13C/31P NMR studies on the mechanism of insulin resistance in obesity

The mechanism of insulin resistance in obesity was examined in ten obese (BMI 33 ± 1 kg/m2) and nine lean (BMI 22 ± 1 kg/m2) Caucasian women during a hyperglycemic-hyperinsulinemic clamp using 13C and 31C/31P nuclear magnetic resonance (NMR) spectroscopy to measure rates of muscle glycogen synthesis and intramuscular glucose-6-phosphate (G-6-P) concentrations. Under similar steady-state plasma concentrations of glucose (~11 mmol/l) and insulin (~340 pmol/l), rates of muscle glycogen synthesis were reduced ~70% in the obese subjects (52 ± 8 μmol/l muscle-min]) as compared with the rates in the lean subjects (176 ± 22 μmol/l muscle-min]; P < 0.0001). Basal concentrations of intramuscular G-6-P were similar in the obese and lean subjects; but during the clamp, G-6-P failed to increase in the obese group (ΔG-6-P obese 0.044 ± 0.011 vs. lean 0.117 ± 0.011 mmol/l muscle; P < 0.001), reflecting decreased muscle glucose transport and/or phosphorylation activity. We conclude that insulin resistance in obesity can be mostly attributed to impairment of insulin-stimulated muscle glycogen synthesis due to a defect in glucose transport and/or phosphorylation activity