalabay L, Cseh K, Pajor A, Baranyi É, Csákány MG, Melczer Z, et al. Correlation of maternal serum fetuin/alpha2-HS-glycoprotein concentration with maternal insulin resistance and anthropometric parameters of neonates in normal pregnancy and gestational diabetes. Eur J Endocrinol. 2002;147(2):243–8.

    CAS  PubMed  Google Scholar 

  207. Mori K, Emoto M, Inaba M. Fetuin-A: a multifunctional protein. Recent Pat Endocr Metab Immune Drug Discov. 2011;5(2):124–46.

    CAS  PubMed  Google Scholar 

  208. Mathews ST, Chellam N, Srinivas PR, Cintron VJ, Leon MA, Goustin AS, et al. α2-HSG, a specific inhibitor of insulin receptor autophosphorylation, interacts with the insulin receptor. Mol Cell Endocrinol. 2000;164(1–2):87–98.

    CAS  PubMed  Google Scholar 

  209. Akbas H, Kahraman S, Sak S, Akkafa F. Minor variant of AHSG gene 767C>G polymorphism may decrease the risk of gestational diabetes mellitus. J Obstet Gynaecol J Inst Obstet Gynaecol. 2020;40(3):303–7.

    CAS  Google Scholar 

  210. Motsenbocker MA, MTappel A. A selenocysteine-containing selenium-transport protein in rat plasma. Biochim Biophysica Acta Gen Subj. 1982;719(1):147–53.

    CAS  Google Scholar 

  211. Akbaba G, Akbaba E, Sahin C, Kara M. The relationship between gestational diabetes mellitus and selenoprotein-P plasma 1 (SEPP1) gene polymorphisms. Gynecol Endocrinol Off J Int Soc Gynecol Endocrinol. 2018;34(10):849–52.

    CAS  Google Scholar 

  212. Olson AL, Pessin JE. Structure, function, and regulation of the mammalian facilitative glucose transporter gene family. Annu Rev Nutr. 1996;16:235–56.

    CAS  PubMed  Google Scholar 

  213. Amini S, Javanmardi M, Mokarizadeh A, Maroofi F, Jalali C, Azadi NA, et al. Association of HaeIII single nucleotide polymorphisms in the SLC2A1 gene with risk of diabetic nephropathy; evidence from Kurdish patients with type 2 diabetes mellitus. QJM Mon J Assoc Phys. 2016;109(6):399–404.

    CAS  Google Scholar 

  214. Soltanian AR, Hosseini B, Mahjub H, Bahreini F, Ghaffari ME. A Bayesian analysis for investigating the association between rs13266634 polymorphism in SLC30A8 gene and type 2 diabetes. J Diabetes Metab Disord. 2020;19(1):337–42.

    PubMed  PubMed Central  Google Scholar 

  215. Egefjord L, Jensen JL, Bang-Berthelsen CH, Petersen AB, Smidt K, Schmitz O, et al. Zinc transporter gene expression is regulated by pro-inflammatory cytokines: a potential role for zinc transporters in beta-cell apoptosis? BMC Endocr Disord. 2009;9(1):7.

    PubMed  PubMed Central  Google Scholar 

  216. Faghih H, Khatami S-R, Azarpira N, Foroughmand A-M. SLC30A8 gene polymorphism (rs13266634 C/T) and type 2 diabetes mellitus in south Iranian population. Mol Biol Rep. 2014;41(5):2709–15.

    CAS  PubMed  Google Scholar 

  217. Mashal S, Khanfar M, Al-Khalayfa S, Srour L, Mustafa L, Hakooz NM, et al. SLC30A8 gene polymorphism rs13266634 associated with increased risk for developing type 2 diabetes mellitus in Jordanian population. Gene. 2021;768:145279.

    CAS  PubMed  Google Scholar 

  218. Bazzi M, Nasr F, Alanazi M, Alamri A, Turjoman A, Moustafa A, et al. Association between FTO, MC4R, SLC30A8, and KCNQ1 gene variants and type 2 diabetes in Saudi population. Genet Mol Res. 2014;13(4):10194–203.

    CAS  PubMed  Google Scholar 

  219. Zhu HJ, Appel DI, Gründemann D, Richelson E, Markowitz JS. Evaluation of organic cation transporter 3 (SLC22A3) inhibition as a potential mechanism of antidepressant action. Pharmacol Res. 2012;65(4):491–6.

    CAS  PubMed  Google Scholar 

  220. Mahrooz A, Alizadeh A, Hashemi-Soteh MB, Ghaffari-Cherati M, Hosseyni-Talei SR. Polymorphic variants rs3088442 and rs2292334 in the organic cation transporter 3 (OCT3) gene and susceptibility against Type 2 diabetes: role of their interaction. Arch Med Res. 2017;48(2):162–8.

    CAS  PubMed  Google Scholar 

  221. Unanue ER, Urano F. Endoplasmic reticulum: an interface between the immune system and metabolism. Diabetes. 2014;63(1):48–9.

    CAS  PubMed  Google Scholar 

  222. Osman AA, Saito M, Makepeace C, Permutt MA, Schlesinger P, Mueckler M. Wolframin expression induces novel ion channel activity in endoplasmic reticulum membranes and increases intracellular calcium. J Biol Chem. 2003;278(52):52755–62.

    CAS  PubMed  Google Scholar 

  223. Scheuner D, Kaufman RJ. The unfolded protein response: a pathway that links insulin demand with beta-cell failure and diabetes. Endocr Rev. 2008;29(3):317–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  224. Kaufman RJ. Beta-cell failure, stress, and type 2 diabetes. N Engl J Med. 2011;365(20):1931–3.

