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 somatostatin 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., hyperglycemia and moderate hypoinsulinemia; (e) diabetic rats (PG = 18.4±2.3 mM). All rats received an infusion of [3-³H]glucose and [U-¹⁴C]lactate. The ratio between hepatic [¹⁴C]UDP-glucose sp act (SA) and 2X [¹⁴C]-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 conditions, 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 increased glucose cycling (by 2.5-fold) and the contribution of gluconeogenesis to HGP (91% vs. 45%), while decreasing that of glycogenolysis (9% vs. 55%). Under identical plasma glucose and insulin concentrations, glucose cycling in diabetic rats was decreased (by 21%) and the percent 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 glycogenolysis 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 glycogenolysis and gluconeogenesis to HGP is similar to control animals.