Loss of hepatic autoregulation after carbohydrate overfeeding in normal man

Abstract

To determine the effect of increased glycogen stores on hepatic carbohydrate metabolism, 15 nondiabetic volunteers were studied before and after 4 d of progressive overfeeding. Glucose production and gluconeogenesis were assessed with [2-3H]glucose and [16-14C]glucose (Study I, n = 6) or [33H]glucose and [U-14C]-alanine (Study II, n = 9) and substrate oxidation was determined by indirect calorimetry. Overfeeding was associated with significant (P < 0.011 increases in plasma glucose (4.97±0.10 to 5.09±0.11 mmol/liter), insulin (18.8±1.5 to 46.6±10.0 pmol/liter) and carbohydrate oxidation (4.7±1.4 to 18.0±1.5 μmol · kg-1 · min-1) and a decrease in lipid oxidation (1.2±11.2 to 0.3±0.1 μmol · kg-1 · min-1). Hepatic glucose output (HGO) increased in Study I (10.2±0.5 to 13.1±0.9 μmol · kg-1 · min-1, P < 0.01) and Study II (11.17±0.67 to 13.33±0.83 μmol · kg-1 · min-1, P < 0.01), and gluconeogenesis decreased (57.6±6.4 to 33.4±4.9 μmol/min, P < 0.01), indicating an increase in glycogenolysis. The increase in glycogenolysis was only partly compensated by an increase in glucose cycle activity (2.2±0.2 to 3.4±0.4 μmol · kg-1 · min-1, P < 0.01) and the fall in gluconeogenesis, thus resulting in increased HGO. The suppression of gluconeogenesis despite increased lactate and alanine (glycerol was decreased) was associated with decreased free fatty acid (FFA) oxidation and negligible FFA enhanced gluconeogenesis. These studies suggest that increased liver glycogen stores alone can overwhelm normal intrahepatic mechanisms regulating carbohydrate metabolism resulting in increased HGO in nondiabetic man.