    CAS  PubMed  PubMed Central  Google Scholar 

  225. Fonseca SG, Ishigaki S, Oslowski CM, Lu S, Lipson KL, Ghosh R, et al. Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells. J Clin Investig. 2010;120(3):744–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  226. Fonseca SG, Fukuma M, Lipson KL, Nguyen LX, Allen JR, Oka Y, et al. WFS1 is a novel component of the unfolded protein response and maintains homeostasis of the endoplasmic reticulum in pancreatic beta-cells. J Biol Chem. 2005;280(47):39609–15.

    CAS  PubMed  Google Scholar 

  227. Fonseca SG, Gromada J, Urano F. Endoplasmic reticulum stress and pancreatic β-cell death. Trends Endocrinol Metab. 2011;22(7):266–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  228. Dayeh TA, Olsson AH, Volkov P, Almgren P, Rönn T, Ling C. Identification of CpG-SNPs associated with type 2 diabetes and differential DNA methylation in human pancreatic islets. Diabetologia. 2013;56(5):1036–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  229. Torkamandi S, Bastami M, Ghaedi H, Tarighi S, Shokri F, Javadi A, et al. Association of CpG-SNP and 3’UTR-SNP of WFS1 with the risk of Type 2 diabetes mellitus in an iranian population. Int J Mol Cell Med. 2017;6(4):197–203.

    PubMed  PubMed Central  Google Scholar 

  230. Xu H, Hertzel AV, Steen KA, Wang Q, Suttles J, Bernlohr DAJM, et al. Uncoupling lipid metabolism from inflammation through fatty acid binding protein-dependent expression of UCP2. Mol Cell Biol. 2015;35(6):1055–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  231. Busiello RA, Savarese S, Lombardi AJF. Mitochondrial uncoupling proteins and energy metabolism. Front Physiol. 2015;6:36.

    PubMed  PubMed Central  Google Scholar 

  232. Rezapour S, Khosroshahi SA, Farajnia H, Mohseni F, Khoshbaten M, Farajnia S. Association of 45-bp ins/del polymorphism of uncoupling protein 2 (UCP2) and susceptibility to nonalcoholic fatty liver and type 2 diabetes mellitus in North-west of Iran. BMC Res Notes. 2021;14(1):169.

    CAS  PubMed  PubMed Central  Google Scholar 

  233. Garver S. Gene-diet interactions in childhood obesity. Curr Genomics. 2011;12(3):180–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  234. Al-Daghri NM, Cagliani R, Forni D, Alokail MS, Pozzoli U, Alkharfy KM, et al. Mammalian NPC1 genes may undergo positive selection and human polymorphisms associate with type 2 diabetes. BMC Med. 2012;10:140.

    CAS  PubMed  PubMed Central  Google Scholar 

  235. Kim W, Egan JM. The role of incretins in glucose homeostasis and diabetes treatment. Pharmacol Rev. 2008;60(4):470–512.

    CAS  PubMed  Google Scholar 

  236. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology. 2007;132(6):2131–57.

    CAS  PubMed  Google Scholar 

  237. Shalaby SM, Zidan HE, Shokry A, Saeed J, El-Sokkary RH. Association of incretin receptors genetic polymorphisms with type 2 diabetes mellitus in Egyptian patients. J Gene Med. 2017;19:9–10.

    Google Scholar 

  238. Chi T, Lin J, Wang M, Zhao Y, Liao Z, Wei P. Non-coding RNA as biomarkers for Type 2 diabetes development and clinical management. Front Endocrinol. 2021;12:630032.

    Google Scholar 

  239. Chen H, Lan HY, Roukos DH, Cho WC. Application of microRNAs in diabetes mellitus. J Endocrinol. 2014;222(1):R1-r10.

    CAS  PubMed  Google Scholar 

  240. Goyal N, Sivadas A, Shamsudheen KV, Jayarajan R, Verma A, Sivasubbu S, et al. RNA sequencing of db/db mice liver identifies lncRNA H19 as a key regulator of gluconeogenesis and hepatic glucose output. Sci Rep. 2017;7(1):8312.

    PubMed  PubMed Central  Google Scholar 

  241. Gao Y, Wu F, Zhou J, Yan L, Jurczak MJ, Lee HY, et al. The H19/let-7 double-negative feedback loop contributes to glucose metabolism in muscle cells. Nucleic Acids Res. 2014;42(22):13799–811.

    CAS  PubMed  PubMed Central  Google Scholar 

  242. Ding GL, Wang FF, Shu J, Tian S, Jiang Y, Zhang D, et al. Transgenerational glucose intolerance with Igf2/H19 epigenetic alterations in mouse islet induced by intrauterine hyperglycemia. Diabetes. 2012;61(5):1133–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  243. Qiu GZ, Tian W, Fu HT, Li CP, Liu B. Long noncoding RNA-MEG3 is involved in diabetes mellitus-related microvascular dysfunction. Biochem Biophys Res Commun. 2016;471(1):135–41.

    CAS  PubMed  Google Scholar 

  244. Ghaedi H, Zare A, Omrani MD, Doustimotlagh AH, Meshkani R, Alipoor S, et al. Genetic variants in long noncoding RNA H19 and MEG3 confer risk of type 2 diabetes in an Iranian population. Gene. 2018;675:265–71.

    CAS  PubMed  Google Scholar 

  245. Ghaedi H, Tabasinezhad M, Alipoor B, Shokri F, Movafagh A, Mirfakhraie R, et al. The pre-mir-27a variant rs895819 may contribute to type 2 diabetes mellitus susceptibility in an Iranian cohort. J Endocrinol Invest. 2016;39(10):1187–93.

