1. Introduction
1.1. Genes associated with T2DM
1.1.1. Genes associated with ion transport
1.1.1.1. KCNJ11
The potassium inwardly rectifying channel subfamily J member 11 (
1.1.1.2. KCNQ1
1.1.1.3. SLC30A8
GWA studies also identified that the zinc transporter solute carrier family 30 member 8 gene (
1.1.1.4. WSF1
Wolfram syndrome 1 (
1.1.2. Genes involved in cell cycles
1.1.2.1. CDKAL1
A variant in the cyclin-dependent kinase 5 (CDK5) regulatory subunit associated protein 1-like 1 (
1.1.2.2. CDKN2A/B
Cyclin-dependent kinase inhibitor-2A/B (CDKN2A/B) gene encode p15INK4b and p16INK4a protein which are tumor suppressors that inhibit cyclin-dependent kianse 6 (CDK6) and CDK4, respectively. CDKN2B and CDKN2A are expressed in pancreatic islets and adipocytes [19, 20, 24]. CDKN2A/2B (rs10811661) was associated with T2DM [45]. SNP rs10811661 located 125 kb upstream of the CDKN2B and CDKN2A genes, has been associated with T2DM in three of the GWA studies (OR for pooled studies 1.20 [95% CI 1.14–1.25],
1.1.2.3. CDC123/CAMK1D
SNP rs12779790 is located ~90 kb from cell division cycle 123 homolog [S. cerevisiae] (
1.1.3. Genes involved in gene transcription
1.1.3.1. TCF2
The SNPs rs7501939 and rs4430796 on 17q12 are located in the first and second intron of the transcription factor 2 isoform b (
1.3.2. TCF7L2
Transcription factor 7-like 2 (
1.1.3.3. HHEX
GWA studies identified that the haematopoietically expressed homeobox (
1.1.3.4. JAZF1
The juxtaposed with another zinc finger gene 1 (
1.1.4. Others
1.1.4.1. PPAR-γ2
Peroxisome proliferator-activated receptor-γ2 (PPAR-γ2) is one of PPAR-γ isoforms and is a member of the nuclear hormone receptor subfamily of transcription factors, which regulates transcription of various genes [70].
1.1.4.2. IGF2BP2
Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) belongs to an mRNA-binding protein family that plays role in RNA localization, stability and translation [76]. IGF2BP2 is highly expressed in pancreatic islets and binds to insulin-like growth factor 2 (IGF-2), which is an important growth and insulin signaling molecule [24]. IGF2BP2 is a homolog of IGF2BP1, which binds to the 5’UTR of IGF2 mRNA and regulates IGF2 translation [77]. Several GWA studies have found that subjects carrying mutant alleles of SNPs rs1470579 and rs4402960 in
Interactions between genetic variation in
1.1.4.3. FTO
Fat mass and obesity associated (
1.1.4.4. THADA
THADA (thyroid adenoma associated) gene encodes thyroid adenoma–associated protein may involve in the death receptor pathway and apoptosis [89]. Disruption of THADA by chromosomal rearrangements (including fusion with intronic sequence from PPAR-γ) is observed in thyroid adenomas [90]. The function of THADA has not been well-characterized, but there is some evidence to suggest that it may be involved in the death receptor pathway and apoptosis [89, 91]. The THADA gene variant was also associated with lower β-cell response to GLP-1 and arginine, suggested lower β-cell mass as a possible pathogenic mechanism [92]. SNP rs7578597 was a non-synonymous SNP causing threonine to alanine in 1187 position which strongly associated with T2DM (combined OR [95%CI] of 1.15[1.10-1.20],
1.1.4.5. TSPAN8/ LGR5
Tetraspanin 8 is a cell-surface glycoprotein, widely expressed cell surface glycoprotein known to form complexes with integrins to regulate cell motility in cancer cell lines [23, 94]. Tetraspanin 8 gene (TSPAN8) polymorphism rs7961581 was one of the strongest statistical signals associated with T2DM. SPAN8/LGR5 rs7961581 was significantly associated with T2DM in a meta-analysis in East Asians [69]. SNP rs7961581 associated with decreased levels of CIR, of AUC-insulin/AUC-glucose ratio, and of the insulinogenic index [51]. SNP rs7961581 resided ~110 kb upstream of
1.1.4.6. ADAMTS9
ADAMTS9 is a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family which has been implicated in the cleavage of proteoglycans [96], the control of organ maturation, development [97] and inhibition of angiogenesis [98]. ADAMTS9 is a secreted metalloprotease that cleaves the proteoglycans versican and aggrecan, and is expressed in skeletal muscle and pancreas [23]. SNP rs4607103 in
1.1.4.7. NOTCH2
Notch 2 (Notch homolog 2 [Drosophila]) expresses when pancreatic buds branch and is restricted to embryonic ducts, should be the source for endocrine and exocrine stem cells in mice [23, 100]. Notch pathway plays key role in dictating endocrine differentiation. Activation of this pathway is critical for the maintenance of the progenitor pool between the first and second transitions of pancreatic development [101]. NOTCH2 is a type 1 transmembrane receptor. The SNP rs10923931 residing in intron 5 of the NOTCH2 gene strongly associate with T2DM susceptibility. SNP rs10923931 is near complete linkage disequilibrium with SNP rs2641348 in the ADAM30 gene [23]. Rs2641348, a non-synonymous SNP (L359P) within the neighboring ADAM metallo-peptidase domain 30 gene (ADAM30) represented the same signal (r2=0.92 based on HapMap CEU data) and was also followed-up.
