A reappraisal of the blood glucose homeostat which comprehensively explains the type 2 diabetes mellitus-syndrome X complex.

Blood glucose concentrations are unaffected by exercise despite very high rates of glucose flux. The plasma ionised calcium levels are even more tightly controlled after meals and during lactation. This implies 'integral control'. However, pairs of integral counterregulatory controllers (e.g. insulin and glucagon, or calcitonin and parathyroid hormone) cannot operate on the same controlled variable, unless there is some form of mutual inhibition. Flip-flop functional coupling between pancreatic alpha- and beta-cells via gap junctions may provide such a mechanism. Secretion of a common inhibitory chromogranin by the parathyroids and the thyroidal C-cells provides another. Here we describe how the insulin:glucagon flip-flop controller can be complemented by growth hormone, despite both being integral controllers. Homeostatic conflict is prevented by somatostatin-28 secretion from both the hypothalamus and the pancreatic islets. Our synthesis of the information pertaining to the glucose homeostat that has accumulated in the literature predicts that disruption of the flip-flop mechanism by the accumulation of amyloid in the pancreatic islets in type 2 diabetes mellitus will lead to hyperglucagonaemia, hyperinsulinaemia, insulin resistance, glucose intolerance and impaired insulin responsiveness to elevated blood glucose levels. It explains syndrome X (or metabolic syndrome) as incipient type 2 diabetes in which the glucose control system, while impaired, can still maintain blood glucose at the desired level. It also explains why it is characterised by high plasma insulin levels and low plasma growth hormone levels, despite normoglycaemia, and how this leads to central obesity, dyslipidaemia and cardiovascular disease in both syndrome X and type 2 diabetes.