The physiological basis of insulin therapy in people with diabetes mellitus.

Insulin therapy has been in use now for 100 years, but only recently insulin replacement has been based on physiology. The pancreas secretes insulin at continuously variable rates, finely regulated by sensitive arterial glucose sensing. Pancreatic insulin is delivered directlyin the portal blood to insulinize preferentially the liver. In the fasting state, insulin is secreted at a low rate to modulate hepatic glucose output. After liver extraction (50%), insulin concentrations in peripheral plasma are 2.4-4 times lower than in portal, but still efficacious to restrain lipolysis. In the prandial condition, insulin is secreted rapidly in large amounts to increase portal and peripheral concentrations to peaks 10-20 times greater vs the values of fasting within 30-40 min from meal ingestion. The prandial portal hyperinsulinemia fully suppresses hepatic glucose production while peripheral hyperinsulinemia increases glucose utilization, thus limitating the post-prandial plasma glucose elevation. Physiology of insulin indicates that insulin should be replaced in people with diabetes mimicking the pancreas, i.e. in a basal-bolus mode, for fasting and prandial state, respectively. Despite the presently ongoing limitations (subcutaneous and peripheral rather than portal and intravenous insulin delivery), basal-bolus insulin allows people with diabetes to achieve A1c in the range with minimal risk of hypoglycaemia, to prevent vascular complications and to ensure good quality of life.