    CAS  PubMed  Google Scholar 

  246. Quagliarini F, Wang Y, Kozlitina J, Grishin NV, Hyde R, Boerwinkle E, et al. Atypical angiopoietin-like protein that regulates ANGPTL3. Proc Natl Acad Sci. 2012;109(48):19751–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  247. Ren G, Kim JY, Smas CM. Identification of RIFL, a novel adipocyte-enriched insulin target gene with a role in lipid metabolism. Am J Physiol Endocrinol Metab. 2012;303(3):E334–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  248. Yi P, Park JS, Melton DA. Betatrophin: a hormone that controls pancreatic β cell proliferation. Cell. 2013;153(4):747–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  249. Rahier J, Guiot Y, Goebbels RM, Sempoux C, Henquin JC. Pancreatic beta-cell mass in European subjects with type 2 diabetes. Diabet Obes Metab. 2008;10(Suppl 4):32–42.

    Google Scholar 

  250. Kugelberg E. Betatrophin—inducing β-cell expansion to treat diabetes mellitus? Nat Rev Endocrinol. 2013;9(7):379.

    PubMed  Google Scholar 

  251. Lickert H. Betatrophin fuels β cell proliferation: first step toward regenerative therapy? Cell Metab. 2013;18(1):5–6.

    CAS  PubMed  Google Scholar 

  252. Boekholdt S, Sacks F, Jukema J, Shepherd J, Freeman D, McMahon A, et al. Cholesteryl ester transfer protein TaqIB variant, high-density lipoprotein cholesterol levels, cardiovascular risk, and efficacy of pravastatin treatment: individual patient meta-analysis of 13 677 subjects. Circulation. 2005;111(3):278–87.

    CAS  PubMed  Google Scholar 

  253. de Grooth GJ, Klerkx AH, Stroes ES, Stalenhoef AF, Kastelein JJ, Kuivenhoven JA. A review of CETP and its relation to atherosclerosis. J Lipid Res. 2004;45(11):1967–74.

    PubMed  Google Scholar 

  254. Padmaja N, Kumar RM, Balachander J, Adithan C. Cholesteryl ester transfer protein TaqIB,− 629C> A and I405V polymorphisms and risk of coronary heart disease in an Indian population. Clin Chim Acta. 2009;402(1–2):139–45.

    CAS  PubMed  Google Scholar 

  255. El-Lebedy D. Interaction between endothelial nitric oxide synthase rs1799983, cholesteryl ester-transfer protein rs708272 and angiopoietin-like protein 8 rs2278426 gene variants highly elevates the risk of type 2 diabetes mellitus and cardiovascular disease. Cardiovasc Diabetol. 2018;17(1):97.

    CAS  PubMed  PubMed Central  Google Scholar 

  256. Ghasemi H, Karimi J, Khodadadi I, Saidijam M, Tavilani H. Association between rs2278426 (C/T) and rs892066 (C/G) variants of ANGPTL8 (betatrophin) and susceptibility to type2 diabetes mellitus. J Clin Lab Anal. 2019;33(1):e22649.

    PubMed  Google Scholar 

  257. Hatefi Z, Soltani G, Khosravi S, Kazemi M, Salehi AR, Salehi R. Micro R-410 binding site single nucleotide polymorphism rs13702 in lipoprotein lipase gene is effective to increase susceptibility to Type 2 diabetes in Iranian population. Adv Biomed Res. 2018;7:79.

    PubMed  PubMed Central  Google Scholar 

  258. Gillingham LG, Harding SV, Rideout TC, Yurkova N, Cunnane SC, Eck PK, et al. Dietary oils and FADS1-FADS2 genetic variants modulate [13C]α-linolenic acid metabolism and plasma fatty acid composition. Am J Clin Nutr. 2013;97(1):195–207.

    CAS  PubMed  Google Scholar 

  259. Standl M, Lattka E, Stach B, Koletzko S, Bauer CP, von Berg A, et al. FADS1 FADS2 gene cluster, PUFA intake and blood lipids in children: results from the GINIplus and LISAplus studies. PLoS ONE. 2012;7(5):e37780.

    CAS  PubMed  PubMed Central  Google Scholar 

  260. Mansouri V, Javanmard SH, Mahdavi M, Tajedini MH. Association of polymorphism in fatty acid desaturase gene with the risk of Type 2 diabetes in iranian population. Adv Biomed Res. 2018;7:98.

    PubMed  PubMed Central  Google Scholar 

  261. Seidah NG, Awan Z, Chrétien M, Mbikay M. PCSK9: a key modulator of cardiovascular health. Circ Res. 2014;114(6):1022–36.

    CAS  PubMed  Google Scholar 

  262. Cnop M, Hannaert JC, Grupping AY, Pipeleers DG. Low density lipoprotein can cause death of islet β-cells by its cellular uptake and oxidative modification. Endocrinology. 2002;143(9):3449–53.

    CAS  PubMed  Google Scholar 

  263. Grupping A, Cnop M, Van Schravendijk C, Hannaert J, Van Berkel TJ, Pipeleers D. Low density lipoprotein binding and uptake by human and rat Isletβ cells. Endocrinology. 1997;138(10):4064–8.

    CAS  PubMed  Google Scholar 

  264. Rutti S, Ehses JA, Sibler RA, Prazak R, Rohrer L, Georgopoulos S, et al. Low-and high-density lipoproteins modulate function, apoptosis, and proliferation of primary human and murine pancreatic β-cells. Endocrinology. 2009;150(10):4521–30.

