Impaired compensatory beta-cell function and growth in response to high-fat diet in LDL receptor knockout mice

Author(s)

d Oliveira, Ricardo B. ^[1] ; Carvalho, Carolina P. d. F. ^{[2, 1]} ; Polo, Carla C. ^[1] ; Dorighello, Gabriel d. G. ^[3] ; Boschero, Antonio C. ^[3] ; d Oliveira, Helena C. F. ^[3] ; Collares-Buzato, Carla B. ^[1]

Affiliation

^[1] Univ Campinas UNICAMP, Dept Histol & Embryol, BR-13083970 Campinas, SP - Brazil

^[2] Univ Fed Sao Paulo, Dept Biosci, Santos, SP - Brazil

^[3] Univ Campinas UNICAMP, Inst Biol, Dept Struct & Funct Biol, BR-13083970 Campinas, SP - Brazil

• Document type: Journal article
• Source: International Journal of Experimental Pathology; v. 95, n. 4, p. 296-308, AUG 2014.
• Web of Science Citations: 10

Abstract

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. (AU)

• FAPESP's process: 10/50789-1 - Role of cell-cell contacts mediated by intercellular junctions and their constitutive proteins in the functional maturation and dysfunction of pancreatic beta cells
• Grantee: Carla Beatriz Collares Buzato
• Support Opportunities: Regular Research Grants
• FAPESP's process: 09/52824-1 - Pancreatic B-cell proliferation and differentiation in animal models of insulin resistance: involvement of the Wnt/beta-catenina signaling pathway
• Grantee: Carla Beatriz Collares Buzato
• Support Opportunities: Regular Research Grants