Elucidation of mechanism for diabetogenesis in Wistar Fatty rats

Wistar Fatty 大鼠糖尿病发生机制的阐明

• 批准号: 04671483
• 负责人: MATSUTANI Akira
• 金额: $ 1.28万
• 依托单位: Yamaguchi University, School of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1992
• 资助国家: 日本
• 起止时间: 1992 至 1993
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-04671483/
• 关键词: Wistar Fatty rats; NIDDM; glucokinase; AD-4833; 6Phosphofructo-2-kinase; PEPCK; 6Phosphofructo-2-kinase; WFラット; AD-4833; 肥満; グルコキナーゼ(GK); 6-フォスフォフルクト-2-キナーゼ; 高インスリン血症

In the first year, whether hyperglycemia and hyperinsulinemia in Wistar Fatty rats are associated with disturbed expression of glucokinase(GK), 6phosphofructo-2-kinae(PFK2) and PEPCK genes was examined. Either activities or mRNA levels of GK, PFK2 and PEPCK were not significantly different between Wistar Fatty rats and their littermates, Witar Lean rats. Next, the effects of AD-4833, which, reportedly, enhances the insulin response, on the expression of GK, PFK2 and PEPCK genes in liver, and intermediates levels in blood were studied in Wistar Fatty rats. AD-4833 treatment resulted in the decrease of blood sugar and insulin levels, but expression of GK, PFK2 and PEPCK genes was not changed. In contrast, intermediate levels were affected by this drug. Glycerol levels were decreased, and lactate and pyruvate levels were increased. Taken these, the mechanisms to cause hyperglycemia in Wistar Fatty rats do not seem to be gene defects ofk GK, PFK2 or PEPCK.Mechanisms of AD-4833 do not seem to be the effects on these enzymes, either. In the next year, the effect of AD-4833 on the insulin-stimulated glucose transport activity in adipocytes isolated from Wistar Fatty rats was studied. This experiment is still in progress. Human genetic factors to cause NIDDM were also sutdied in pararell with the study in animal model. Islet promotor region was studied regarding the association with NIDDM.Consequently, sequence variants were found, which resulted in defects of promotor activities. The physiological significance of this promotor variants are now being studied. The possibilitiy of GK promotor defect as the cause of hyperglycemia in Wistar Fatty rats are also planned to be studied.

在第一年，检测了Wistar肥胖大鼠的高血糖和高胰岛素血症是否与葡萄糖激酶（GK）、6-磷酸果糖-2-激酶（PFK 2）和PEPCK基因表达紊乱有关。GK、PFK 2和PEPCK的活性和mRNA水平在Wistar Fatty大鼠和同窝Witar Lean大鼠之间均无显著差异。接下来，在Wistar肥胖大鼠中研究了AD-4833（据报道其增强胰岛素应答）对肝脏中GK、PFK 2和PEPCK基因表达以及血液中中间水平的影响。AD-4833处理导致血糖和胰岛素水平降低，但GK、PFK 2和PEPCK基因表达没有改变。相比之下，中间水平受到这种药物的影响。甘油水平降低，乳酸和丙酮酸水平升高。由此可见，引起Wistar Fatty大鼠高血糖的机制似乎不是k GK、PFK 2或PEPCK的基因缺陷，AD-4833的作用机制似乎也不是对这些酶的影响。在接下来的一年中，研究了AD-4833对从Wistar肥胖大鼠分离的脂肪细胞中胰岛素刺激的葡萄糖转运活性的影响。这项实验仍在进行中。在动物模型研究的同时，还探讨了人类遗传因素对NIDDM发病的影响。对胰岛启动子区与NIDDM的关系进行了研究，发现了导致启动子活性缺陷的序列变异。目前正在研究这种启动子变体的生理意义。GK启动子缺陷作为Wistar肥胖大鼠高血糖症原因的可能性也计划进行研究。

项目成果

Akira Matsutani, Rachel Janssen, Helen Donis-Keller, and M.Alan Permutt.: "Polymophic (CA)n Repeat Element Maps the Human Glucokinase Gene (GCK) to Chromosome 7p" Genomics 12. 319-325 (1992)

Akira Matsutani、Rachel Janssen、Helen Donis-Keller 和 M.Alan Permutt.：“多态性 (CA)n 重复元件将人类葡萄糖激酶基因 (GCK) 映射到染色体 7p” Genomics 12. 319-325 (1992)

Akira Matsutani: "A Polymorphic(CA)n Repeat Element Maps the Human Glucokinase Gene(GCK)to Chromosome 7P." Genomics. 12. 319-325 (1992)

Akira Matsutani：“多态性 (CA)n 重复元件将人类葡萄糖激酶基因 (GCK) 映射到 7P 染色体。”

Yukio Tanizawa, Akira Matsutani, Ken C.Chiu, and M.Alan Permutt: "Human Glucokinase Gene : Isolation, Structural Characterization, and Identification of a Microsatellite Repeat Polymorphism" Molecular Endocrinology 6. 1070-1081 (1992)

Yukio Tanizawa、Akira Matsutani、Ken C.Chiu 和 M.Alan Permutt：“人类葡萄糖激酶基因：微卫星重复多态性的分离、结构表征和鉴定”分子内分泌学 6. 1070-1081 (1992)

Akira Matsutani: "Insulin Resistance in Human Disease.Evaluation of glucokinase gene in Japanese NIDDM." Huh KB,Sinn SH,Kaneko T 編,Elsevier Science Publishers B.V., 412 (1993)

Akira Matsutani：“人类疾病中的胰岛素抵抗。日本 NIDDM 中葡萄糖激酶基因的评估。”Huh KB、Sinn SH、Kaneko T 编辑，Elsevier Science Publishers B.V.，412 (1993)

Yukio Tanizawa: "Human Glucokinase Gene:Isolation,Structual characterization and Identification of a Microzatellite Repeat Polymorphism." Molecular Endocrindogy. 6. 1070-1081 (1992)

Yukio Tanizawa：“人类葡萄糖激酶基因：微卫星重复多态性的分离、结构表征和鉴定。”