    CAS  PubMed  Google Scholar 

  265. Nuglozeh E, Fazaludeen MF, Hasona N, Malm T, Mayor LB, Al-Hazmi A, et al. Genotyping and frequency of PCSK9 variations among hypercholesterolemic and diabetic subjects. Indian J Clin Biochem IJCB. 2019;34(4):444–50.

    CAS  PubMed  Google Scholar 

  266. Zhang HH, Souza SC, Muliro KV, Kraemer FB, Obin MS, Greenberg AS. Lipase-selective functional domains of perilipin A differentially regulate constitutive and protein kinase A-stimulated lipolysis. J Biol Chem. 2003;278(51):51535–42.

    CAS  PubMed  Google Scholar 

  267. Mottagui-Tabar S, Rydén M, Löfgren P, Faulds G, Hoffstedt J, Brookes AJ, et al. Evidence for an important role of perilipin in the regulation of human adipocyte lipolysis. Diabetologia. 2003;46(6):789–97.

    CAS  PubMed  Google Scholar 

  268. Saravani R, Galavi HR, Noorzehi N, Ranjbar N, Mollashahee-Kohkan F. Common variations in perilipin rs1052700 and FTO rs3751812 gene variants, and risk for obesity and Type-2 diabetes. Rep Biochem Mol Biol. 2017;6(1):80–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  269. Brown MS, Goldstein JL. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell. 1997;89(3):331–40.

    CAS  PubMed  Google Scholar 

  270. Galavi H, Noorzehi N, Saravani R, Sargazi S, Mollashahee-Kohkan F, Shahraki H. Association study of SREBF-2 gene polymorphisms and the risk of type 2 diabetes in a sample of Iranian population. Gene. 2018;660:145–50.

    CAS  PubMed  Google Scholar 

  271. Zelmanovitz T, Gerchman F, Balthazar AP, Thomazelli FC, Matos JD, Canani LH. Diabetic nephropathy. Diabetol Metab Syndr. 2009;1(1):10.

    PubMed  PubMed Central  Google Scholar 

  272. CfD C. Prevention %J Atlanta GUDoH, services H. Natl Diabet Statist Rep Estim Diabet Burden USA. 2014;2014:2014.

    Google Scholar 

  273. Zhu S, Wang Z, Wu X, Shu Y, Lu D. Apolipoprotein E polymorphism is associated with lower extremity deep venous thrombosis: color-flow Doppler ultrasound evaluation. Lipids Health Dis. 2014;13(1):1–5.

    PubMed Central  Google Scholar 

  274. De Andrade F, Maluf S, Schuch J, Voigt F, Barros A, Lucatelli J, et al. The influence of the S19W SNP of the APOA5 gene on triglyceride levels in southern Brazil: interactions with the APOE gene, sex and menopause status. Nutr Metab Cardiovasc Dis. 2011;21(8):584–90.

    PubMed  Google Scholar 

  275. Mahrooz A, Zargari M, Ansari V, Makhlough A, Hashemi-Sooteh MB. Association of APOA5 gene promoter region -1131T>C polymorphism (rs662799) to plasma triglyceride level in patients with type 2 diabetic nephropathy. J Clin Diagn Res JCDR. 2016;10(5):9–13.

    Google Scholar 

  276. Alharbi KK, Khan IA, Syed R. Association of apolipoprotein E polymorphism with type 2 diabetes mellitus in a Saudi population. DNA Cell Biol. 2014;33(9):637–41.

    CAS  PubMed  Google Scholar 

  277. Aalto-Setälä K, Fisher E, Chen X, Chajek-Shaul T, Hayek T, Zechner R, et al. Mechanism of hypertriglyceridemia in human apolipoprotein (apo) CIII transgenic mice: diminished very low density lipoprotein fractional catabolic rate associated with increased apo CIII and reduced apo E on the particles. J Clin Investig. 1992;90(5):1889–900.

    PubMed  PubMed Central  Google Scholar 

  278. Mendivil CO, Zheng C, Furtado J, Lel J, Sacks FM. Metabolism of very-low-density lipoprotein and low-density lipoprotein containing apolipoprotein C-III and not other small apolipoproteins. Arterioscler Thromb Vasc Biol. 2010;30(2):239–45.

    CAS  PubMed  Google Scholar 

  279. Marcelo CL, Duell EA, Stawiski MA, Anderson TF, Voorhees JJ. Cyclic nucleotide levels in psoriatic and normal keratomed epidermis. J Investig Dermatol. 1979;72(1):20–4.

    CAS  PubMed  Google Scholar 

  280. Alborn WE, Prince MJ, Konrad RJ. Relationship of apolipoprotein A5 and apolipoprotein C3 levels to serum triglycerides in patients with type 2 diabetes. Clin Chim Acta. 2007;378(1–2):154–8.

    CAS  PubMed  Google Scholar 

  281. Shoulders C, Harry P, Lagrost L, White S, Shah N, North J, et al. Variation at the apo AI/CIII/A1V gene complex is associated with elevated plasma levels of apo CIII. Atherosclerosis. 1991;87(2–3):239–47.

    CAS  PubMed  Google Scholar 

  282. Alharbi KK, Hussain T, Alharbi FK, Tabassum SN, Mohammed AA, Gambhir D, et al. Apolipoprotein C3 gene variants and risk of developing Type 2 diabetes in saudi subjects. Metab Syndr Relat Disord. 2015;13(7):298–303.

    CAS  PubMed  Google Scholar 

  283. Ilhan N, Kahraman N, Seçkin D, Ilhan N, Colak R. Apo E gene polymorphism on development of diabetic nephropathy. Cell Biochem Funct. 2007;25(5):527–32.

