β-Cell Failure in Type 2 Diabetes: Postulated Mechanisms and Prospects for Prevention and Treatment
Open Access
- 1 June 2014
- journal article
- review article
- Published by The Endocrine Society in Journal of Clinical Endocrinology & Metabolism
- Vol. 99 (6), 1983-1992
- https://doi.org/10.1210/jc.2014-1425
Abstract
OBJECTIVE: This article examines the foundation of β-cell failure in type 2 diabetes (T2D) and suggests areas for future research on the underlying mechanisms that may lead to improved prevention and treatment. RESEARCH DESIGN AND METHODS: A group of experts participated in a conference on 14–16 October 2013 cosponsored by the Endocrine Society and the American Diabetes Association. A writing group prepared this summary and recommendations. RESULTS: The writing group based this article on conference presentations, discussion, and debate. Topics covered include genetic predisposition, foundations of β-cell failure, natural history of β-cell failure, and impact of therapeutic interventions. CONCLUSIONS: β-Cell failure is central to the development and progression of T2D. It antedates and predicts diabetes onset and progression, is in part genetically determined, and often can be identified with accuracy even though current tests are cumbersome and not well standardized. Multiple pathways underlie decreased β-cell function and mass, some of which may be shared and may also be a consequence of processes that initially caused dysfunction. Goals for future research include to 1) impact the natural history of β-cell failure; 2) identify and characterize genetic loci for T2D; 3) target β-cell signaling, metabolic, and genetic pathways to improve function/mass; 4) develop alternative sources of β-cells for cell-based therapy; 5) focus on metabolic environment to provide indirect benefit to β-cells; 6) improve understanding of the physiology of responses to bypass surgery; and 7) identify circulating factors and neuronal circuits underlying the axis of communication between the brain and β-cells.Keywords
This publication has 86 references indexed in Scilit:
- Identification of CpG-SNPs associated with type 2 diabetes and differential DNA methylation in human pancreatic isletsDiabetologia, 2013
- Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypesDiabetologia, 2012
- DNA methylation profiling identifies epigenetic dysregulation in pancreatic islets from type 2 diabetic patientsThe EMBO Journal, 2012
- Beta cell function following 1 year vildagliptin or placebo treatment and after 12 week washout in drug-naive patients with type 2 diabetes and mild hyperglycaemia: a randomised controlled trialDiabetologia, 2011
- Insulin promoter DNA methylation correlates negatively with insulin gene expression and positively with HbA1c levels in human pancreatic isletsDiabetologia, 2010
- Global Epigenomic Analysis of Primary Human Pancreatic Islets Provides Insights into Type 2 Diabetes Susceptibility LociCell Metabolism, 2010
- Finding the missing heritability of complex diseasesNature, 2009
- Glucolipotoxicity of the pancreatic beta cellBiochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 2009
- Epigenetic regulation of PPARGC1A in human type 2 diabetic islets and effect on insulin secretionDiabetologia, 2008
- A pancreatic islet-specific microRNA regulates insulin secretionNature, 2004