Which genes increase the risk for developing type 2 diabetes mellitus (DM)?

Updated: Sep 27, 2021
  • Author: Romesh Khardori, MD, PhD, FACP; Chief Editor: George T Griffing, MD  more...
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Genome-wide association studies of single-nucleotide polymorphisms (SNPs) have identified a number of genetic variants that are associated with beta-cell function and insulin resistance. Some of these SNPs appear to increase the risk for type 2 diabetes. Over 40 independent loci demonstrating an association with an increased risk for type 2 diabetes have been shown. [16] A subset of the most potent are shared below [17] :

  • Decreased beta-cell responsiveness, leading to impaired insulin processing and decreased insulin secretion (TCF7L2)

  • Lowered early glucose-stimulated insulin release (MTNR1B, FADS1, DGKB, GCK)

  • Altered metabolism of unsaturated fatty acids (FSADS1)

  • Dysregulation of fat metabolism (PPARG)

  • Inhibition of serum glucose release (KCNJ11) [18]

  • Increased adiposity and insulin resistance (FTO and IGF2BP2) [19, 20]

  • Control of the development of pancreatic structures, including beta-islet cells (HHEX) [21]

  • Transport of zinc into the beta-islet cells, which influences the production and secretion of insulin (SLC30A8) [21]

  • Survival and function of beta-islet cells (WFS1) [22]

Susceptibility to type 2 diabetes may also be affected by genetic variants involving incretin hormones, which are released from endocrine cells in the gut and stimulate insulin secretion in response to digestion of food. For example, reduced beta-cell function has been associated with a variant in the gene that codes for the receptor of gastric inhibitory polypeptide (GIPR). [23]

The high mobility group A1 (HMGA1) protein is a key regulator of the insulin receptor gene (INSR). [24] Functional variants of the HMGA1 gene are associated with an increased risk of diabetes.

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