Primary hypercholesterolaemia impairs glucose homeostasis and insulin secretion in low-density lipoprotein receptor knockout mice independently of high-fat diet and obesity

We investigated whether primary hypercholesterolaemia per se affects glucose homeostasis and insulin secretion in low-density lipoprotein receptor knockout mice (LDLR-/-). Glucose plasma levels were increased and insulin decreased in LDLR-/- compared to the wild-type mice. LDLR-/- mice presented impaired glucose tolerance, but normal whole body insulin sensitivity. The dose-response curve of glucose-stimulated insulin secretion was shifted to the right in LDLR-/- islets. Significant reductions in insulin secretion in response to L-leucine or 2-ketoisocaproic acid were also observed in LDLR-/-. Islet morphometric parameters, total insulin and DNA content were similar in both groups. Glucose uptake and oxidation were reduced in LDLR-/- islets. Removal of cholesterol from LDLR-/- islets corrected glucos-estimulated insulin secretion. These results indicate that enhanced membrane cholesterol content due to hypercholesterolaemia leads to a lower insulin secretion and glucose intolerance without affecting body insulin sensitivity. This represents an additional risk factor for diabetes and atherosclerosis in primary hypercholesterolaemia. (C) 2009 Elsevier B.V. All rights reserved.