This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This study will utilize baboons. Type 2 diabetes (non-insulin requiring diabetes) and impaired fasting glucose (a state that precedes temporally the onset of diabetes) are diagnosed by simply finding high glucose levels (over 100mg/dl) after overnight fasting, in humans. Type 2 diabetes is caused by: 1) insulin resistance, that is the inability of the body to respond by lowering glucose at normal insulin concentration and therefore requiring higher insulin concentrations to overcome this resistance and 2) insufficient insulin secretion by the cells that produce insulin in the pancreas, that are called beta-cells. When the body is no longer capable of producing insulin in sufficient amounts to metabolize glucose, glucose levels are high and diabetes is diagnosed clinically. Despite intensive research we do not know the molecular mechanisms that cause the death of the cells that produce insulin in humans. We hypothesize that under certain conditions, that is very early in the disease and employing certain medications that promote regeneration, it would be possible to prevent type 2 diabetes mellitus or at least to prevent insulin therapy, be being able to preserve and to generate new insulin producing cells. The drug that we propose to test is EXENATIDE, which is very similar to a hormone called GLP-1 (Glucagon like peptide 1), that is produced in the gastrointestinal tract following a meal. GLP-1 acts on the insulin producing cells causing them to produce more insulin in response to glucose. Also, recent studies in mice and rats suggest that GLP-1 might promote regeneration of insulin producing cells, that is the formation of new insulin producing cells and also might prevent the death of the same cells. In order to precisely measure the amount of insulin secreted, we will administer glucose intravenously to reach a predefined glucose level in all animals for a certain period of time. This procedure is called """"""""hyperglycemic clamp"""""""". It means that the glucose concentration is maintained (clamped) at a higher (hyperglycemic) than normal concentration. We expect to see a decrease in glucose levels and an increase in insulin concentration after exenatide treatment. We also expect to see an increase in the number of insulin producing cells and a reduced number of insulin ?producing cells that show sign of imminent death (apoptosis ?scientific term). This kind of research is extremely valuable for helping to develop new and better treatments for type 2 diabetes, which is an enormous problem worldwide, especially for its complications, such as heart attacks, strokes and amputations, which are several millions every year.
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