Abstract
MafA, a recently isolated pancreatic beta-cell-specific transcription factor, is a potent activator of insulin gene transcription. In this study, we show that MafA overexpression, together with PDX-1 (pancreatic and duodenal homeobox factor-1) and NeuroD, markedly increases insulin gene expression in the liver. Consequently, substantial amounts of insulin protein were induced by such combination. Furthermore, in streptozotocin-induced diabetic mice, MafA overexpression in the liver, together with PDX-1 and NeuroD, dramatically ameliorated glucose tolerance, while combination of PDX-1 and NeuroD was much less effective. These results suggest a crucial role of MafA as a novel therapeutic target for diabetes.
Highlights
It is known that the insulin gene is expressed in pancreatic -cells and that insulin plays a crucial role in maintaining blood glucose levels
These results suggest a crucial role of MafA as a novel therapeutic target for diabetes and imply that such combination should be useful for replacing the reduced -cell function found in diabetes
In this study we examined the effects of adenovirus-mediated expression of a recently identified pancreatic -cell-specific transcription factor MafA on insulin gene expression and glucose tolerance with and without pancreatic and duodenal homeobox factor-1 (PDX-1) and/or NeuroD and found that MafA overexpression, together with PDX-1 and NeuroD, drastically induces insulin production in the liver (Figs. 2 and 3) and ameliorates glucose tolerance in diabetic animal models (Fig. 4)
Summary
It is known that the insulin gene is expressed in pancreatic -cells and that insulin plays a crucial role in maintaining blood glucose levels. MafA expression is first detected at the beginning of the principal phase of insulin-producing cell production [4], while other important transcription factors such as the pancreatic and duodenal homeobox factor-1 (PDX-1) (8 –11) and NeuroD [12, 13] are expressed from the early stage of pancreas development While both PDX-1 and NeuroD are expressed in various types of cells in islets, MafA is the only -cell-specific transactivator for the insulin gene. We show that MafA expression in the liver, together with PDX-1 and NeuroD, markedly induces insulin gene transcription and dramatically ameliorates glucose tolerance in diabetic model animals These results suggest a crucial role of MafA as a novel therapeutic target for diabetes and imply that such combination should be useful for replacing the reduced -cell function found in diabetes
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