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

Summary 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,...

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Bibliographic Details
Published in:	International journal of experimental pathology Vol. 95; no. 4; pp. 296 - 308
Main Authors:	Oliveira, Ricardo B. d., Carvalho, Carolina P. d. F., Polo, Carla C., Dorighello, Gabriel d. G., Boschero, Antônio C., Oliveira, Helena C. F. d., Collares-Buzato, Carla B.
Format:	Journal Article
Language:	English
Published:	England Blackwell Publishing Ltd 01-08-2014 BlackWell Publishing Ltd
Subjects:	Animals Apoptosis - drug effects Beta-cell mass Cell Proliferation - drug effects connexin 36 Connexins - metabolism Diet, High-Fat - adverse effects Dietary Fats - pharmacology Disease Models, Animal Female Gap Junction delta-2 Protein Gap Junctions - metabolism Glucose - metabolism Glucose - pharmacology high-fat diet Hypercholesterolemia - congenital Hypercholesterolemia - etiology Hypercholesterolemia - metabolism Hypercholesterolemia - physiopathology Insulin - metabolism Insulin-Secreting Cells - drug effects Insulin-Secreting Cells - pathology Insulin-Secreting Cells - physiology LDL receptor Male Mice Mice, Inbred C57BL Mice, Knockout Original prediabetes Prediabetic State - etiology Prediabetic State - metabolism Prediabetic State - physiopathology Receptors, LDL - deficiency Receptors, LDL - genetics Receptors, LDL - metabolism connexin 36 Beta-cell mass prediabetes high-fat diet LDL receptor
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Summary:	Summary 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.
Bibliography:	ark:/67375/WNG-LPR61WG4-X FAPESP - No. 2009/52824-1; No. 2010/50789-1 CAPES/PROEX istex:C6B8EB885299FCCCF4E92AE68C67F7A469BD41AA ArticleID:IEP12084 ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 Authors contributed equally to this work.
ISSN:	0959-9673 1365-2613
DOI:	10.1111/iep.12084