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 hepatic glucose production and decreased metabolic clearance of glucose. Our report summarizes recent work conducted in our laboratory to investigate the regulatory factors involved in the control of glucose turnover in diabetes. The action of insulin, both directly and indirectly, in regulating glucose turnover in diabetic dogs is considered. 1) In the depancreatized diabetic dog, peripheral rather than portal insulin levels determine the suppression of hepatic glucose production via indirect 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 effects on glucose turnover were masked under conditions of clamped hyperglycaemia in the depancreatized dog. 3) In a paradoxical dichotomous fashion, hyperglycaemia both contributes to, and compensates for, defective glucose clearance in diabetes. Acute restoration of euglycaemia significantly improves glucose clearance at rest and normalizes the exerciseinduced increment in clearance in alloxan-diabetic dogs. 4) Our model of centrally-induced stress also shows that an increase in glucose utilization and clearance is largely independent of changes in insulin and that the combined effects of catecholamines and glucagon are responsible for increasing glucose production.