HORMONAL COUNTERREGULATION FAILURE IN RATS IS RELATED TO PREVIOUS HYPERGLYCEMIA-HYPERINSULINEMIA

Hyperglycaemia and hyperinsulinaemia were induced in rats by a continu ous 48-h infusion with glucose. Discontinuation of glucose infusion re sulted in marked, persistent hypoglycaemia. To further delineate the m echanism underlying this condition, we measured counterregulatory horm one levels, in vivo glucose kinetics (glucose production=rate of appea rance=Ra; glucose utilization=rate of disappearance = Rd), and in vitr o gluconeogenesis during the 48-h post-infusion period. Prior to cessa tion of glucose infusion, Rd was increased 6-fold when compared to con trol rats, whereas Ra was totally abolished. During the first hour aft er the end of glucose infusion, Ra increased and Rd decreased (but was still higher than Ra), inducing hypoglycaemia which stabilized after 1 h at \\126\\ 3.5 mmol/l when both Ra and Rd became equal. Despite hy poglycaemia, plasma glucagon and catecholamine levels did not increase during the 3-to 36-h time interval. The increase in Ra during the fir st hour post-infusion was not related to changes in counterregulatory hormone response. The increase in glucose production was accounted for by glycogenolysis, as shown by total depletion in liver glycogen with in 6 h and thereafter by gluconeogenesis. In vitro experiments using i solated hepatocytes suggested that gluconeogenesis was supported durin g the first 24 h by substrates entering the pathway beyond the step ca talysed by the PEPCK enzyme. Thereafter, lactate became the major subs trate, and this condition was associated with a progressive rise in gl ucagon concentration: It is concluded that 48 h of hyperglycaemia/hype rinsulinaemia resulted in a failure of counterregulatory hormonal resp onse to hypoglycaemia. Yet, despite this lack of counterregulatory res ponse, hepatic gluconeogenesis was stimulated in response to hypoglyca emia.