Glucolipotoxicity of the pancreatic β-cell: myth or reality?
- 19 September 2008
- journal article
- review article
- Published by Portland Press Ltd. in Biochemical Society Transactions
- Vol. 36 (5), 901-904
- https://doi.org/10.1042/bst0360901
Abstract
The glucolipotoxicity hypothesis postulates that chronically elevated levels of glucose and fatty acids adversely affect pancreatic β-cell function and thereby contribute to the deterioration of insulin secretion in Type 2 diabetes. Whereas ample experimental evidence in in vitro systems supports the glucolipotoxicity hypothesis, the contribution of this phenomenon to β-cell dysfunction in human Type 2 diabetes has been questioned. The reasons for this controversy include: differences between in vitro systems and in vivo situations; time-dependent effects of fatty acids on insulin secretion (acutely stimulatory and chronically inhibitory); and the ill-defined use of the suffix ‘-toxicity’. In vitro, prolonged exposure of insulin-secreting cells or isolated islets to concomitantly elevated levels of fatty acids and glucose impairs insulin secretion, inhibits insulin gene expression and, under certain circumstances, induces β-cell death by apoptosis. Recent studies in our laboratory have shown that cyclical and alternate infusions of glucose and Intralipid in rats impair insulin gene expression, providing evidence that inhibition of the insulin gene under glucolipotoxic conditions is an early defect that might indeed contribute to β-cell failure in Type 2 diabetes, although this hypothesis remains to be tested in humans.Keywords
This publication has 31 references indexed in Scilit:
- Glucolipotoxicity: Fuel Excess and β-Cell DysfunctionEndocrine Reviews, 2008
- Cyclical and Alternating Infusions of Glucose and Intralipid in Rats Inhibit Insulin Gene Expression and Pdx-1 Binding in IsletsDiabetes, 2008
- Effects on insulin secretion and insulin action of a 48-h reduction of plasma free fatty acids with acipimox in nondiabetic subjects genetically predisposed to type 2 diabetesAmerican Journal of Physiology-Endocrinology and Metabolism, 2007
- Lipid-induced β-cell dysfunction in vivo in models of progressive β-cell failureAmerican Journal of Physiology-Endocrinology and Metabolism, 2007
- Islet cell failure in type 2 diabetesJCI Insight, 2006
- Palmitate Inhibits Insulin Gene Expression by Altering PDX-1 Nuclear Localization and Reducing MafA Expression in Isolated Rat Islets of LangerhansOnline Journal of Public Health Informatics, 2005
- Palmitate Inhibition of Insulin Gene Expression Is Mediated at the Transcriptional Level via Ceramide SynthesisOnline Journal of Public Health Informatics, 2003
- Glucose and Insulin Stimulate Heparin-releasable Lipoprotein Lipase Activity in Mouse Islets and INS-1 CellsOnline Journal of Public Health Informatics, 2001
- Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)The Lancet, 1998
- Interactions of long-chain fatty acids and albumin: Determination of free fatty acid levels using the fluorescent probe ADIFABBiochemistry, 1993