DETERMINANTS OF GLUCOSE-TURNOVER IN THE PATHOPHYSIOLOGY OF DIABETES -AN IN-VIVO ANALYSIS IN DIABETIC DOGS

Hyperglycaemia in diabetes results from a combination of increased hep atic glucose production and decreased metabolic clearance of glucose. Our report summarizes recent work conducted in our laboratory to inves tigate the regulatory factors involved in the control of glucose turno ver in diabetes. The action of insulin, both directly and indirectly i n regulating glucose turnover in diabetic dogs is considered. 1) In th e depancreatized diabetic dog, peripheral rather than portal insulin l evels determine the suppression of hepatic glucose production via indi rect mechanisms such as limiting precursors for gluconeogenesis and/or inhibiting glucagon secretion. 2) The differential effects of insulin and insulin-like growth factor I on glucose turnover may be dependent on a decline in glycaemia since previously observed differential effe cts on glucose turnover were masked under conditions of clamped hyperg lycaemia in the depancreatized dog. 3) In a paradoxical dichotomous fa shion, hyperglycaemia both contributes to, and compensates for, defect ive glucose clearance in diabetes. Acute restoration of euglycaemia si gnificantly improves glucose clearance at rest and normalizes the exer cise-induced increment in clearance in alloxan-diabetic dogs. 4) Our m odel of centrally-induced stress also shows that an increase in glucos e utilization and clearance is largely independent of changes in insul in and that the combined effects of catecholamines and glucagon are re sponsible for increasing glucose production.