Decreased skeletal muscle
glucose disposal and increased endogenous
glucose production (EGP) contribute to
postprandial hyperglycemia in
type 2 diabetes, but the contribution of
hepatic glycogen metabolism remains uncertain.
Hepatic glycogen metabolism and EGP were monitored in type 2 diabetic patients and nondiabetic volunteer control subjects (CON) after mixed meal ingestion and during hyperglycemic-hyperinsulinemic-
somatostatin clamps applying 13C nuclear magnetic resonance spectroscopy (NMRS) and variable infusion dual-tracer technique. Hepatocellular
lipid (HCL) content was quantified by 1H NMRS. Before dinner,
hepatic glycogen was lower in type 2 diabetic patients (227 +/- 6 vs. CON: 275 +/- 10 mmol/l liver, P < 0.001). After meal ingestion, net synthetic rates were 0.76 +/- 0.16 (type 2 diabetic patients) and 1.36 +/- 0.15 mg x kg(-1) x min(-1) (CON, P < 0.02), resulting in peak concentrations of 283 +/- 15 and 360 +/- 11 mmol/l liver. Postprandial rates of EGP were approximately 0.3 mg x kg(-1) x min(-1) (30-170 min; P < 0.05 vs. CON) higher in type 2 diabetic patients. Under clamp conditions, type 2 diabetic patients featured approximately 54% lower (P < 0.03) net
hepatic glycogen synthesis and approximately 0.5 mg x kg(-1) x min(-1) higher (P < 0.02) EGP. Hepatic
glucose storage negatively correlated with HCL content (R = -0.602, P < 0.05). Type 2 diabetic patients exhibit 1) reduction of postprandial
hepatic glycogen synthesis, 2) temporarily impaired suppression of EGP, and 3) no normalization of these defects by controlled hyperglycemic
hyperinsulinemia. Thus, impaired
insulin sensitivity and/or chronic glucolipotoxicity in addition to the effects of an altered
insulin-to-
glucagon ratio or increased
free fatty acids accounts for defective
hepatic glycogen metabolism in type 2 diabetic patients.