Date of Award

5-1-2014

Degree Name

Doctor of Philosophy

Department

Molecular, Cellular, and Systemic Physiology

First Advisor

Strader, April

Abstract

The most effective way to treat morbid obesity is bariatric surgery, which results in a high rate of rapid resolution of diabetes independent of body weight changes. To study the mechanisms of the resolution many surgical and obese/diabetic animal models were used. The primary surgical model utilized was ileal interposition (IT). This surgical manipulation allows one to examine the role of lower intestinal stimulation of the ileum without other surgical confounds such as restriction and malabsorption. The general hypothesis is that lower intestinal stimulation may be necessary for improvement in glucose control. In Specific Aim 1, ileal interposition on diabetic rats improved glucose tolerance independent of body weight. In addition, the glycemic improvement was associated with increased secretion of glucagon like peptide 1 (GLP-1), dramatically altered intestinal gene expression profiles and significant changes in bile salt profiles. Interestingly, rats that received IT surgery prior to the onset of diabetes could not be improved. In addition, if a small segment of ileum is removed from the intestinal tract rats can still maintain euglycemia. Because the ileum is physiologically necessary for the uptake and recycling of bile acids, we tested whether direct stimulation of the ileum with biliary secretions could improve glucose tolerance alone in Specific Aim 2. Diversion of bile to the lower intestine was sufficient for improving insulin sensitivity and increasing GLP-1 secretion. Lastly, because obesity and glucose control is governed by both the peripheral organs as well as the central nervous system, we examined in Specific Aim 3 whether rats that were deficient for the central melanocortin 4 receptor (MC4R) would exhibit metabolic benefits from ileal interposition surgery. MC4R deficient rats are extremely obese and insulin resistant. Ileal interposition improved glucose tolerance in MC4R deficient rats, even when obese knockout rats were pair-fed and matched in body weight to their lean littermates. These findings suggest that the presence of the melanocortin 4 receptor is not necessary for the glycemic improvement following ileal interposition. In summary, ileal interposition and biliary diversion resulted in improved glucose tolerance and improved insulin sensitivity associated with increased secretion of GLP-1, suggesting that GLP-1 may be an important mechanism for improved glucose homeostasis. Interestingly, gene expression analysis following ileal interposition determined that the interposed segment increased synthesis of many genes involved in metabolic functions. Interestingly, the gene expression in the remnant ileum and colon was also elevated in IT rats, suggesting that much of the metabolic improvement following ileal interposition may not be solely due to the effects occurring at the interposed ileum alone. In fact, genes normally found within the jejunum were increased in the interposed ileum suggesting that it becomes "jejunized" after relocation and may take on characteristics of the jejunum. Bile acid profiles also suggest that changes in bile salt conjugation may be an important component for improved glucose tolerance. Lastly, because MC4R rats benefited from the glucose lowering effect of ileal interposition, this receptor may not be necessary for improving glucose tolerance following this surgical procedure. Overall, these data point to the complexity and multi-organ interaction of glucose control. These studies add to the existing literature in that they show that surgical procedures used for weight loss can alter other intestinal segments and reveal important gene changes that may potentially lead to the development of therapeutic targets for the treatment of obesity and/or type-2 diabetes.

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