The Genetic Mutation of Diabetes
Diabetes or diabetes mellitus (DM) includes wide-ranging metabolic disorders diagnosed by chronic hyperglycemia. The variants of this disease include type 1 DM (T1DM), type 2 DM (T2DM), gestational DM (GDM), and maturity-onset diabetes of the young (MODY) (Prokopenko, McCarthy, and Lindgren 614). T2DM is a multifactorial condition caused by mutations involving multiple susceptible genes. Mutations in the alleles expressed in beta cells “peroxisome proliferator-activates receptor gamma (PPRAG), insulin receptor substrate (IRS) 1 and 2, and potassium inwardly-rectifying channel (KCNJ11)” have been shown to increase the risk of T2DM, especially in European-descent samples. The alleles encode for nuclear receptors; therefore, the mutations cause beta-cell dysfunction, causing subpar insulin production.
Further, T2DM susceptibility has been linked to polymorphisms in the transcription factor 7-like 2 (TCF7L2) gene. TCF7L2 expression has been shown through genome-wide association studies (GWAS) to affect pancreatic islet activity, causing repressed insulin production that leads to T2DM (Prokopenko, McCarthy, and Lindgren 617). The TCF7L2 mutations have a higher impact on T2DM susceptibility than KCNJ11 or PPRAG variants, as the odds ratio is 1.4 versus 1.15 (Prokopenko, McCarthy, and Lindgren 617). This result indicates that people homozygous for the TCF7L2 allele have a twofold risk of suffering from T2DM compared to those without this allele.
Single nucleotide polymorphisms (SNPs) in three other loci have been confirmed to increase T2D risk through GWAS studies involving Asian and European subjects. The first one is a mutation in the fat mass and obesity-associated (FTO) gene, which compounds the obesity risk. In addition, SNPs in the hematopoietically expressed homeobox (HHEX) gene, an allele encoding for insulin-degrading factor, and IDE loci have been shown to affect serum insulin concentration. Other mutations that increase T2DM risk through repression of insulin secretion include SNPs in the IGF2BP2, CDKN2A, and SLC30A8 loci.