Most cases of type 2 diabetes involved many genes contributing small amount to the overall condition. As of 2011 more than 36 genes have been found that contribute to the risk of type 2 diabetes. All of these genes together still only account for 10% of the total genetic component of the disease.
There are a number of rare cases of diabetes that arise due to an abnormality in a single gene (known as monogenic forms of diabetes). These include maturity onset diabetes of the young (MODY), Donohue syndrome, and Rabson–Mendenhall syndrome, among others. Maturity onset diabetes of the young constitute 1–5% of all cases of diabetes in young people.
Polygenic
Genetic cause and mechanism of type 2 diabetes is largely unknown. However, single nucleotide polymorphism (SNP) is one of many mechanisms that leads to increased risk for type 2 diabetes. To locate genes and loci that are responsible for the risk of type 2 diabetes, genome wide association studies (GWAS) was utilized to compare the genomes of diabetic patient group and the non-diabetic control group. The diabetic patients’ genome sequences differ from the controls' genome in specific loci along and around numerous genes, and these differences in the nucleotide sequences alter phenotypic traits that exhibit increased susceptibility to the diabetes. GWAS has revealed 65 different loci (where single nucleotide sequences differ from the patient and control group's genomes), and genes associated with type 2 diabetes, including TCF7L2, PPARG, FTO, KCNJ11, NOTCH2, WFS1, IGF2BP2, SLC30A8, JAZF1, HHEX, DGKB, CDKN2A, CDKN2B, KCNQ1, HNF1A, HNF1B MC4R, GIPR, HNF4A, MTNR1B, PPARG, ZBED3, SLC30A8, CDKAL1, GLIS3, GCK, GCKR, among others.KCNJ11 (potassium inwardly rectifying channel, subfamily J, member 11), encodes the islet ATP-sensitive potassium channel Kir6.2, and TCF7L2 (transcription factor 7–like 2) regulates proglucagon gene expression and thus the production of glucagon-like peptide-1. In addition, there is also a mutation to the Islet Amyloid Polypeptide gene that results in an earlier onset, more severe, form of diabetes. However, this is not a comprehensive list of genes that affects the proneness to the diabetes.
SNP rs7873784 located in the 3′-untranslated region (3′-UTR) of TLR4 gene and associated with the development of type-2 diabetes mellitus. PU.1 binding to the minor C allele of rs7873784 may be responsible for elevated TLR4 expression in the monocytes of affected individuals, contributing to an inflammation-prone environment that predisposes minor allele carriers to development of certain pathologies with an inflammatory component. rs7873784 was also associated with the abnormal metabolic phenotype accompanying T2DM (levels of fasting insulin and triglycerides, abnormal low-density lipoprotein and high-density lipoprotein cholesterol levels). However, there is growing evidence that T2DM is not only a purely metabolic, but also an inflammatory disorder. The link between certain TLR4 SNPs alleles and T2DM may be directly related to elevated TLR4 expression since its signaling can regulate diet-induced obesity and insulin resistance and, therefore, influence the pathogenesis of T2DM. TLR4 expression is elevated in adipose tissue of obese mice and its activation triggered insulin resistance in adipocytes. LPS-mediated TLR4 activation can suppress glucose-induced insulin secretion by β-cells. Monocytes from T2DM patients demonstrate increased TLR4 expression, NFκB activity, and production of proinflammatory cytokines and chemokines. A number of endogenous TLR4 ligands are elevated in patients with diabetes. Oxidized LDL upregulates TLR4 expression in macrophages and provokes TLR4-dependent inflammation in the arterial wall, further TLR4 activation results in a strong inhibition of cholesterol efflux from macrophages. The hepatic secretory glycoprotein fetuin-A correlates with increased risk of developing T2DM and may promote lipid-induced insulin resistance via TLR4 activation, resulting in production of proinflammatory cytokines. Additionally, mice with deficiencies in TLR4 signaling were protected from insulin resistance caused by high-fat diet and from secondary complications of T2DM such as atherosclerosis.