The role of impaired glucagon secretion in life-threatening hypoglycaemia of type 1 diabetes: mechanism and therapeutic potential

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The pancreatic islets play a central role in the regulation of blood glucose. They do so, by secreting the two hormones insulin (glucose-lowering) and glucagon (glucose-increasing). Type-1 diabetes (T1D) is caused by an autoimmune attack killing the insulin-secreting beta-cells but the other islet cells (including the glucagon-producing alpha-cells) remain. Our understanding of the acute and longterm impact of T1D on the alpha-cells is sketchy but it is clear that defects in the release exacerbate the impact of the insulin deficiency and make T1D more difficult to treat. In type-1 diabetes (T1D), the loss of endogenous insulin production must be treated with insulin injections. However, insulin must be carefully dosed so that a fall in blood glucose below the normal range (hypoglycaemia) does not occur. Normally, a fall in blood glucose triggers strong stimulation of glucagon release but this mechanism ('counter-regulation') is faulty in many people with T1D. This increases the risk of severe hypoglycaemia and may result in coma and death. It has been estimated that one in ten T1D patients die of hypoglycaemia. Hypoglycaemia is also a problem in insulin-treated patients with type 2 diabetes (T2D). In fact, because 90% of all diabetic patients have T2D (>400 million worldwide), hypoglycaemia affect a far greater number of patients with T2D than with T1D. Once hypoglycaemia has occurred, the risk of experiencing another hypoglycaemic episode is dramatically increased. The underlying mechanisms are not known.Our preliminary data suggest that the loss of counter-regulatory glucagon secretion is caused by a 'glucose blindness' of the glucagon-releasing alpha-cells. We will now determine how and when this defect develops during the onset and progression of T1D and whether it can be corrected by medicines, some of which are already used to treat patients with T2D. Our laboratory pioneered the characterisation of the islet alpha-cells: first using mouse islets and subsequently in human islets (from the Oxford Clinical Islet Isolation and Transplantation Centre). However, access to human pancreatic islets from donors with T1D is very limited (they are not used for transplantation) and for some of pilot studies we will also use a well-established and widely used model of human T1D (the NOD mouse). There have been no functional studies of glucagon secretion in NOD mice. Our preliminary studies suggest that they faithfully recapitulate the glucagon secretion defects seen clinically in patients with T1D.The ultimate goal of this project is to prevent (or reduce the risk of) hypoglycaemia. This would enable more aggressive insulin therapy to achieve better glucose control with resultant reduction of secondary complications (heart and kidney failure, blindness etc.).