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Prediabetes and the maintenance of beta cell mass
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Insulin resistance is the hallmark of prediabetes. The disease has not yet set in because the pancreas can compensate for this by increasing the amount of insulin it secretes. This can go on for many years but eventually the pancreas poops out. The beta cells die from overwork and the patient slides into type 2 diabetes. What factors are involved in this process?
Recently a University research group, led by Dr. Dorris Stoffers published an important answer to this question in the Proceedings of the National Academy of Sciences (PNAS). They began by considering an interesting protein called Pdx1. Pdx1 is something we call a transcription factor. Our genes code for proteins and some of these proteins, in turn, function to regulate large families of genes. Complex physiological processes then can be regulated by a very small number of these transcription factors which induce the production of different proteins in many different tissues all for some common purpose. Pdx1 is of interest to people studying diabetes because it sits on the insulin gene and promotes the production of insulin. This research group knew that it must do other things so they set about looking at its functions in a more global manner.
Using gene array technology, they were able to identify a large number of genes regulated by Pdx1 and after some analysis decided to focus on the endoplasmic reticulum (ER). The ER is the place where proteins that are associated with membranes are folded, sorted, and ultimately shepherded to their appropriate drawers (sort of like laundry). We have long known that the ER plays a role in cellular changes associated with diabetes. What was new here was the finding that a transcription factor associated with insulin secretion was also involved in maintaining the components of the ER needed to handle stress.
In parallel experiments they modified mice to have less Pdx1 in their pancreatic beta cells. When these mice were fed a high fat diet their pancreatic beta cells looked terrible. More specifically, their ER looked terrible. After 1 month on the high fat diet these Pdx1 deficient mice had sky high fasting blood glucose levels and after 4 months they had full blown diabetes. In comparison, the wild type control mice were able to compensate. When pancreatic tissues from the two populations were examined at 4 months it was found that the normal mice had increased the number of beta cells. This is how they compensated for the high fat diet. In comparison, the Pdx1 deficient mice had no change in their beta cell mass.
These data would suggest that genetic variations in Pdx1 in people could play a big role in determining how long they can compensate for their insulin resistance. Furthermore it suggests that therapeutics which target Pdx1 function may help patients maintain beta cell function.
For a more complete description of this study click here. Or, visit A Sweet Life, the magazine for the healthy diabetic. http://asweetlife.org
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