Effects of fasting on hepatic and peripheral glucose metabolism in conscious rats with near-total fat depletion

Abstract

Experimental diabetes and fasting are both associated with hypoinsulinaemia and share several other metabolic features. We investigated hepatic and peripheral glucose metabolism in young rats after near-total depletion of their fat mass. Conscious rats were fasted for 72 h (n = 13), while 6 h-fasted animals (n = 14) served as controls. Rats were studied either during saline infusion or insulin (18 m-units/kg per min)-clamp studies. In fasting, despite a 2-fold increase in hepatic glucose-6-phosphatase (Glc-6-Pase) Vmax. (from 16 +/- 2 mumol/g of liver per min in control; P < 0.001), the basal hepatic glucose production (HGP) decreased by 47% [from 88 +/- 3 mumol/kg lean body mass (LBM) per min in control; P < 0.01]. The decreased HGP in fasting was associated with a 70% decrease in the hepatic levels of glucose 6-phosphate (Glc-6-P) (from 366 +/- 53 nmol/g wet wt. in control; P < 0.01). Thus Glc-6-Pase activity assayed in the presence of the Glc-6-P levels found in vivo was decreased by 44%. During hyperinsulinaemia, peripheral glucose uptake was decreased by 15% with 3 days of fasting (from 272 +/- 17 mumol/kg LBM per min in control; P < 0.01). This was completely accounted for by a 42% decrease in whole-body glycolysis (P < 0.01), while the rate of glycogen synthesis was unchanged. Thus fasting (after near-total fat depletion) differs from experimental diabetes because: (1) despite markedly increased Glc-6-Pase, HGP is decreased in fasting, due to a marked decrease in the substrate level (Glc-6-P) in vivo; and (2) the impairment in peripheral insulin sensitivity in fasting is due to a decrease in the glycolytic, and not the glycogen-synthetic, pathway.