    CAS  PubMed  Google Scholar 

  284. Garme Y, Moudi M, Saravani R, Galavi H. Nitric oxide synthase 2 polymorphisms (rs2779248T/C and rs1137933C/T) and the risk of Type 2 diabetes in Zahedan, Southeastern Iran. Iran J Public Health. 2018;47(11):1734–41.

    PubMed  PubMed Central  Google Scholar 

  285. Garme Y, Saravani R, Galavi HR. Association of nitric oxide synthase 3 gene polymorphism with the risk of type 2 diabetes. Biomed Rep. 2017;7(1):85–9.

    PubMed  PubMed Central  Google Scholar 

  286. Tso AW, Tan KC, Wat NM, Janus ED, Lam TH. Endothelial nitric oxide synthase G894T (Glu298Asp) polymorphism was predictive of glycemic status in a 5-year prospective study of Chinese subjects with impaired glucose tolerance. Metab Clin Exp. 2006;55(9):1155–8.

    CAS  PubMed  Google Scholar 

  287. Pieper GM. Enhanced, unaltered and impaired nitric oxide-mediated endothelium-dependent relaxation in experimental diabetes mellitus: importance of disease duration. Diabetologia. 1999;42(2):204–13.

    CAS  PubMed  Google Scholar 

  288. Mehrab-Mohseni M, Tabatabaei-Malazy O, Hasani-Ranjbar S, Amiri P, Kouroshnia A, Bazzaz JT, et al. Endothelial nitric oxide synthase VNTR (intron 4 a/b) polymorphism association with type 2 diabetes and its chronic complications. Diabet Res Clin Pract. 2011;91(3):348–52.

    CAS  Google Scholar 

  289. Bellini MH, Figueira MN, Piccoli MF, Marumo JT, Cendoroglo MS, Neto MC, et al. Association of endothelial nitric oxide synthase gene intron 4 polymorphism with end-stage renal disease. Nephrology (Carlton). 2007;12(3):289–93.

    CAS  Google Scholar 

  290. Ahluwalia TS, Ahuja M, Rai TS, Kohli HS, Sud K, Bhansali A, et al. Endothelial nitric oxide synthase gene haplotypes and diabetic nephropathy among Asian Indians. Mol Cell Biochem. 2008;314(1–2):9–17.

    CAS  PubMed  Google Scholar 

  291. Rahimi Z, Rahimi Z, Shahvaisi-Zadeh F, Sadeghei S, Vessal M, Yavari N. eNOS 4a/b polymorphism and its interaction with eNOS G894T variants in type 2 diabetes mellitus: modifying the risk of diabetic nephropathy. Dis Markers. 2013;34(6):437–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  292. Moguib O, Raslan HM, Rasheed IA, Effat L, Mohamed N, El Serougy S, et al. Endothelial nitric oxide synthase gene (T786C and G894T) polymorphisms in Egyptian patients with type 2 diabetes. J Genetic Eng Biotechnol. 2017;15(2):431–6.

    Google Scholar 

  293. Schrijvers BF, De Vriese AS, Flyvbjerg A. From hyperglycemia to diabetic kidney disease: the role of metabolic, hemodynamic, intracellular factors and growth factors/cytokines. Endocr Rev. 2004;25(6):971–1010.

    CAS  PubMed  Google Scholar 

  294. El-Din Bessa SS, Hamdy SM. Impact of nitric oxide synthase Glu298Asp polymorphism on the development of end-stage renal disease in type 2 diabetic Egyptian patients. Ren Fail. 2011;33(9):878–84.

    PubMed  Google Scholar 

  295. Shoukry A, Shalaby SM, Abdelazim S, Abdelazim M, Ramadan A, Ismail MI, et al. Endothelial nitric oxide synthase gene polymorphisms and the risk of diabetic nephropathy in type 2 diabetes mellitus. Genet Test Mol Biomark. 2012;16(6):574–9.

    CAS  Google Scholar 

  296. Abbaszadegan MR, Riahi A, Forghanifard MM, Moghbeli M. WNT and NOTCH signaling pathways as activators for epidermal growth factor receptor in esophageal squamous cell carcinoma. Cell Mol Biol Lett. 2018;23:42.

    PubMed  PubMed Central  Google Scholar 

  297. Moghbeli M, Forghanifard MM, Aarabi A, Mansourian A, Abbaszadegan MR. Clinicopathological sex- related relevance of musashi1 mRNA expression in esophageal squamous cell carcinoma patients. Pathol Oncol Res. 2014;20(2):427–33.

    CAS  PubMed  Google Scholar 

  298. Moghbeli M, Rad A, Farshchian M, Taghehchian N, Gholamin M, Abbaszadegan MR. Correlation between Meis1 and Msi1 in esophageal squamous cell carcinoma. J Gastrointest Cancer. 2016;47(3):273–7.

    CAS  PubMed  Google Scholar 

  299. Moghbeli M, Sadrizadeh A, Forghanifard MM, Mozaffari HM, Golmakani E, Abbaszadegan MR. Role of Msi1 and PYGO2 in esophageal squamous cell carcinoma depth of invasion. J Cell Commun Signal. 2016;10(1):49–53.

    PubMed  Google Scholar 

  300. Schinner SJH. Wnt-signalling and the metabolic syndrome. Hormone Metab Res. 2009;41(02):159–63.

    CAS  Google Scholar 

  301. Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007;87(4):1409–39.

    CAS  PubMed  Google Scholar 

  302. Tangjittipokin W, Chongjarean N, Plengvidhya N, Homsanit M, Yenchitsomanus PT. Transcription factor 7-like 2 (TCF7L2) variations associated with earlier age-onset of type 2 diabetes in Thai patients. J Genet. 2012;91(2):251–5.

    PubMed  Google Scholar 

  303. Song K, Wang S, Mani M, Mani A. Wnt signaling, de novo lipogenesis, adipogenesis and ectopic fat. Oncotarget. 2014;5(22):11000–3.

    PubMed  PubMed Central  Google Scholar 

  304. Palizban A, Nikpour M, Salehi R, Maracy MR. Association of a common variant in TCF7L2 gene with type 2 diabetes mellitus in a Persian population. Clin Exp Med. 2012;12(2):115–9.

    CAS  PubMed  Google Scholar 

  305. Palizban A, Rezaei M, Khanahmad H, Fazilati M. Transcription factor 7-like 2 polymorphism and context-specific risk of metabolic syndrome, type 2 diabetes, and dyslipidemia. J Res Med Sci. 2017;22:40.

    PubMed  PubMed Central  Google Scholar 

  306. Vatankhah Yazdi K, Kalantar SM, Houshmand M, Rahmanian M, Manaviat MR, Jahani MR, et al. SLC30A8, CDKAL1, TCF7L2, KCNQ1 and IGF2BP2 are associated with Type 2 diabetes mellitus in Iranian patients. Diabet Metab Syndr Obes Targets Ther. 2020;13:897–906.

    Google Scholar 

  307. Shokouhi S, Delpisheh A, Haghani K, Mahdizadeh M, Bakhtiyari S. Association of rs7903146, rs12255372, and rs290487 polymorphisms in TCF7L2 gene with type 2 diabetes in an Iranian Kurdish ethnic group. Clin Lab. 2014;60(8):1269–76.

    CAS  PubMed  Google Scholar 

  308. Alami FM, Ahmadi M, Bazrafshan H, Tabarraei A, Khosravi A, Tabatabaiefar MA, et al. Association of the TCF7L2 rs12255372 (G/T) variant with type 2 diabetes mellitus in an Iranian population. Genet Mol Biol. 2012;35(2):413–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  309. El-Lebedy D, Ashmawy I. Common variants in TCF7L2 and CDKAL1 genes and risk of type 2 diabetes mellitus in Egyptians. J Genetic Eng Biotechnol. 2016;14(2):247–51.

    Google Scholar 

  310. Ereqat S, Nasereddin A, Cauchi S, Azmi K, Abdeen Z, Amin R. Association of a common variant in TCF7L2 gene with type 2 diabetes mellitus in the Palestinian population. Acta Diabetol. 2010;47(Suppl 1):195–8.

    CAS  PubMed  Google Scholar 

  311. Erkoç Kaya D, Arikoğlu H, Kayiş SA, Öztürk O, Gönen MS. Transcription factor 7-like 2 (TCF7L2) gene polymorphisms are strong predictorsof type 2 diabetes among nonobese diabetics in the Turkish population. Turk J Med Sci. 2017;47(1):22–8.

    PubMed  Google Scholar 

  312. Khan SM, El Karte N, El Hajj CS, Hassoun A, Afandi B, Tay GK, et al. Association between type 2 diabetes mellitus & TCF7L2 gene variants in the Emirati population: genetics of diabetes in the United Arab Emirates. Am J Hum Biol. 2021;33(1):e23434.

    PubMed  Google Scholar 

  313. Saadi H, Nagelkerke N, Carruthers SG, Benedict S, Abdulkhalek S, Reed R, et al. Association of TCF7L2 polymorphism with diabetes mellitus, metabolic syndrome, and markers of beta cell function and insulin resistance in a population-based sample of Emirati subjects. Diabetes Res Clin Pract. 2008;80(3):392–8.

    CAS  PubMed  Google Scholar 

  314. Palizban AA, Yazdani AH, Jahanbani-Ardakani H. Role of rs7903146 polymorphism and adropin serum level in patients with diabetes mellitus; a case-control study from Isfahan, Iran. Archiv Physiol Biochem. 2019;2019:1–4.

    Google Scholar 

  315. Cai Y, Yi J, Ma Y, Fu D. Meta-analysis of the effect of HHEX gene polymorphism on the risk of type 2 diabetes. Mutagenesis. 2011;26(2):309–14.

    CAS  PubMed  Google Scholar 

  316. Pascoe L, Tura A, Patel SK, Ibrahim IM, Ferrannini E, Zeggini E, et al. Common variants of the novel type 2 diabetes genes CDKAL1 and HHEX/IDE are associated with decreased pancreatic beta-cell function. Diabetes. 2007;56(12):3101–4.

    CAS  PubMed  Google Scholar 

  317. Galavi H, Mollashahee-Kohkan F, Saravani R, Sargazi S, Noorzehi N, Shahraki H. HHEX gene polymorphisms and type 2 diabetes mellitus: a case-control report from Iran. J Cell Biochem. 2019;120(10):16445–51.

    CAS  PubMed  Google Scholar 

  318. Mansoori Y, Daraei A, Naghizadeh MM, Salehi R. The HHEX rs1111875A/G gene polymorphism is associated with susceptibility to type 2 diabetes in the Iranian population. Mol Biol. 2015;49(4):601–9.

    CAS  Google Scholar 

  319. Kyriakis JM, Avruch J. Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update. Physiol Rev. 2012;92(2):689–737.

    CAS  PubMed  Google Scholar 

  320. Mokhtari D, Myers JW, Welsh N. MAPK kinase kinase-1 is essential for cytokine-induced c-Jun NH2-terminal kinase and nuclear factor-kappaB activation in human pancreatic islet cells. Diabetes. 2008;57(7):1896–904.

