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Our goal is to dissect the molecular mechanisms by which gut hormones, namely GLP-1 and PYY, improve glucose-mediated insulin and glucagon secretion in pancreatic islets. Dysfunction of both secretory processes contributes to the onset of type 2 diabetes and represents the target of effective diabetes intervention.

Pancreatic islet and gut hormones

Our research focuses on metabolic and islet physiology. We are investigating the regulation and failure of the insulin-secreting beta-cell and glucagon-secreting alpha-cell in normal health, diabetes and weight-loss surgery. Type 2 diabetes is a global epidemic with over 300 million sufferers worldwide. It results from a combination of insufficient insulin secretion and over-secretion of glucagon, but the role of glucagon as a counter-regulatory hormone in diabetes has been largely overlooked.

The gut hormone glucagon-like peptide 1 (GLP-1) can both enhance insulin secretion and inhibit glucagon release, making it a successful diabetes therapy. However, the mechanism by which GLP-1 inhibits glucagon secretion is currently unknown. Recent data from our laboratory indicate that GLP-1 inhibits glucagon secretion from isolated islets by a direct effect not involving paracrine signals (for example insulin or somatostatin), but possibly mediated by a novel receptor that is expressed in alpha-cells but not in beta-cells. We are currently exploring the existence of a potential novel receptor for GLP-1 in human islets. Ultimately, this work may result in novel therapies that specifically target the hypersecretion of glucagon seen in diabetes.

 

Pancreatic Islet and Gut Hormones in Health, Diabetes and Metabolic Surgery research group team photo.

 

In parallel, we are also investigating the impact of weight-loss surgery on pancreatic islet functions. In collaboration with experts in Norway we have recently demonstrated an important role of the much neglected gut hormone peptide tyrosine tyrosine (PYY) on human pancreatic islet function and reversal of diabetes following gastric bypass surgery. The surgery-induced dramatic reversal of diabetes implies that the metabolic defect in diabetes lies between the gut and the islets. The metabolic benefits of weight-loss surgery are so compelling that surgery is now being considered as a therapeutic option for type 2 diabetes in obese patients. However, this option is life-changing, risky and unsuitable for many patients. Thus, our lab is exploring the roles of gut hormones such as GLP-1 and PYY, on human diabetes and their effects on islet physiology through the application of novel in-vitro methods (which cannot be done in humans) to investigate if the beneficial effects of surgery on glycaemia can be translated in man by non-surgical procedures. Like GLP-1, PYY is a substrate for the proteolytic enzyme dipeptidyl peptidase-IV (DDP-IV), which is highly expressed in the islets. We are also exploring whether DPP-IV inhibition can influence PYY metabolism in islets and whether agents that enhance PYY release or its action can provide a novel, non-surgical therapy for type 2 diabetes. 

Work in our laboratory involve an array of techniques including islet isolation, secretion studies with rodent and donor human islets, light microscopy and calcium imaging, cell culture, gene knockdown and biochemical assays. We also collaborate with scientists for electrophysiology measurements.

Our team

Collaborations

Prof Duan Chen, St Olav’s Hospital, Norway

Dr Graham Ladds, University of Cambridge

Prof Patrik Rorsman, Oxford Centre for Diabetes, Endocrinology & Metabolism

Prof Paul Johnson, Oxford Centre for Diabetes, Endocrinology & Metabolism


Lab Alumni

Laura J McCulloch

Related research themes