A medical bypass. Can the manipulation of gut hormone levels replicate the favourable effects on energy and glucose homeostasis seen following gastric bypass surgery?

The obesity crisis has reached epidemic proportions. Medical therapies are few and far between, offering only modest benefit, with maximal weight loss at one year in the region of 5-6%. Gastric bypass surgery and specifically Roux-en-Y gastric bypass (RYGB) is the only obesity treatment which has shown a marked and sustained weight loss, with initial remission of diabetes in up to 75% of patients. An increase in the post-prandial secretion of satiety gut hormones glucagon-like peptide-1 (GLP-1), peptide tyrosine-tyrosine (PYY) and oxyntomodulin (OXM) following gastric bypass may mediate these favourable effects. GLP-1 promotes insulin secretion in response to an oral glucose load. PYY also increases insulin sensitivity in rodents, and OXM increases energy expenditure (EE). All three hormones increase satiety. Work in this thesis investigates the contributions of these hormones both alone and in combination on the favourable effects on food intake, body weight, and glycaemic control following gastric bypass surgery. Acute co-infusion of GLP-1 and glucagon (as a surrogate for OXM) as well as glucagon alone increased EE by around 150Kcal per day, an effect that was mediated via the glucagon receptor. GLP-1 did not increase EE but was able to partially counter the hyperglycaemia induced by high doses of glucagon. Acute co-infusion of GLP-1 and glucagon at subanorectic doses reduced food intake by 13% compared to placebo, with no effect seen following administration of either peptide alone. GLP-1 neutralised the hyperglycaemic effect of glucagon at these subanorectic doses. Acute infusion of GLP-1 and PYY(3-36) alone and in combination demonstrated that GLP-1 augments the acute insulin response to glucose (AIRg) as assessed by an intravenous glucose tolerance test. PYY did not modify the AIRg, and neither hormone alone or in combination had any effect on insulin sensitivity or glucose disposal. Chronic administration of long acting analogues of GLP-1, PYY and OXM in combination to diet induced obese (DIO) mice resulted in a marked and sustained reduction in body weight of approximately 16% compared to placebo. This was independent of a reduction in food intake suggesting an increase in EE, possibly mediated via fibroblast growth factor-21. In addition, the combination of analogues improved glucose tolerance compared to placebo. These results suggest that a combination of the gut hormones GLP-1, PYY and OXM, or analogues thereof, offers potential as a novel obesity therapy and may be able to mimic the beneficial metabolic effects seen after gastric bypass.Open Acces