    CAS  PubMed  PubMed Central  Google Scholar 

  321. King GL, Park K, Li Q. Selective insulin resistance and the development of cardiovascular diseases in diabetes: the 2015 Edwin Bierman Award Lecture. Diabetes. 2016;65(6):1462–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  322. Johnson GL, Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science (New York, NY). 2002;298(5600):1911–2.

    CAS  Google Scholar 

  323. Carlson CJ, Koterski S, Sciotti RJ, Poccard GB, Rondinone CM. Enhanced basal activation of mitogen-activated protein kinases in adipocytes from type 2 diabetes: potential role of p38 in the downregulation of GLUT4 expression. Diabetes. 2003;52(3):634–41.

    CAS  PubMed  Google Scholar 

  324. Torkamandi S, Bastami M, Ghaedi H, Moghadam F, Mirfakhraie R, Omrani MD. MAP3K1 may be a promising susceptibility gene for Type 2 diabetes mellitus in an Iranian population. Int J Mol Cell Med. 2016;5(3):134–40.

    PubMed  PubMed Central  Google Scholar 

  325. Lawrence DA. Transforming growth factor-beta: an overview. Kidney Int Suppl. 1995;49:S19-23.

    CAS  PubMed  Google Scholar 

  326. Lin HM, Lee JH, Yadav H, Kamaraju AK, Liu E, Zhigang D, et al. Transforming growth factor-beta/Smad3 signaling regulates insulin gene transcription and pancreatic islet beta-cell function. J Biol Chem. 2009;284(18):12246–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  327. El-Sherbini SM, Shahen SM, Mosaad YM, Abdelgawad MS, Talaat RM. Gene polymorphism of transforming growth factor-β1 in Egyptian patients with type 2 diabetes and diabetic nephropathy. Acta Biochim Biophys Sin. 2013;45(4):330–8.

    CAS  PubMed  Google Scholar 

  328. Khan T, Muise ES, Iyengar P, Wang ZV, Chandalia M, Abate N, et al. Metabolic dysregulation and adipose tissue fibrosis: role of collagen VI. Mol Cell Biol. 2009;29(6):1575–91.

    CAS  PubMed  Google Scholar 

  329. Muona P, Jaakkola S, Zhang RZ, Pan TC, Pelliniemi L, Risteli L, et al. Hyperglycemic glucose concentrations up-regulate the expression of type VI collagen in vitro—relevance to alterations of peripheral nerves in diabetes mellitus. Am J Pathol. 1993;142(5):1586–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  330. Marson BP, Lacchini R, Belo V, Mattos SG, da Costa BP, Poli-de-Figueiredo CE, et al. Functional matrix metalloproteinase (MMP)-9 genetic variants modify the effects of hemodialysis on circulating MMP-9 levels. Clin Chim Acta Int J Clin Chem. 2012;414:46–51.

    CAS  Google Scholar 

  331. Saravani S, Yari D, Saravani R, Azadi AC. Association of COL4A3 (rs55703767), MMP-9 (rs17576)and TIMP-1 (rs6609533) gene polymorphisms with susceptibility to type 2 diabetes. Biomed Rep. 2017;6(3):329–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  332. Cooley J, Takayama TK, Shapiro SD, Schechter NM, Remold-O’Donnell E. The serpin MNEI inhibits elastase-like and chymotrypsin-like serine proteases through efficient reactions at two active sites. Biochemistry. 2001;40(51):15762–70.

    CAS  PubMed  Google Scholar 

  333. Talukdar S, Oh DY, Bandyopadhyay G, Li D, Xu J, McNelis J, et al. Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nat Med. 2012;18(9):1407–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  334. Huasong G, Zongmei D, Jianfeng H, Xiaojun Q, Jun G, Sun G, et al. Serine protease inhibitor (SERPIN) B1 suppresses cell migration and invasion in glioma cells. Brain Res. 2015;1600:59–69.

    PubMed  Google Scholar 

  335. Kassem DH, Adel A, Sayed GH, Kamal MM. A Novel SERPINB1 single-nucleotide polymorphism associated with glycemic control and β-cell function in Egyptian Type 2 diabetic patients. Front Endocrinol. 2020;11:450.

    Google Scholar 

  336. Marshall C, Hitman GA, Partridge CJ, Clark A, Ma H, Shearer TR, et al. Evidence that an isoform of calpain-10 is a regulator of exocytosis in pancreatic beta-cells. Mol Endocrinol (Baltimore, Md). 2005;19(1):213–24.

    CAS  Google Scholar 

  337. Suzuki K, Hata S, Kawabata Y, Sorimachi H. Structure, activation, and biology of calpain. Diabetes. 2004;53(Suppl 1):S12–8.

    CAS  PubMed  Google Scholar 

  338. Paul DS, Harmon AW, Winston CP, Patel YM. Calpain facilitates GLUT4 vesicle translocation during insulin-stimulated glucose uptake in adipocytes. Biochem J. 2003;376(Pt 3):625–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  339. Zaharna MM, Abed AA, Sharif FA. Calpain-10 gene polymorphism in type 2 diabetes mellitus patients in the Gaza Strip. Med Princ Practice Int J Kuwait Univ Health Sci Centre. 2010;19(6):457–62.

    Google Scholar 

  340. Demirci H, Yurtcu E, Ergun MA, Yazici AC, Karasu C, Yetkin I. Calpain 10 SNP-44 gene polymorphism affects susceptibility to type 2 diabetes mellitus and diabetic-related conditions. Genet Test. 2008;12(2):305–9.

    CAS  PubMed  Google Scholar 

  341. van Ham TJ, Kokel D, Peterson RT. Apoptotic cells are cleared by directional migration and elmo1- dependent macrophage engulfment. Curr Biol CB. 2012;22(9):830–6.

