Genetic and biochemical pathways of beta-cell failure in type 2 diabetes.
We review mechanisms of beta-cell failure in type 2 diabetes. A wealth of information indicates that it is caused by impaired insulin secretion and decreased beta-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 beta-cell mass, largely via increased beta-cell replication. In contrast, following the onset of overt diabetes, there is a slowly progressive loss of beta-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 beta-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 beta-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 beta-cells links insulin secretion with cellular proliferation and survival.
Talchai
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Naomi Berrie Diabetes Center, Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, NY, USA.
Lin
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Kitamura
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Accili
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D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002452:Cell Count; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000503:physiopathology*; D006965:Hyperplasia / Q000235:genetics / Q000503:physiopathology; D007328:Insulin / Q000096:biosynthesis / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics; D007333:Insulin Resistance / Q000502:physiology*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000473:pathology / Q000502:physiology*; D051379:Mice; D015398:Signal Transduction / Q000502:physiology
D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse