Mechanisms of Diabetes Control After Weight Loss Surgery

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DESCRIPTION (provided by applicant): Obesity and type 2 diabetes (DM) are increasing in the US. One third of patients seeking bariatric surgery have DM. Although all surgeries result in significant weight loss and often 'cure' the DM, the rapid onset and the magnitude of the benefits of gastric bypass (GBP) on DM has thus far baffled clinical scientists. Limited data suggest that the improvement in DM after GBP occurs very rapidly, and may not be wholly accounted for by weight loss. Secretion of incretins (gut peptides secreted in response to meals which enhance insulin secretion) is impaired in DM and improves after GBP, possibly due to the specific anatomical changes after this surgery. While some determinants of impaired insulin secretion, such as glucotoxicity, improve equally after diet or surgical weight loss, the improvement in the incretin effect after GBP might be specific to this surgery. We will determine in AIM 1 whether the magnitude of the incretin effect on insulin secretion is greater after GBP than after an equivalent diet-induced weight loss. We will compare, in obese diabetic patients randomized to very low calorie diet or to GBP, the effect of a 3 to 6-week equivalent weight loss on the incretin effect (difference in insulin secretion after comparable oral and intravenous (IV) glucose loads). Experimental data suggest that bypassing the upper gut, rather than weight loss per se, improves glucose tolerance in DM after GBP. AIM 2 will be to determine whether the magnitude of the incretin effect is greater after GBP than after gastric banding (a procedure not known to change the incretins). We will measure the incretin effect before and up to 9 months after GBP or gastric banding. A major determinant of impaired insulin secretion in DM is decreased insulin sensitivity (Si). Diet-induced weight loss improves insulin secretion and Si equally. After GBP, dissociation between the relative changes in insulin secretion and Si has been reported, suggesting a mechanism other than compensation for changes in Si may be involved in insulin secretion. AIM 3 will be to determine whether the changes of insulin secretion (AIRg), relative to changes of Si, are greater after GBP than after gastric banding. We will measure, with IV glucose tolerance tests, before and up to 9 months after surgery, whether, for an equivalent change of Si, AIRg will improve more after GBP than after gastric banding. As more obese diabetic patients undergo GBP, understanding the mechanisms that produce improvement in their diabetes is increasingly important.