1.1.4.8. PTPRD
A GWA study in Chinese population identified two genes, PTPRD and SRR, which were not previously described to be involved in diabetes or glucose metabolism [102]. PTPRD is the protein tyrosine phosphatase receptor type D gene and widely expressed in skeletal muscle, pancreas, and brain which belong to the receptor type IIA (R2A) subfamily of protein tyrosine phosphatases (PTPs). The R2A PTP subfamily comprises leukocyte common antigen-related (LAR), protein tyrosine phosphatase sigma (PTPRS), and PTPRD. The R2A family has been implicated in neural development, cancer, and diabetes [103]. PTPRD-deficient mice exhibited impaired learning and memory, early growth retardation, neonatal mortality, posture and motor defects [104]. LAR- and PTPRS-deficient mice showed defected glucose homeostasis and insulin sensitivity [105-107]. Transgenic mice over expressing LAR in skeletal muscle showed whole-body insulin resistance [108]. R2A subfamily members have similar structure [109]. PTPRD could act in T2DM pathogenesis and affect insulin signaling on its target cells. But it need further
characterize.
1.1.4.9. SRR
SRR (serine racemase) gene encodes aserine racemase that synthesizes D-serine from L-serine [110, 111]. D-serine (co-agonist) and the neurotransmitter glutamate bind to the N-methyl Daspartate (NMDA) receptors and trigger excitatory neurotransmission in the brain [102, 112, 113]. NMDA receptor activation requires binding of glutamate and D-serine, which plays a neuromodulatory role in NMDA receptor transmission, synaptic plasticity, cell migration, and neurotoxicity [62]. D-serine and SRR express in the pancreas [114]. Glutamate signaling has function involved in positively regulates insulin and glucagon secretion in pancreatic islets [115-117]. Thus, SRR and D-serine may play roles in the etiology of T2DM. SNPs rs391300 and rs4523957 in the SRR gene were associated with T2DM in a Han Chinese GWA study. SNPs rs391300 and rs4523957 were in tight LD with each other (r2 = 0.942 in HapMap HCB)[102]. The nearby SNP rs216193 also showed significant association; this SNP resides 3.8 kb upstream from SRR. SNP rs216193 was in tight LD with rs391300 (r2 = 0.942 in HapMap HCB) [102].
2. Anti-diabetic drugs pharmacogenetics
2.1. Insulin secretagogue agents ------sulfonylureas (SUs)
The sulfonylurea anti-diabetic agents are insulin secretogogues including the first generation sulfonylureas (acetohexomide, chlorpropamide, tolazamide and tolbutamide) and second generation sulfonylureas (glibenclamide (glyburide), glipizide, gliclazide, and glimepiride) which are most widely used for T2DM treatment by closing the pancreatic β-cell potassium channels and stimulation insulin secretion [119].
2.1.1. Cytochrome P450
Sulfonylurea hypoglycemic agents are metabolized by cytochrome P450 2C9 (CYP2C9) enzyme. Genetic polymorphisms Arg144Cys (
2.1.2. Sulfonylurea receptor
The sulphonylurea receptor is a subunit of the ATP-sensitive potassium channel located in pancreatic β-cell. The variants in the exon 16 -3C/T variant (rs1799854) of
2.1.3. Others
It was described that the exon 33 of the ABCC8 (rs757110) and KCNJ11 (rs5210) genes were associated with gliclazide antidiabetic efficacy [127]. SNPs of TCF7L2 had been consistently associated with T2DM in different ethnic descent and also had great impact on the T2DM patients’ response to sulfonylureas [128]. The Go-DARTS2 study reported that the T allele of rs7903146 was associated with increased HbA1c in both cases and controls [129]. The same study group revealed that carriers of TCF7L2 variants were more likely to fail sulfonylurea therapy but not metformin (HbA1c > 7 %) within 3-12 months of treatment initiation [62].
Hepatocyte nuclear factor-1α (HNF-1α) is a homeodomain-containing transcription factor that expressed in the pancreatic β-cell and HNF-1α SNPs have been associated with β-cell dysfunction and maturity onset diabetes of the young (MODY) [130]. Variations in HNF-1α polymorphisms of T2DM were reported to be more sensitive to the hypoglycaemic effects of sulfonylureas [131-133].
