ESPE Abstracts

Diabetes mellitus is a bihormonal disorder involving both insufficient insulin secretion (from the beta-cells(and dysregulation of glucagon secretion (from the alpha-cells). In healthy people, a fall in plasma glucose increases glucagon and stimulates counterregulatory hepatic glucose production. This response is impaired in many patients with type-1 diabetes (T1D). Why this defect develops is unknown but it may lead to fatal hypoglycaemia, which accounts for up to 10% of the mortality in patients with T1D. Somaotstatin (secreted locally by the delta-cells of the islets) is a powerful paracrine regulator of glucagon secretion. We hypothesised that the loss of physiologically adequate counterregulation in T1D is the result of enhanced somatostatin signalling in the islets. T1D is associated with the autoimmune destruction of the the beta-cells. Because the beta-cells outnumber the delta-cells by a factor >10, delta-cells will be in direct physical contact with several beta-cells. The interaction is so tight that electrical contacts (mediated by gap junctions) form between the two cells. Accordingly, electrical stimulation or inhibition of the beta-cells increase or decrease delta-cell electrical activity/somatostatin release, respectively. There was an inverse regulation between beta-cell number and somatostatin release, which would be consistent with the idea that the beta-cells provide an "electrical brake" on the delta-cells. Thus, experimental approaches that prevent electrical signalling between beta- and delta-cells increased somatostatin secretion under hypoglycaemic conditions. This culminates in supression of counterregulatory glucagon secretion and somatostatin receptor antagonists restore glucagon secretion at low glucose in T1D mice and in isolated human/mouse T1D islets. These data suggest that agents that reduce somatostatin action/secretion should be considered as an adjunct to insulin therapy. They also suggest a new mode of intercellular communication between different types of cells in the endocrine pancreas and that electrical signals may be (at least) as important as paracine signals. Finally, this concept provides an explanation to the observation that residual beta-cell function (<10% of normal) protects against hypoglycaemia.