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


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.
Hao
Mingming
M
Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Head
W Steven
WS
Gunawardana
Subhadra C
SC
Hasty
Alyssa H
AH
Piston
David W
DW
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000494:pharmacology*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000503:physiopathology; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005941:Glucokinase / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D006949:Hyperlipidemias / Q000453:epidemiology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D007515:Islets of Langerhans / Q000503:physiopathology*; D008798:Mevalonic Acid / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052248:Nitric Oxide Synthase Type I / Q000172:deficiency / Q000235:genetics
D005230:Fatty Acids, Nonesterified; D007328:Insulin; D002784:Cholesterol; D052248:Nitric Oxide Synthase Type I; D005941:Glucokinase; D005947:Glucose; D008798:Mevalonic Acid