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Type 2 diabetes - a membrane trafficking disease?


I heard a great talk yesterday by Dr. Patrik Rorsman from the University of Oxford, who has a new way of thinking about type 2 diabetes. He believes some individuals who develop the disease may have a deficit in insulin exocytosis, but not by the mechanism that anyone would have predicted.
It is abundantly clear that type-2 diabetes is not caused by a lack of available insulin in the pancreas. Therefore, Dr. Rorsman hypothesized that the mechanism of exocytic release of insulin may be perturbed in diabetic patients. However, when he made classical measurements to detect exocytic release in primary tissues, such as amperometry of cargo release and monitoring membrane capacitance, he saw no differences between healthy and diseased cells. It wasn’t until he engineered an elegant ATP-sensitive, feedback biosensor into his recording set-up that he detected a difference in exocytosis.
What he found suggests that the equilibrium between kiss-and-run and full-fusion exocytic events is slightly perturbed in diabetic tissue, such that insulin-containing granules are a little bit less likely to fully fuse with the membrane and release all their cargo. During the kiss-and-run events, the neck of the fusing granule acts as a sieve and prevents insulin from leaking out. The overall effect of too many kiss-and-run events then is reduced insulin release and decreased glucose sensitivity.
Furthermore, he found that this subtle change in exocytic equilibrium in beta cells correlates very well with the expression of Sox4, a transcription factor identified in a screen of tissues from hundreds of patients, both diabetic and healthy. Sox4 regulates Amisyn, a syntaxin-6 binding protein that appears to compete with normal SNAREs to inhibit full granule fusion. Amycin correlated with increased resting blood glucose levels and decreased insulin release in the patient screen as well, further implying a link to its role in granule exocytosis.
Dr. Rorsman is interested now in targeting this pathway to correct the balance of exocytic events in the pancreas and restore glucose sensitivity to diabetic tissue, and he already has some therapeutic ideas. He also believes Sox4 expression is likely misregulated in a subset of diabetic individuals and we should pay attention to it as a potential biomarker for development of the disease. It will be interesting to know whether some genotypes are more susceptible to Sox4 misregulation, or if lifestyle also plays a role in its expression.




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