Cellular connectivity in pancreatic islets: role in type-1 diabetes

The pancreatic islet hormones glucagon and insulin (secreted by the alpha- and beta-cells) ensure that your blood sugar levels are kept at ~5mM.

Normally, a fall in plasma glucose (hypoglycaemia) during fasting or exercise stimulates glucagon secretion, thereby restoring normal blood glucose levels.

This life-saving mechanism is impaired in many patients with type-1 diabetes, with increased risk of severe hypoglycaemia and - potentially - coma and even death. Consequently, many patients with type-1 diabetes (T1D) are treated less aggressively with insulin than they should. Despite these measures, hypoglycaemia accounts for 4-10% of deaths in insulin-treated patients with T1D.

I hypothesise that this results from a ménage-à-trois of islet hormone secretion defects that affect the alpha-cell itself and its paracrine regulation.

I will approach this - using healthy and T1D mouse and human islets - by a multidisciplinary strategy that (i) defines how T1D affects alpha-cell function; (ii) establishes the role of the somatostatin-secreting delta cells; iii) explores how the changes in islet architecture that occur during the autoimmune destruction of the beta-cells affect alpha- and delta-cell function; and (iv) tests in vivo whether the alpha- and delta-cells can be pharmacologically targeted to restore physiologically appropriate counterregulatory glucagon secretion.

These observations will provide a solid experimental base for planned clinical studies.