    PubMed  Google Scholar 

  342. Mehrabzadeh M, Pasalar P, Karimi M, Abdollahi M, Daneshpour M, Asadolahpour E, et al. Association between ELMO1 gene polymorphisms and diabetic nephropathy in an Iranian population. J Diabet Metab Disord. 2015;15:43.

    Google Scholar 

  343. Bayoumy NMK, El-Shabrawi MM, Leheta OF, Abo El-Ela AEM, Omar HH. Association of ELMO1 gene polymorphism and diabetic nephropathy among Egyptian patients with type 2 diabetes mellitus. Diabet Metab Res Rev. 2020;36(5):e3299.

    CAS  Google Scholar 

  344. Al-Daghri NM, Costa AS, Alokail MS, Zanzottera M, Alenad AM, Mohammed AK, et al. Synaptosomal protein of 25 kDa (Snap25) polymorphisms associated with glycemic parameters in type 2 diabetes patients. J Diabet Res. 2016;2016:1.

    Google Scholar 

  345. Ku BJ, Kim TH, Lee JH, Buras ED, White LD, Stevens RD, et al. Mig-6 plays a critical role in the regulation of cholesterol homeostasis and bile acid synthesis. PLoS ONE. 2012;7(8):e42915.

    CAS  PubMed  PubMed Central  Google Scholar 

  346. Staal B, Williams BO, Beier F, Vande Woude GF, Zhang YW. Cartilage-specific deletion of Mig-6 results in osteoarthritis-like disorder with excessive articular chondrocyte proliferation. Proc Natl Acad Sci USA. 2014;111(7):2590–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  347. Zhang YW, Vande Woude GF. Mig-6, signal transduction, stress response and cancer. Cell Cycle (Georgetown, Tex). 2007;6(5):507–13.

    CAS  Google Scholar 

  348. Chen YC, Colvin ES, Maier BF, Mirmira RG, Fueger PT. Mitogen-inducible gene 6 triggers apoptosis and exacerbates ER stress-induced β-cell death. Mol Endocrinol (Baltimore, Md). 2013;27(1):162–71.

    CAS  Google Scholar 

  349. Ferby I, Reschke M, Kudlacek O, Knyazev P, Pantè G, Amann K, et al. Mig6 is a negative regulator of EGF receptor-mediated skin morphogenesis and tumor formation. Nat Med. 2006;12(5):568–73.

    CAS  PubMed  Google Scholar 

  350. Asgarbeik S, Mohammad Amoli M, Enayati S, Bandarian F, Nasli-Esfahani E, Forouzanfar K, et al. The role of ERRFI1+808T/G polymorphism in diabetic nephropathy. Int J Mol Cell Med. 2019;8(Suppl1):49–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  351. Gardemann A, Nguyen QD, Humme J, Stricker J, Katz N, Tillmanns H, et al. Angiotensin II type 1 receptor A1166C gene polymorphism. Absence of an association with the risk of coronary artery disease and myocardial infarction and of a synergistic effect with angiotensin-converting enzyme gene polymorphism on the risk of these diseases. Eur Heart J. 1998;19:1657.

    CAS  PubMed  Google Scholar 

  352. Companioni Nápoles O, Sautié Castellanos M, Leal L, Casalvilla R, Camacho H, Ferrer A, et al. ACE I/D polymorphism study in a Cuban hypertensive population. Clin Chim Acta Int J Clin Chem. 2007;378:112.

    Google Scholar 

  353. Assali A, Ghayour-Mobarhan M, Sahebkar A, Hassani M, Kasaian J, Tatari F, et al. Association of angiotensin II type 1 receptor gene A1166C polymorphism with the presence of diabetes mellitus and metabolic syndrome in patients with documented coronary artery disease. Eur J Intern Med. 2011;22(3):254–61.

    CAS  PubMed  Google Scholar 

  354. Ehlers MR, Riordan JF. Angiotensin-converting enzyme: new concepts concerning its biological role. Biochemistry. 1989;28(13):5311–8.

    CAS  PubMed  Google Scholar 

  355. Wang JG, Staessen JA. Genetic polymorphisms in the renin-angiotensin system: relevance for susceptibility to cardiovascular disease. Eur J Pharmacol. 2000;410(2–3):289–302.

    CAS  PubMed  Google Scholar 

  356. Zarouk WA, Hussein IR, Esmaeil NN, Raslan HM, Reheim HA, Moguib O, et al. Association of angiotensin converting enzyme gene (I/D) polymorphism with hypertension and type 2 diabetes. Bratisl Lek Listy. 2012;113(1):14–8.

    CAS  PubMed  Google Scholar 

  357. Al-Saikhan FI, Abd-Elaziz MA, Ashour RH. Association between risk of type 2 diabetes mellitus and angiotensin-converting enzyme insertion/deletion gene polymorphisms in a Saudi Arabian population. Biomed Rep. 2017;7(1):56–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  358. Al-Harbi EM, Farid EM, Gumaa KA, Darwish AH, Alenizi M, Singh J. Genetic combination of angiotensin-converting enzyme with methylene tetrahydrofolate reductase polymorphisms and the risk of type 2 diabetes mellitus in Bahrain. J Renin Angiotensin Aldosterone Syst JRAAS. 2015;16(1):172–7.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

Not applicable.

Author information

Authors and Affiliations

Authors

Contributions

IA, ARB, MRM, and AF were contributed equally in drafting. ARE, SKK, ABB, MEK, and NT were involved in search strategy and revision. MM was involved in conception and designing and supervised the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Meysam Moghbeli.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article