title: Primary hypercholesterolaemia impairs glucose homeostasis and insulin secretion in low-density lipoprotein receptor knockout mice independently of high-fat diet and obesity.
abstract: 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.
authors.affiliation: Departamento de Anatomia, Biologia Celular, Fisiologia e Biofísica, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil.
authors.forename: Maria Lúcia
authors.initials: ML
authors.lastname: Bonfleur
authors.forename: Emerielle Cristine
authors.initials: EC
authors.lastname: Vanzela
authors.forename: Rosane Aparecida
authors.initials: RA
authors.lastname: Ribeiro
authors.forename: Gabriel
authors.initials: G
authors.lastname: de Gabriel Dorighello
authors.forename: Carolina Prado
authors.initials: CP
authors.lastname: de França Carvalho
authors.forename: Carla Beatriz
authors.initials: CB
authors.lastname: Collares-Buzato
authors.forename: Everardo Magalhães
authors.initials: EM
authors.lastname: Carneiro
authors.forename: Antonio Carlos
authors.initials: AC
authors.lastname: Boschero
authors.forename: Helena Coutinho Franco
authors.initials: HC
authors.lastname: de Oliveira
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D004041:Dietary Fats; D005260:Female; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006706:Homeostasis; D006937:Hypercholesterolemia / Q000378:metabolism* / Q000473:pathology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D007930:Leucine / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity; D010084:Oxidation-Reduction; D011973:Receptors, LDL / Q000502:physiology*; D047392:beta-Cyclodextrins / Q000378:metabolism
chemical_list: D004041:Dietary Fats; D007328:Insulin; D008055:Lipids; D011973:Receptors, LDL; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D002784:Cholesterol; D007930:Leucine; D005947:Glucose