MECHANISM BY WHICH HYPERGLYCEMIA INHIBITS HEPATIC GLUCOSE-PRODUCTION IN CONSCIOUS RATS - IMPLICATIONS FOR THE PATHOPHYSIOLOGY OF FASTING HYPERGLYCEMIA IN DIABETES

To examine the relationship between the plasma glucose concentration ( PG) and the pathways of hepatic glucose production (HGP), five groups of conscious rats were studied after a 6-h fast: (a) control rats (PG = 8.0+/-0.2 mM); (b) control rats (PG = 7.9+/-0.2 mM) with somatostati n and insulin replaced at the basal level; (c) control rats (PG = 18.1 +/-0.2 mM) with somatostatin, insulin replaced at the basal level, and glucose infused to acutely raise plasma glucose by 10 mM; (d) control rats (PG = 18.0+/-0.2 mM) with somatostatin and glucose infusions to acutely reproduce the metabolic conditions of diabetic rats, i.e., hyp erglycemia and moderate hypoinsulinemia; (e) diabetic rats (PG = 18.4/-2.3 mM). All rats received an infusion of [3-H-3]glucose and IU-C-14 ] lactate. The ratio between hepatic [C-14]UDP-glucose sp act (SA) and 2X [C-14]-phosphoenolpyruvate (PEP) SA (the former reflecting glucose -6-phosphate SA) measured the portion of total glucose output derived from PEP-gluconeogenesis. In control rats, HGP was decreased by 58% in hyperglycemic compared to euglycemic conditions (4.5+/-0.3 vs. 10.6+/ -0.2 mg/kg-min; P < 0.01). When evaluated under identical glycemic con ditions, HGP was significantly increased in diabetic rats (18.9+/-1.4 vs. 6.2+/-0.4 mg/kg . min; P < 0.01). In control rats, hyperglycemia i ncreased glucose cycling (by 2.5-fold) and the contribution of glucone ogenesis to HGP (91% vs. 45%), while decreasing that of glycogenolysis (9% vs. 55%). Under identical plasma glucose and insulin concentratio ns, glucose cycling in diabetic rats was decreased (by 21%) and the pe rcent contribution of gluconeogenesis to HGP (73%) was similar to that of controls (84%). These data indicate that: (a) hyperglycemia causes a marked inhibition of HGP mainly through the suppression of glycogen olysis and the increase in glucokinase flux, with no apparent changes in the fluxes through gluconeogenesis and glucose-6-phosphatase; under similar hyperglycemic hypoinsulinemic conditions: (b) HGP is markedly increased in diabetic rats; however, (c) the contribution of glycogen olysis and gluconeogenesis to HGP is similar to control animals.