| Budget Amount *help |
¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000)
Fiscal Year 2011: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2010: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
Fiscal Year 2009: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
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| Research Abstract |
It has been known that type 2 diabetes is caused by not only the dysfunction of pancreatic beta cells but also the dysfunction of alpha cells. However, it is still unclear how alpha cell dysfunction occurs. Previous studies revealed that transcription factor FoxO1 and ATF3 regulats proglucagon promoter activity. Therefore we attempted in this study to elucidate the physiological roles of FoxO1 and ATF3 in pancreatic alpha cells by generating alpha cell specific FoxO1 or ATF3 knockout mice. However, due to the low efficiency of cre expression in alpha cells, we couldn't see any metabolic phenotype in these mice. So, we next generated alpha cell specific FoxO1 knockin (a-FoxO1 KI) mice by using Rosa26 system. In this system, upon cre expression, stop cassette removed and then FoxO1 expression is induced by endogenous Rosa26 promoter. We confirmed alpha cell-specific expression of FoxO1 in these mice. Interestingly a-FoxO1 KI mice showed higher fed blood glucose levels than control mice,
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which was accompanied with higher plasma glucagon levels. Glucose tolerance test showed impaired glucose tolerance in these mice. We concluded that FoxO1 is a key regulator of glucagon gene expression in alpha cells and contribute to the regulation of glucose metabolism in vivo. On the other hand, with respect to ATF3, we crossed ATF3 flox mice with Pdx1-cre mice, in which cre is expressed in both pancreas and hypothalamus, and generate pancreas-and hypothalamus-specific ATF3 knockout mice (PHT-ATF3-KO). We found that PHT-ATF3-KO mice lean due to decreased food intake and increased energy expenditure, which leads to increased insulin sensitivity and better glucose tolerance. We also revealed that hypothalamic ATF3 regulates Agrp transcription via interacting with FoxO1 on the Agrp promoter. Therefore, ATF3 in the hypothalamus plays an important role in the regulation of glucose and energy metabolism. However, we couldn't see any change in plasma glucagon and plasma insulin levels. Also, there was no change in glucose responsive glucagon or insulin secretion from islets isolated from PHT-ATF3-KO mice. Furthermore, there was no difference in beta cell mass and alpha cell mass in these mice compared to the control mice. Therefore, we concluded that the physiological role of ATF3 in pancreas is not so significant. Less
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