glucose metabolism in pancrateic beta-cell via circadian clock genes DBP and E4BP4

2016 Fiscal Year Final Research Report

• Project/Area Number: 26460489
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Yamaguchi University
• Principal Investigator: OHTA Yasuharu 山口大学, 医学部, 准教授(寄附講座等) (60448280)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: 体内時計 / 時計遺伝子 / インスリン分泌 / 2型糖尿病

Outline of Final Research Achievements

In Wfs1-/- Ay/a islets, Dbp expression decreased and E4bp4 expression increased, leading to reduced DBP transcriptional activity. Transgenic mice expressing E4BP4 under the control of the mouse insulin Ⅰ gene promoter (MIP), in which E4BP4 in β-cells is expected to compete with DBP for D-box, displayed remarkable glucose intolerance with severely impaired insulin secretion. Basal ATP/ADP ratios in MIP-E4BP4 islets were elevated without the circadian oscillations observed in wild-type islets. Neither elevation of the ATP/ADP ratio nor an intracellular Ca2+ response was observed after glucose stimulation. RNA expressions of genes involved in insulin secretion gradually increase in wild-type islets early in the feeding period. In MIP-E4BP4 islets, however, these increases were not observed. Molecular clock output DBP transcriptional activity, susceptible to ER stress, plays pivotal roles in β-cell priming for insulin release by regulating β-cell metabolism and gene expressions.

Free Research Field

糖尿病学