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USING GASTRIC BYPASS SURGERY TO IDENTIFY NEW T2D TREATMENTS

It is now generally accepted that GBP provokes remission of T2D in most (80%) cases. Therefore T2D patients undergoing GBP can be examined to identify preventive and curative processes in the disease. Glycemia is normalized prior to substantial weight loss. Hence, weight loss cannot account for remission of T2D. Using GBP patients with a gastrostomy catheter to the bypassed stomach and a porcine model of GBP, we showed that GBP has beneficial effects on metabolism independent of both weight loss and meal size. Furthermore, we have recently shown that meal size alone cannot account for exaggerated insulin and incretin responses after GBP. Interestingly, in pigs we showed that GBP led to improved glycemia, improved beta cell function and increased beta cell mass, despite identical body weight and food intake as in the control group. Thus, the explanation of the anti-diabetic effect of GBP must be found in how the GI-tract interacts with the pancreatic islets, and the target tissues of insulin (liver, skeletal muscle, adipose tissue). Hitherto, the field has focused on changes in single hormones as mechanistic explanation for the remission of T2D after GBP, e.g. increased secretion of the insulinotropic hormone glucagon-like peptide-1 (GLP-1) or reduced levels of the insulinostatic hormone ghrelin after GBP. Although, we have provided anatomical explanation for these effects of GBP in humans and pigs, we believe that these single hormone-based theories are insufficient to explain the effects of GBP. Instead, an array of events acting in concert underlies the beneficial effects observed. If the mechanisms behind the remission were to be resolved new treatment regimens for T2D could be developed.

Specific aims: 1) Assess whether GBP-induced T2D remission is under genetic influence. 2) Compare immediate effects of GBP with that of food restriction. 3) Assess how GBP-induced microbiota alterations affect T2D remission and epigenetic regulation and gene expression in the gut. 4) Assess whether altered splanchnic blood flow is key to GBP-induced remission of T2D using PET-MRI.