| Summary: | Obesity is associated with type-2 diabetes mellitus. Gut hormones are peptides secreted in response to nutrient intake that act to regulate food intake, energy and glucose homeostasis. Thus, alterations in gut hormone abundance and/or signalling can contribute to the development of the obese and T2DM phenotype. The incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic hormone augment glucose-mediated insulin secretion. Peptide YY is released from the gut post-prandially and acts primarily as a satiety signal. Recently studies have highlighted a role for PYY in regulating glucose homeostasis, which to date remains partially understood. Dipeptidyl peptidase-4 is involved in the biological inactivation of the incretins hence; DPP-4 inhibition is used to treat T2DM. DPP-4 also regulates PYY. Thus, DPP-4 inhibition may potentially impact on pancreatic PYY function and signalling and may alter the effects of the PYY system on glucose homeostasis. In addition, gut peptides have been identified as possible contributors to cases of hyperinsulinaemic-hypoglycaemia resulting from bariatric surgery. Therefore, this thesis aimed to (1) determine the contribution of pancreatic PYY deletion to the intra-islet PYY system; glucose homeostasis and body weight phenotype and (2) establish the impact of hyperinsulinism on DPP-4 and its gut hormone substrates. To address the first point, pancreatic-specific Pyy null mice were phenotyped for changes in the pancreatic endocrine system, followed by body weight and glucose metabolism, in vivo. Further investigations measuring gut hormone mRNA suggested the intra-islet system was contributing to the observed reduction in weight gain and hyperinsulinaemia. Finally, patients with congenital forms of HI were evaluated for PYY, the incretins and DPP-4. This study highlighted a role for DPP-4, PYY and GIP in mediating HI. In conclusion, this thesis demonstrates a role for gut hormones in energy and glucose homeostasis. Further work is required to understand the interaction of gut peptides on islet function.
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