1999 Fiscal Year Final Research Report Summary
Investigation of transcription factors involved in the β-cell glucose toxicity
| Project/Area Number |
10671071
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Metabolomics
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| Research Institution | Osaka University |
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Principal Investigator |
KAJIMOTO Yoshitaka Osaka University Medical School, Assistant Professor, 医学系研究科, 助手 (60301256)
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| Co-Investigator(Kenkyū-buntansha) |
MATSUHISA Munehide Osaka University Hospital, Medical Staff, 医学部附属病院, 医員
YAMASAKI Yoshimitsu Osaka University Medical School, Associate Professor, 医学系研究科, 助教授 (40201834)
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| Project Period (FY) |
1998 – 1999
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| Keywords | type 2 diabetes / transcription factor / glucose toxicity / antioxidant / insulin gene |
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| Research Abstract |
In general, the development of type 2 diabetes is associated with pancreatic β-cell dysfunction occurring together with insulin resistance. Normal β-cells can compensate for insulin resistance by increasing insulin secretion, but insufficient compensation leads to the onset of glucose intolerance. Once hyperglycemia becomes apparent, the β-cell function progressively deteriorates : glucose-induced insulin secretion becomes further impaired and degranulation of β-cells becomes evident, often accompanied by a decrease in the number of β-cells.
Oxidative stress is produced under diabetic conditions and possibly causes various tissue damage in patients of diabetes. The aim of this study was to examine the involvement of oxidative stress in the progression of pancreatic β-cell dysfunction in type 2 diabetes and also to evaluate the potential usefulness of antioxidants in treatment of type 2 diabetes. We used diabetic C57BL/KsJ-db/db mice, in whom antioxidant treatment (N-acetyl-L-cysteine (N
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AC) and/or vitamin C plus E) was started at 6 weeks of age and its effects were evaluated at 10 and 16 weeks of age. According to an intraperitoneal glucose tolerance test, the treatment with NAC retained glucose-stimulated insulin secretion and moderately decreased blood glucose levels. Vitamin C and E were not effective when used alone but slightly effective when used in combination with NAC. No effect on insulin secretion was observed when the same set of antioxidants was given to non-diabetic control mice. Histological analyses of the pancreata revealed that the β-cell mass is significantly larger in the mice treated with the antioxidants. As possible cause of this, the antioxidant treatment suppressed apoptosis in β-cells without changing the rate of β-cell proliferation, supporting the hypothesis that oxidative stress-induced apoptosis causes reduction of β-cell mass due to chronic hyperglycemia. The antioxidant treatment also preserved the amounts of insulin content and insulin mRNA, making the extent of insulin degranulation less evident. Furthermore, expression of pancreatic and duodenal homeobox factor-1 (also known as IDX-1/STF-1/IPF1), a β-cell specific transcription factor was more clearly visible in the nuclei of islet cells after the antioxidant treatment. In conclusion, our present observations indicated that antioxidant treatment can exert beneficial effects for diabetes with preservation of in vivo β-cell function. This suggests a potential usefulness of antioxidants for diabetes and provides further support for the implication of oxidative stress in β-cell dysfunction in diabetes. Less
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Research Products
(8 results)
