Genetic predisposition of β-cell failure
المؤلف:
Holt, Richard IG, and Allan Flyvbjerg
المصدر:
Textbook of diabetes (2024)
الجزء والصفحة:
6th ed , page 228-229
2025-11-27
208
More light has been shed in recent years on the genetic predisposition to type 2 diabetes (Figure 1). Early linkage and candidate gene analyses and, more recently, genome- wide association studies (GWAS) have identified many genetic variants associated with increased risk of developing type 2 diabetes, although most have limited size effects that seldom exceed 10–15%. The only exception is represented by variants of the TCF7L2 gene encoding for a transcription factor involved in the Wnt- β catenin- signalling pathway. In particular, the T allele of the genotypes of the single- nucleotide polymorphism (SNP) rs7903146 confers a greater risk of developing type 2 diabetes in all populations so far evaluated, except for the Pima. More interestingly, the same genotype is associated with impaired in vivo and ex vivo insulin secretion. The TCF7L2 genetic variants may exert both direct and indirect effects on the β cell. Thus, the increased TCF7L2 expression found in human pancreatic islets carrying the risk allele T was inversely correlated with glucose- stimulated insulin release. Moreover, people carrying the risk alleles have impaired potentiation of insulin secretion in response to GLP- 1 infusion. In summary, the TCF7L2 genetic variants may be associated with reduced insulin secretion in response to both glucose and incretin hormones. Other studies have reported reduced expression of the TCF7L2 gene in type 2 diabetes pancreatic islets along with impaired insulin secretion and β- cell survival.
Fig1. Type 2 diabetes and glycaemic trait–associated variants. The variants are represented by gene names here, which could indicate that the location is present either in the gene or in the vicinity of the gene. The white circle represents type 2 diabetes and the gene names in black in that circle represent variants only associated with type 2 diabetes. The overlapping circles indicate additional reporting associations for that variant. Source: Prasad and Groop 2015. Creative Commons Attribution License (CC BY).
A reduced early insulin response to both oral and intravenous glucose and greater susceptibility to diabetes have been reported for carriers of the single- nucleotide polymorphism (SNP) rs10830963 in the melatonin receptor gene (MTNR1B). These individuals have increased melatonin receptor expression in β cells, which may lead to increased melatonin binding and reduced cyclic adenosine monophosphate (cAMP)/cyclic guanosine monophosphate (cGMP) generation, accounting for impaired insulin secretion.
Other gene variants that have been associated with impaired insulin action include the G/G variants of calpain- 10 gene (CAPN10) and KCNJ11. The G/G variant of SNP- 43 of CAPN10 is associated with impaired insulin response to glucose in people without diabetes [40]. Variants of the KCNJ11 gene may result in gain of function of the ATP- sensitive potassium channels, resulting in impaired depolarization of the β- cell membrane and altered insulin release, although such an effect becomes more apparent when the β cell is under stress conditions (i.e. glucotoxicity).
Many other genes, including HHEXZ/IDE, GIPR, PROX1, DGKB, CDKAL1, SLC30A8, CGK, and CDKN2A/2B, have been associated with abnormal insulin secretion. It is of interest that the majority of the gene variants so far associated with type 2 diabetes exert their main effect on insulin secretion, which worsens significantly with an increase in the two- hour plasma glucose level, even in people with normal glucose tolerance (i.e. two- hour plasma glucose < 140 mg/dl; 7.8 mmol/l). In both lean individuals and those with obesity and two- hour plasma glucose levels of 120–140 mg/dl (6.7–7.8 mmol/l), β- cell function is already reduced by 60% compared with those with a two- hour plasma glucose level of < 100 mg/dl (5.6 mmol/l) (Figure 2). The abnormalities of β- cell function become fully apparent when the insulin- secretion rate is plotted against prevalent plasma glucose levels. This analysis clearly shows how β cells of people with a predisposition to diabetes secrete less insulin than healthy individuals for the same glucose stimulus. This abnormality is often referred to as impaired glucose sensitivity and it is better defined when mathematical modelling approaches are applied.
Fig2. Relationship between the insulin secretion/insulin resistance index (ΔI/ΔG factored by the severity of insulin resistance measured with the euglycaemic insulin clamp) and (a) the fasting plasma glucose (FPG) and (b) the two- hour plasma glucose (two- hour PG) concentration (log–log scale). IGT, impaired glycose tolerance; NGT, normal glucose tolerance; T2DM, type 2 diabetes. Source: Gastaldelli et al. 2004, Figure 12.4. Reproduced with permission of Springer.
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