Genetic and biochemical pathways of β‐cell failure in type 2 diabetes

Abstract

We review mechanisms of β-cell failure in type 2 diabetes. A wealth of information indicates that it is caused by impaired insulin secretion and decreased β-cell mass. Interestingly, there appears to be a link between these two mechanisms. The earliest reaction to peripheral insulin resistance is an increase in insulin production, owing primarily to increased secretion, and to a lesser extent to decreased clearance. Experimental animal models indicate that hyperinsulinaemia promotes an increase in β-cell mass, largely via increased β-cell replication. In contrast, following the onset of overt diabetes, there is a slowly progressive loss of β-cell function and mass, both in animal models and in diabetic humans. It is of great interest that most diabetes-associated genes identified in genome-wide association studies appear to be enriched in the β-cell and to have the potential to regulate mass and/or function. Here, we review evidence derived from experimental animal models to unravel the mechanisms underlying β-cell dysfunction. We focus primarily on signalling pathways, as opposed to nutrient sensing, and specifically on the notion that insulin and growth factor signalling via Foxo1 in pancreatic β-cells links insulin secretion with cellular proliferation and survival.

Metabolic Inflexibility Impairs Insulin Secretion and Results In MODY-like Diabetes in Triple FoxO-Deficient Mice

“…We have proposed that, as they rapidly respond to the β-cell’s nutritional state, FoxO are better positioned to translate the latter into an appropriate transcriptional programa than other transcription factors that don’t respond as nimbly to changes in glucose, lipid, and hormone levels. (Talchai et al, 2009) If the stress persists, FoxO levels drop through deacetylation-induced degradation that prevents the normal autoregulatory loop of FoxO expression (Kitamura et al, 2005; Talchai et al, 2012a). We now report that the loss of all three FoxO (likely through similar mechanisms) impairs the homeostatic MODY-related gene network, and activates Pparα-dependent lipid oxidative pathways, possibly resulting in increased supply of fatty acyl-derived acetyl-CoA for mitochondrial oxidation.…”

High glucose and free fatty acids induce beta cell apoptosis via autocrine effects of ADP acting on the P2Y13 receptor

“…While chronic exposure to high levels of glucose or free fatty acids is well known to have detrimental effects on beta cell function and survival [1,2,13], the mechanisms leading to initiation of the cell death program are complex, and the details remain to be clarified. In a previous study, we showed that stimulation of purinergic P2Y 13 receptors on beta cells activates apoptotic pathways [6].…”

“…Elevated glucose and increased FFA have been shown to trigger pancreatic beta cell loss and dysfunction in type 2 diabetes [1], and increasing evidences demonstrate that longterm exposure to high glucose or FFA generates peripheral insulin resistance, both in vivo and in vitro resulting in pancreatic stress and increased susceptibility to beta cell apoptosis and, as a consequence, suppression of insulin secretion [2]. Although the overall picture is known, the detailed mechanisms underlying these effects are only partially understood.…”

Regulation of forkhead box O1 (FOXO1) by protein kinase B and glucocorticoids: different mechanisms of induction of beta cell death in vitro

“…The underlying mechanism of glucocorticoidinduced beta cell dysfunction is not well understood. Many observations point to a crucial role of the transcription factor forkhead box O1 (FOXO1) in beta cell failure [5]. However, the role of FOXO1 in the maintenance of beta cell function and appropriate beta cell mass is controversial [6].…”