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Reshma Ramracheya


Cell and Molecular Biology

Hyperglycaemia results from a combination of insufficient insulin secretion and over-secretion of glucagon.  Therefore, treatments for diabetes should address both the lack of insulin release as well as the glucagon impairment. However, to date most therapies have focused on improving the defect in insulin secretion alone and the role of glucagon as a counter-regulatory hormone in diabetes has been overlooked.

The gut hormone GLP-1 is unique as it enhances insulin secretion and inhibits glucagon release: this contributes ~50% of its hypoglycaemic action. However, the mechanisms by which GLP-1 inhibits glucagon secretion are unknown. Recent data from our laboratory indicate that GLP-1 inhibits glucagon secretion from mouse islets by a direct effect not involving paracrine signals (for example insulin or somatostatin), but possibly mediated by a novel receptor for GLP-1 that is expressed in α-cells but not in β-cells. My team is investigating the mechanism of action of GLP-1 on glucagon secretion in human islets and exploring whether a novel GLP-1 receptor is involved. Ultimately, this work may result in novel therapies that specifically target the hypersecretion of glucagon seen in diabetes. This work should ideally be performed on human islets as it is now becoming increasingly clear that there are major and important differences between rodent and human islets.

In parallel, my laboratory is also investigating the impact of bariatric surgery on pancreatic islet functions. Bariatric surgery can dramatically reverse type 2 diabetes, independently of weight loss, but the underlying physiological mechanisms are unknown. The metabolic benefits are so compelling that weight-loss surgery is now being considered as a therapeutic option for type diabetes in obese patients. However, this option is life-changing, risky and unsuitable for many patients. In collaboration with experts in Norway, we are exploring the physiological mechanisms that result in the reversal of diabetes following bariatric surgery. We have recently shown that peptide tyrosine tyrosine (PYY), a gut hormone regulating appetite, acts as an important mediator in this process. We are now studying the role of PYY in diabetes and islet physiology including insulin, glucagon and somatostatin release. We also have exciting preliminary data showing that DPP-IV inhibition therapy can influence PYY metabolism, indicating that targeting PYY or its action may provide a novel, non-surgical therapy for diabetes. 

Hyperglycaemia results from a combination of insufficient insulin secretion and over-secretion of glucagon.  Therefore, treatments for diabetes should address both the lack of insulin release as well as the glucagon impairment. However, to date most therapies have focused on improving the defect in insulin secretion alone and the role of glucagon as a counter-regulatory hormone in diabetes has been overlooked.

The gut hormone GLP-1 is unique as it enhances insulin secretion and inhibits glucagon release: this contributes ~50% of its hypoglycaemic action. However, the mechanisms by which GLP-1 inhibits glucagon secretion are unknown. Recent data from our laboratory indicate that GLP-1 inhibits glucagon secretion from mouse islets by a direct effect not involving paracrine signals (for example insulin or somatostatin), but possibly mediated by a novel receptor for GLP-1 that is expressed in α-cells but not in β-cells. My team is investigating the mechanism of action of GLP-1 on glucagon secretion in human islets and exploring whether a novel GLP-1 receptor is involved. Ultimately, this work may result in novel therapies that specifically target the hypersecretion of glucagon seen in diabetes. This work should ideally be performed on human islets as it is now becoming increasingly clear that there are major and important differences between rodent and human islets.

In parallel, my laboratory is also investigating the impact of bariatric surgery on pancreatic islet functions. Bariatric surgery can dramatically reverse type 2 diabetes, independently of weight loss, but the underlying physiological mechanisms are unknown. The metabolic benefits are so compelling that weight-loss surgery is now being considered as a therapeutic option for type diabetes in obese patients. However, this option is life-changing, risky and unsuitable for many patients. In collaboration with experts in Norway, we are exploring the physiological mechanisms that result in the reversal of diabetes following bariatric surgery. We have recently shown that peptide tyrosine tyrosine (PYY), a gut hormone regulating appetite, acts as an important mediator in this process. We are now studying the role of PYY in diabetes and islet physiology including insulin, glucagon and somatostatin release. We also have exciting preliminary data showing that DPP-IV inhibition therapy can influence PYY metabolism, indicating that targeting PYY or its action may provide a novel, non-surgical therapy for diabetes. 

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