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 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.
Bonfleur
Maria Lúcia
ML
Departamento de Anatomia, Biologia Celular, Fisiologia e Biofísica, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil.
Vanzela
Emerielle Cristine
EC
Ribeiro
Rosane Aparecida
RA
de Gabriel Dorighello
Gabriel
G
de França Carvalho
Carolina Prado
CP
Collares-Buzato
Carla Beatriz
CB
Carneiro
Everardo Magalhães
EM
Boschero
Antonio Carlos
AC
de Oliveira
Helena Coutinho Franco
HC
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
D004041:Dietary Fats; D007328:Insulin; D008055:Lipids; D011973:Receptors, LDL; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D002784:Cholesterol; D007930:Leucine; D005947:Glucose