2.2. Insulin secretagogue agents ------ Non-sulfonylureas
Meglitinides (repaglinide and nateglinide) represent a new class of insulin secretagogue, structurally unrelated to sulphanylureas by very rapid onset and abbreviated duration of action [135]. Meglitinides stimulate first-phase insulin release in a glucose-sensitive manner and reduce the risk of hypoglycemic events.
2.2.1. Cytochrome P450 and transporters
Repaglinide is metabolized by CYP2C8 and CYP3A4 [136]. The
The oral bioavailability of nateglinide is about 73%, and it is rapidly absorbed and extensively metabolized primarily by CYP2C9 in the liver and a smaller fraction by CYP3A4 and CYP2D6 [139]. Nateglinide is confirmed as a substrate of CYP2C9. A previous report showed that the
The meglitinide class drug nateglinide is metabolized by CYP2C9. According to pharmacokinetic data, moderate dose adjustments based on CYP2C9 genotypes may help in reducing interindividual variability in the anti hyperglycemic effects of nateglinide [173]. Carriers of the
Polymorphic organic anion transporting polypeptide 1B1 (SLCO1B1) is a major determinant of repaglinide pharmacokinetics [141]. SLCO1B1 (which codes the
2.2.2. Others
An association of (
2.3. Biguanides
Metformin (a biguanide) is among the most widely prescribed drugs and has a gluco-regulator effect in the presence of endogenous insulin by reducing gastrointestinal glucose absorption, decreasing endogenous glucose production and reducing peripheral resistance to insulin [147].
2.3.1. Transporters
Organic cation transporter 1 (OCT1, gene name SLC22A1) is the major mechanism for metformin entry into hepatocytes and enterocytes [148]. Human OCT1 is highly polymorphic. Shu’ study provided proof of concept that genetic variation in OCT1 may be associated with variation in response to metformin OCT1 Met420del had reduced activity for metformin [149]. Another study in healthy subjects also confirmed polymorphisms in OCT1 were associated with the renal clearance of metformin [150]. Low-function OCT1 amino acid substitutions Arg61Cys, Ser401Gly, Met420del, and Gly465Arg, and the OCT1 promoter-linked variant rs1867351, were associated with an increase in the renal clearance of metformin by~20% and ~30%, respectively. These data suggested that a reduction in OCT1 expression or activity may increase renal excretion of metformin [150]. But in T2DM patients, the OCT1 loss-of-function variants, Arg61Cys and Met420del, did not attenuate the HbA1C reduction achieved by metformin [151].
2.3.2. Others
Recently, serine-threonine kinase 11 (
2.4. Euglycemic agents
Thiazolidinediones (pioglitazone, rosiglitazone) are insulin sensitizing agents and have glucose and lipid lowering activity. They are selective agonists for the PPAR-γ and decrease insulin resistance and enhance the biological response to endogenously produced insulin.
2.4.1. Cytochrome P450
Both rosiglitazone and pioglitazone are extensively metabolized in the liver by CYP2C8 [155, 156]. Kirchheiner and colleagues considered the influence of the
2.4.2. Others
Rosiglitazone improves insulin sensitivity by reducing plasma glucose levels and serum insulin, NEFA and triglyceride and by increasing HDL cholesterol levels [160, 161].
Himelfarb et al investigated TNF-α and IL-6 expression in leukocytes and their association with polymorphisms and bone markers in diabetic individuals treated with pioglitazone.
3. Conclusion
The rapidly increasing prevalence of T2DM is becoming a tremendous public health problem that affects more than 170 million patients worldwide. T2DM is a complex metabolic disorder with two major pathophysiological features: insulin resistance and pancreatic β-cell dysfunction. The mechanism of this disease remains unknown; however, environmental factors and genetic variations are considered two major contributors to onset and development of T2DM. In this chapter, we introduced gene associated with T2DM, such as: KCNJ11, KCNQ1, SLC30A8, WSF1, CDKAL1, CDKN2A/B, TCF2, TCF7L2, HHEX, JAZF1, PPAR-γ2, IGF2BP2, FTO, THADA, TSPAN8/ LGR5, ADAMTS9, NOTCH2, PTPRD, and SRR. Meanwhile, we described four anti-diabetic drugs pharmacogenetics, including insulin secretagogue agent sulfonylureas (SUs) and meglitinides, biguanides, and euglycemic agents. Genetic polymorphisms in drug-metabolizing enzymes, transporters, receptors, and other drug targets have been linked to interindividual differences in the efficacy and toxicity of a number of medications. Mutations in genes important in drug absorption, distribution, metabolism and excretion (ADME) play critical role in pharmacogenetics of diabetes. Numerous genes that influence pharmacogenetics of oral antidiabetics have been described. The investigations of genes associated with T2DM benefits of personalized medicine. And different types of genetic mutations and their influence on the response to therapy with oral antidiabetics are needed future study.
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