Regulation of metabolism and food intake by enteropancreatic hormones

Enteropancreatic hormones such as pancreatic polypeptide (PP), peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) are secreted post-prandially by the gut and the pancreas. They act to regulate metabolism and appetite. An understanding of the physiology of these hormones and how they can be delivered in a practical manner is required to allow their translation into clinical treatments for obesity and diabetes. Work in this thesis investigated the effect of subcutaneously injected PP in healthy human volunteers, and demonstrated a significant reduction in food intake. A novel peptidase resistant analogue of PP, PP 1420, was administered in combination with metformin to rodents. This combination reduced food intake and body weight additively, suggesting that the combination of PP 1420 and metformin may well be beneficial in patients with obesity and diabetes. A subsequent study of PP 1420 in human volunteers, in a first-in-man Phase 1 trial, confirmed that PP 1420 was safe, well tolerated and possessed an extended terminal elimination half-life compared to native PP. In this thesis, I also explored the physiological effects of gut hormone combinations. The administration of single gut hormones such as PP, PYY or GLP-1 can reduce food intake, but may cause side effects such as nausea. The combination of gut hormones offers the possibility of increased efficacy with fewer side effects, for example, PYY+GLP-1 in combination have previously been shown to possess additive effects on food intake. The effects of a PYY+GLP-1 combination on carbohydrate metabolism have not yet been investigated. Work in this thesis examined the effects of a PYY+GLP-1 combination intravenous infusion on insulin secretion and sensitivity in healthy volunteers. Administration of PYY alone did not significantly affect insulin secretion. PYY+GLP-1 in combination stimulated insulin secretion to a similar extent to GLP-1 alone. There were no significant acute effects of PYY, GLP-1 or PYY+GLP-1 on insulin sensitivity. These findings suggest that gut hormone analogues may represent safe, effective and practical treatments for obesity. Combination PYY+GLP-1 treatment may provide the metabolic benefits of bariatric surgery without the surgery itself.Open Acces