Scientists use transcription factors to increase insulin production in diabetic mice

A group of Japanese scientists has used gene therapy to deliver three insulin transcription factors, MafA, PDX-1, and NeuroD, to the livers of diabetic mice. As a result, the mice experienced an increase in insulin gene expression and insulin production, raising the possibility that this could eventually be used to treat diabetes.

The research appears as the "Paper of the Week" in the April 15 issue of the Journal of Biological Chemistry, an American Society for Biochemistry and Molecular Biology journal.

Diabetes, which is marked by high blood-sugar levels, results when the body is unable to produce a sufficient amount of insulin or when it is unable to use insulin properly. There are several ways to restore normal blood sugar levels, including administration of insulin or pancreas and islet transplantation. However, the former involves daily injections and the latter requires life-long immunosuppressive therapy and is limited by tissue supply.

An alternative way to increase the amount of insulin circulating in the body is to enhance insulin gene transcription which in turn results in an increase in the production of insulin. One possible way to do this is by increasing the body's production of transcription factors, the molecules that are in charge of turning gene transcription on and off.

Dr. Hideaki Kaneto, of the Osaka University Graduate School of Medicine, and his colleagues did just that and over-expressed the insulin transcription factors MafA, PDX-1, and NeuroD in the liver of mice. The researchers did this by inserting the transcription factors into adenovirus and then injecting the adenovirus into the cervical vein of the mice. Each transcription factor was detected only in the liver and not in other tissues after infection with the adenovirus. The result was that the mice had a marked increase in insulin gene expression and therefore insulin production.

The researchers also discovered that overexpression of these three transcription factors in the livers of diabetic mice dramatically ameliorated glucose tolerance in these animals. "Glucose tolerance is a capacity to maintain normal glucose levels in our body," explains Dr. Kaneto. "Under normal conditions, insulin is released from pancreatic beta-cells after glucose load. The released insulin facilitates glucose uptake into peripheral tissues such as muscle and fat and suppresses glucose production in the liver in order to maintain glucose tolerance. In contrast, under diabetic conditions, beta-cell dysfunction and insulin resistance are often observed, which disturbs glucose tolerance."

PDX-1 and NeuroD are transcription factors that are found in the pancreas. They play a crucial role in pancreas development and beta-cell differentiation and also maintain normal beta-cell function by regulating several beta-cell-related genes including insulin. While these two transcription factors contributed to the increase in insulin gene expression, MafA was the most important molecule in this study. The researchers discovered that a combination of only PDX-1 and NeuroD was much less effective at increasing insulin production than all three transcription factors together.

"MafA, a recently isolated transcription factor, is expressed only in pancreatic beta-cells and is very important for insulin gene expression," notes Dr. Kaneto. "In this study, we show that MafA overexpression, together with some other pancreatic factors, markedly increases insulin gene expression in the liver, and dramatically decreases blood glucose levels in diabetic mice. These results suggest a crucial role of MafA as a novel therapeutic target for diabetes."

Although this technique is successful in mice, adenovirus cannot be used to deliver genes into humans. Thus, it will be necessary to modify the vector or to develop some other technique to deliver the transcription factor genes into humans.

The Journal of Biological Chemistry's Papers of the Week is an online feature which highlights the top one percent of papers received by the journal. Brief summaries of the papers and explanations of why they were selected for this honor can be accessed directly from the home page of the Journal of Biological Chemistry online at www.jbc.org.

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