Direct effect of cholesterol on insulin secretion: a novel mechanism for pancreatic beta-cell dysfunction.

Hao M, Head WS, Gunawardana SC, Hasty AH, Piston DW
Diabetes. 2007 56 (9): 2328-38

PMID: 17575085 · DOI:10.2337/db07-0056

OBJECTIVE - Type 2 diabetes is often accompanied by abnormal blood lipid and lipoprotein levels, but most studies on the link between hyperlipidemia and diabetes have focused on free fatty acids (FFAs). In this study, we examined the relationship between cholesterol and insulin secretion from pancreatic beta-cells that is independent of the effects of FFAs.

RESEARCH DESIGN AND METHODS - Several methods were used to modulate cholesterol levels in intact islets and cultured beta-cells, including a recently developed mouse model that exhibits elevated cholesterol but normal FFA levels. Acute and metabolic alteration of cholesterol was done using pharmacological reagents.

RESULTS - We found a direct link between elevated serum cholesterol and reduced insulin secretion, with normal secretion restored by cholesterol depletion. We further demonstrate that excess cholesterol inhibits secretion by downregulation of metabolism through increased neuronal nitric oxide synthase dimerization.

CONCLUSIONS - This direct effect of cholesterol on beta-cell metabolism opens a novel set of mechanisms that may contribute to beta-cell dysfunction and the onset of diabetes in obese patients.

MeSH Terms (18)

Animals Cell Survival Cholesterol Diabetes Mellitus, Type 2 Fatty Acids, Nonesterified Glucokinase Glucose Humans Hyperlipidemias Insulin Insulin-Secreting Cells Insulin Secretion Islets of Langerhans Mevalonic Acid Mice Mice, Inbred C57BL Mice, Knockout Nitric Oxide Synthase Type I

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