KCNJ11: Genetic Polymorphisms and Risk of Diabetes Mellitus

Abstract

Diabetes mellitus (DM) is a major worldwide health problem and its prevalence has been rapidly increasing in the last century. It is caused by defects in insulin secretion or insulin action or both, leading to hyperglycemia. Of the various types of DM, type 2 occurs most frequently. Multiple genes and their interactions are involved in the insulin secretion pathway. Insulin secretion is mediated through the ATP-sensitive potassium (KATP) channel in pancreatic beta cells. This channel is a heteromeric protein, composed of four inward-rectifier potassium ion channel (Kir6.2) tetramers, which form the pore of the KATP channel, as well as sulfonylurea receptor 1 subunits surrounding the pore. Kir6.2 is encoded by the potassium inwardly rectifying channel, subfamily J, member 11 (KCNJ11) gene, a member of the potassium channel genes. Numerous studies have reported the involvement of single nucleotide polymorphisms of the KCNJ11 gene and their interactions in the susceptibility to DM. This review discusses the current evidence for the contribution of common KCNJ11 genetic variants to the development of DM. Future studies should concentrate on understanding the exact role played by these risk variants in the development of DM.

Role of KCNJ11 Gene Polymorphisms and Risk of Type 2 Diabetes Mellitus

“…Structurally, Kir6.2 tetramers form the pore and four high-affinity SUR1 subunits surround the pore of the KATP channel located at the plasma membrane of pancreatic beta cells. This channel modulates insulin production and secretion through glucose metabolism 27,93 .…”

“…Mutations in the KCNJ11 gene can cause T2DM because of the reduced ability of ATP to inhibit the activity of the KATP channel and the enhanced ability of MgATP to simultaneously stimulate the function of this channel. This is associated with defective insulin secretion, ultimately causing T2DM 28,93 .…”

“…Diabetes mellitus type 2 (formerly noninsulindependent diabetes mellitus (NIDDM) or adult-onset diabetes) is a metabolic disorder due to hyperglycemia in the context of insulin resistance and relative lack of insulin. This is in contrast to Type 1 Diabetes Mellitus (T1DM), in which there is an absolute lack of insulin due to the breakdown of islet cells in the pancreas 2,93 .…”

“…This disease has early and late-stage complications. Early complications include hyperglycemia, polyphagia, polydipsia, polyuria and blurred vision, leading to complications manifested later such as vascular disease, heart disease, stroke, peripheral neuropathy, nephropathy and predisposition to infection 4,93 . The DM is classified into various types, of which type 2 (T2DM) occurs most frequently.…”

“…The DM is classified into various types, of which type 2 (T2DM) occurs most frequently. Approximately more than 90% of patients are affected by T2DM 5,93 . T2DM is contributed by a complex interaction between genetic condition and environment.…”