Impaired compensatory beta-cell function and growth in response to high-fat diet in LDL receptor knockout mice.
In this study, we investigated the effect of low density lipoprotein receptor (LDLr) deficiency on gap junctional connexin 36 (Cx36) islet content and on the functional and growth response of pancreatic beta-cells in C57BL/6 mice fed a high-fat (HF) diet. After 60 days on regular or HF diet, the metabolic state and morphometric islet parameters of wild-type (WT) and LDLr-/- mice were assessed. HF diet-fed WT animals became obese and hypercholesterolaemic as well as hyperglycaemic, hyperinsulinaemic, glucose intolerant and insulin resistant, characterizing them as prediabetic. Also they showed a significant decrease in beta-cell secretory response to glucose. Overall, LDLr-/- mice displayed greater susceptibility to HF diet as judged by their marked cholesterolaemia, intolerance to glucose and pronounced decrease in glucose-stimulated insulin secretion. HF diet induced similarly in WT and LDLr-/- mice, a significant decrease in Cx36 beta-cell content as revealed by immunoblotting. Prediabetic WT mice displayed marked increase in beta-cell mass mainly due to beta-cell hypertrophy/replication. Nevertheless, HF diet-fed LDLr-/- mice showed no significant changes in beta-cell mass, but lower islet-duct association (neogenesis) and higher beta-cell apoptosis index were seen as compared to controls. The higher metabolic susceptibility to HF diet of LDLr-/- mice may be explained by a deficiency in insulin secretory response to glucose associated with lack of compensatory beta-cell expansion.
Department of Histology and Embryology, University of Campinas (UNICAMP), Campinas, SP, Brazil.
Ricardo B
RB
d Oliveira
Carolina P d F
CP
Carvalho
Carla C
CC
Polo
Gabriel d G
Gd
Dorighello
Antônio C
AC
Boschero
Helena C F
HC
d Oliveira
Carla B
CB
Collares-Buzato
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D017630:Connexins / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D004041:Dietary Fats / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D017629:Gap Junctions / Q000378:metabolism; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006937:Hypercholesterolemia / Q000151:congenital / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000473:pathology* / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011236:Prediabetic State / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D000097004:Gap Junction delta-2 Protein
D017630:Connexins; D004041:Dietary Fats; D005947:Glucose; D007328:Insulin; D011973:Receptors, LDL; D000097004:Gap Junction delta-2 Protein
Beta-cell mass; LDL receptor; connexin 36; high-fat diet; prediabetes