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

• Published in: Biochimica et biophysica acta 2010-02, Vol.1801 (2), p.183-190
• Main Authors: Bonfleur, Maria Lúcia, Vanzela, Emerielle Cristine, Ribeiro, Rosane Aparecida, de Gabriel Dorighello, Gabriel, de França Carvalho, Carolina Prado, Collares-Buzato, Carla Beatriz, Carneiro, Everardo Magalhães, Boschero, Antonio Carlos, de Oliveira, Helena Coutinho Franco
• Format: Article
• Language: English
• Subjects: Animals; beta-Cyclodextrins - metabolism; Cholesterol; Cholesterol - metabolism; Dietary Fats; Female; Glucose - metabolism; Glucose homeostasis; Glucose Tolerance Test; Homeostasis; Hypercholesterolaemia; Hypercholesterolemia - metabolism; Hypercholesterolemia - pathology; Insulin - metabolism; Insulin Secretion; Islets of Langerhans - metabolism; LDL receptor; Leucine - metabolism; Lipids - blood; Male; Mice; Mice, Knockout; Obesity; Oxidation-Reduction; Pancreatic islet; Receptors, LDL - physiology
• ISSN: 1388-1981; 0006-3002; 1879-2618
• DOI: 10.1016/j.bbalip.2009.10.012

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 glucose-stimulated 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.