Regulation of glucose metabolism in man

Insulin is the dominant glucoregulatory factor; by suppressing endogenous glucose production and stimulating glucose utilization, it lowers the plasma glucose concentration. Normally, feedback-regulated changes in insulin secretion play a key role in maintaining plasma glucose levels within a rather narrow range (approximately 4.0-7.0 mmol l-1) despite marked changes in glucose influx (e.g. following a meal, compared to fasting), efflux (e.g. during exercise), or both. Severe insulin deficiency causes insulin-dependent diabetes mellitus (IDDM), and substantial insulin excess causes hypoglycaemia. However, the regulation of systemic glucose balance normally involves a highly co-ordinated interplay between the glucose-lowering effects of insulin and the glucose-elevating actions of an array of glucose counterregulatory hormones, primarily glucagon (and epinephrine under some conditions). Thus there are redundant glucoregulatory factors, and a hierarchy exists among the latter. Although insulin stands at the top of that hierarchy, glucoregulation is not achieved by insulin alone. This is emphasized by the glycaemic chaos of IDDM, with wide swings from hyperglycaemia to hypoglycaemia. The latter is not exclusively the result of the intermittent hyperinsulinaemia inherent in imperfect insulin replacement therapy. Deficient glucagon and epinephrine secretory responses occur, and are now known to increase the risk of iatrogenic hypoglycaemia. However, insulin is generally the dominant glucoregulatory hormone under physiological conditions. The glucose counterregulatory hormones approach parity with insulin only when plasma glucose concentrations are lowered to levels that threaten brain function.