The relation between the impaired islet microcirculation and diabetes

2004 Fiscal Year Final Research Report Summary

• Project/Area Number: 14370341
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Metabolomics
• Research Institution: JUNTENDO UNIVERSITY
• Principal Investigator: KAWAMORI Ryuzo Juntendo University, School of Medicine, Professor, 医学部, 教授 (00116021)
• Co-Investigator(Kenkyū-buntansha): WATADA Hirotaka Juntendo University, School of Medicine, Lecturer, 医学部, 講師 (60343480) ; TANAKA Yasuhi Juntendo University, School of Medicine, Associate Professor, 医学部, 助教授 (40276499) ; INOUE Masahiro Osaka Medal Center In Cancer and Cardiovascular Disease, Chief director, 部長 (10342990) ; HASHIZUME Hiroya Niigata University, School of Medicine, Lecturer, 大学院・医歯学総合研究科, 講師 (90261289)
• Project Period (FY): 2002 – 2004
• Keywords: Pancreatic β cell / Pancreatic microcirculation / Diabetes Mellitus / VEGF-A / Cre recombinase / Insulin

Research Abstract

Altered regulation of insulin secretion and islet mass is characteristic of individuals with type 2 diabetes. While many previous studies reported the importance of several factors in b cells, there have been no clear studies showing the importance of islet vasculature in b cell function. In the present study, using the mice with disrupted VEGF-A gene specifically in b cells (RIP-Cre : Vegf^<fl/fl>) as model of impaired islet vasculature, we elucidated the relation between b cell function and islet vasculature. Electromicroscopic and immunohistochemical analysis identified reduced vascularization with the impaired formation of fenestrae and the increase in caveolae in endothelial cells in RIP-Cre : Vegf^<fl/fl> islets. While fasting glucose and body weight of RIP-Cre : Vegf^<fl/fl> mice were similar to control RIP-Cre and Vegf^<fl/fl> mice, RIP-Cre : Vegf^<fl/fl> mice exhibited impaired glucose tolerance with the decrease in rapid insulin release. However, glucose responsive insulin release assessed by batch incubation and perifusion studies using isolated islets from RLP-Cre : Vegf^<fl/fl> mice were not impaired. High fat diet for 12 weeks markedly deteriorated glucose tolerance and fasting glucose level in RIP-Cre : Vegf^<fl/fl> mice compared with control mice. However, high-fat-fed RIP-Cre : Vegf^<fl/fl> mice showed significant increase in islet mass compared with high-fat-fed control mice. Isolated islets from high-fat-fed RIP-Cre : Vegf^<fl/fl> mice exhibited enhanced glucose responsive insulin secretion. In summary, impaired rapid insulin release into blood stream observed in RIP-Cre : Vegf^<fl/fl> mice is due to abnormal quality and quantity of blood vessels in the islet, not due to the defect in β cells. With the existence of insulin resistance caused by high fat diet, these mice develop to diabetes without the failure of the regulation of islet mass.