Abstract
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.
Highlights
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
This study provides the time course of cumulative glycogen storage and rates of net hepatic glycogen synthesis in type 2 diabetic patients under physiological conditions of mixed-meal ingestion as well as under that of experimental stimulation of glycogen accumulation
Postprandial glycogen synthesis is reduced in mildly overweight type 2 diabetic patients and is accompanied by a temporarily impaired EGP suppression
Summary
Hepatic glycogen concentrations increased linearly in both groups (Fig. 3B), but VSyn was ϳ46% lower in type 2 diabetic patients (0.63 Ϯ 0.12 vs CON: 1.17 Ϯ 0.15 mg 1⁄7 kgϪ1 1⁄7 minϪ1, P Ͻ 0.05), with similar contribution of the direct pathway in both groups (type 2 diabetic patients: 60 Ϯ 10% vs CON: 65 Ϯ 2%, P ϭ 0.416). Simultaneous VOut (Fig. 5A) was not different (type 2 diabetic patients: 0.21 Ϯ 0.07 vs CON: 0.23 Ϯ 0.11 mg 1⁄7 kgϪ1 1⁄7 minϪ1, P ϭ 0.895), resulting in ϳ54% lower rates of net hepatic glycogen synthesis (Fig. 5A) in type 2 diabetic patients (0.42 Ϯ 0.10 vs CON: 0.91 Ϯ 0.16 mg 1⁄7 kgϪ1 1⁄7 minϪ1, P Ͻ 0.05). Hepatocellular lipid content was three times higher in type 2 diabetic patients (9.9 Ϯ 2.5 AU vs. CON: 2.8 Ϯ 0.7 AU, P Ͻ 0.05) and negatively correlated across the whole study population with rates of net hepatic glycogen synthesis (R ϭ Ϫ0.602, P Ͻ 0.05) as well as with rates of whole-body glucose uptake (R ϭ Ϫ0.576, P Ͻ 0.05) during the clamp test
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