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Sustained endogenous glucose production, diminished lipolysis and non-esterified fatty acid appearance and oxidation in non-obese women at high risk of type 2 diabetes

Section of Endocrinology and Metabolic Medicine, Faculty of Medicine, Imperial College London, St Mary’s Hospital, 2nd Floor, Mint Wing, Praed Street, London W2 1NY, UK, ¹ School of Biomedical Sciences, University of Nottingham Medical School, Nottingham, UK and ² Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK

(Correspondence should be addressed to S Forbes; Email: shareen.forbes{at}imperial.ac.uk)

Objective: To evaluate early defects in glucose production, lipolysis and fatty acid oxidation in non-obese, normally glucose tolerant women, who are nevertheless at risk of type 2 diabetes.

Methods: Ten women with previous gestational diabetes (pGDM) and ten controls were studied in two 4 h infusions of stable isotopes 6,6-²H₂-glucose, 1-¹³C-palmitate, and 1,1,2,3,3-²H₅-glycerol with and without infusion of adrenaline. Fatty acid oxidation was quantified using indirect calorimetry and ¹³CO₂ measurements. Insulin sensitivity was evaluated using the short insulin tolerance test.

Results: The pGDM and control women were non-obese and carefully matched for body mass index and fat mass. Whole body insulin sensitivity and basal insulin concentrations did not differ significantly but basal glucose concentrations were increased in women with pGDM. During a 0.9% saline infusion, glucose appearance was not significantly different at the first (90–120 min) and second (210–240 min) steady states. However, glucose appearance decreased in controls but was maintained in the pGDM women (–0.33 ± 0.02 vs –0.03 ± 0.08 mg/kg per min; P = 0.004). Basal glycerol appearance (0.27 ± 0.02 vs 0.38 ± 0.03 mg/kg per min; P = 0.02), palmitate appearance (0.74 ± 0.09 vs 1.05 ± 0.09 mg/kg per min; P = 0.03) and palmitate oxidation (0.07 ± 0.01 vs 0.10 ± 0.01 mg/kg per min; P = 0.03) were lower in the pGDM women. During the adrenaline infusion, changes in glucose, glycerol and palmitate concentrations and kinetics were similar in both groups.

Conclusions: Sustained glucose production during fasting is an early abnormality in non-obese subjects at risk of type 2 diabetes. Lipolysis and non-esterified fatty acid appearance and oxidation are diminished, suggesting an increased tendency to store fat. The observations are not readily attributable to differences in insulin or catecholamine sensitivity.