It has long been an important goal to predict the onset of Type 2 diabetes. It is now known that early intervention can be used to delay if not prevent the disease. Various approaches have been used to assess risk for Type 2 diabetes, and most have focused on the importance of insulin resistance, and the loss of the ability of the cells of the pancreas to compensate for insulin resistance by increasing insulin release. This compensatory ability has been quantified by our laboratory as the disposition index, which is an accepted indicator of early diabetes risk. Another factor is known to exist which can also play a role in the pathogenesis of Type 2 diabetes. This factor was termed glucose effectiveness (GE) and it is related to the effects of glucose itself to normalize its own concentration independent of acute changes in insulin. The precise role of glucose effectiveness in the pathogenesis of Type 2 diabetes will be examined in this proposal. Mechanisms underlying glucose's ability to self-normalize will be measured with carefully designed experimental protocols. The latter mechanisms will be revealed in normal, obese, metabolically impaired and frankly diabetic animals. We will examine and attempt to validate a novel mathematical model-based approach which easily captures glucose effectiveness; the model is based on glucose uptake by the liver, and conversion to and release of lactate from the liver. We will also examine the role of changes in GE in the improvement in carbohydrate regulation by several medicines, including metformin and exenatide. Lastly, we will investigate the role of improvements in GE in the remarkable improvements in carbohydrate metabolism observed in bariatric surgery. The studies supported by this proposal will enhance our understanding of glucose effectiveness, and the explicit role it plays in the pathogenesis of diabetes, and the mechanisms of action by which improvements in glucose effectiveness can ameliorate disease.
Type 2 diabetes, a failure to maintain normal blood sugar, is increasing at an alarming rate, not only in North America, but in most countries of the world. While the hormone insulin, released by the pancreas, is important to maintaining normal sugar in the blood, it is now clear that there are functions of other tissues, especially the liver, whic do not depend upon insulin, but which are also are important to keep blood sugar normal. We may find that these liver-dependent functions can explain how bypass surgery can correct the blood sugar level; if so, we can design therapies which will normalize sugar without surgery, which would have an enormous impact to treat diabetes itself, and greatly reduce the burden diabetes causes to the health care systems of the United States and many other countries.
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