High‐fat diet induces early‐onset diabetes in heterozygous Pax6 mutant mice. Issue 6 (September 2014)

• Record Type: Journal Article
• Authors: Chen, Yuanyuan; Feng, Ruopeng; Wang, Hong; Wei, Rui; Yang, Jin; Wang, Liang; Wang, Haining; Zhang, Lin; Hong, Tian‐pei; Wen, Jinhua; Weng, Jianping; Pozzilli, Paolo
• Is Part Of: Diabetes/metabolism research and reviews. Volume 30:Issue 6(2014:Sep.)
• Page Start: 467
• Page End: 475
• Publication Date: 2014-09
• Subjects: Diabetes -- Periodicals; Metabolism -- Periodicals; 616.642
• DOI: 10.1002/dmrr.2572
• Languages: English
• ISSNs: 1520-7552

Abstract

<abstract abstract-type="main"> <title>Abstract</title> <sec id="dmrr2572-sec-0001" sec-type="section"> <title>Background</title> <p>Type 2 diabetes is caused by interactions between genetic and environmental factors. Our previous studies reported that paired box 6 mutation heterozygosity (<italic>Pax6</italic><sup><italic>m</italic>/+</sup>) led to defective proinsulin processing and subsequent abnormal glucose metabolism in mice at 6 months of age. However, high‐fat diet exposure could be an important incentive for diabetes development. In this study, we aimed to develop a novel diabetic model imitating human type 2 diabetes by exposing <italic>Pax6</italic><sup><italic>m</italic>/+</sup> mice to high‐fat diet and to explore the underlying mechanism of diabetes in this model.</p> </sec> <sec id="dmrr2572-sec-0002" sec-type="section"> <title>Methods</title> <p>Over 300 <italic>Pax6</italic><sup><italic>m</italic>/+</sup> and wild‐type male weanling mice were randomly divided into two groups and were fed an high‐fat diet or chow diet for 6–10 weeks. Blood glucose and glucose tolerance levels were monitored during this period. Body weights, visceral adipose weights, blood lipid profiles and insulin sensitivity (determined with an insulin tolerance test) were used to evaluate obesity and insulin resistance. Proinsulin processing and insulin secretion levels were used to evaluate pancreatic <italic>β</italic> cell function.</p> </sec> <sec id="dmrr2572-sec-0003" sec-type="section"> <title>Results</title> <p>After 6 weeks of high‐fat diet exposure, only the <italic>Pax6</italic><sup><italic>m</italic>/+</sup> mice showed dramatic postloading hyperglycaemia. These mice exhibited significant high‐fat diet‐induced visceral obesity and insulin resistance and displayed defective prohormone convertase 1/3 production, an increased proinsulin:total insulin ratio and impaired early‐phase insulin secretion, because of the <italic>Pax6</italic> mutation. Hyperglycaemia worsened progressively over time with the high‐fat diet, and most <italic>Pax6</italic><sup><italic>m</italic>/+</sup> mice on high‐fat diet developed diabetes or impaired glucose tolerance after 10 weeks. Furthermore, high‐fat diet withdrawal partly improved blood glucose levels in the diabetic mice.</p> </sec> <sec id="dmrr2572-sec-0004" sec-type="section"> <title>Conclusions</title> <p>By combining the <italic>Pax6</italic><sup><italic>m</italic>/+</sup> genetic background with an high‐fat diet environment, we developed a novel diabetic model to mimic human type 2 diabetes. This model is characterized by impaired insulin secretion, caused by the <italic>Pax6</italic> mutation, and high‐fat diet‐induced insulin resistance and therefore provides an ideal tool for research on type 2 diabetes pathogenesis and therapies. Copyright © 2014 John Wiley & Sons, Ltd.</p> </sec> </abstract>