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Metabolism Unit (A.G., M.P., E.B., E.F.), C.N.R. Institute of Clinical Physiology and Department of Internal Medicine, University of Pisa School of Medicine, 56100 Pisa, Italy; and Diabetes Division (A.G., Y.M., S.M., E.F., R.A.D.), University of Texas Health Science Center, San Antonio, Texas 78229-3900
Address all correspondence and requests for reprints to: Ralph A. DeFronzo, M.D., Diabetes Division, University of Texas Health Science Center, 7703 Floyd Curl Drive MS 7886, San Antonio, Texas 78229-3900. E-mail: albarado{at}uthscsa.edu.
The contribution of increased gluconeogenesis (GNG) to the excessive rate of endogenous glucose production (EGP) in type 2 diabetes (T2DM) is well established. However, the separate effects of obesity (total body fat), visceral adiposity, and T2DM have not been investigated. We measured GNG (by the 2H2O technique) and EGP (with 3-3H-glucose) after an overnight fast in 44 type 2 diabetic and 29 gender/ethnic-matched controls. Subjects were classified as obese (body mass index 30 kg/m2 or greater) or nonobese (body mass index < 30 kg/m2); diabetic subjects were further subdivided according to the severity of fasting hyperglycemia [fasting plasma glucose (FPG) < 9 mM or 
9 mM]. EGP was similar in nondiabetic controls and T2DM with FPG less than 9 mM but was increased in T2DM with FPG 9 mM (P < 0.001). Within the diabetic groups, obesity had an independent effect to further increase basal EGP (P < 0.01). In both nonobese diabetic groups, both the percent GNG and gluconeogenic flux were increased, compared with nonobese nondiabetic controls. In both diabetic groups, obesity further increased both percent GNG and gluconeogenic flux. In obese and nonobese T2DM, the increase in gluconeogenic flux was not accompanied by a reciprocal decrease in glycogenolysis, indicating a loss of hepatic autoregulation. By multivariate analysis, gluconeogenic flux was positively correlated with percent body fat, visceral fat, and the fasting plasma free fatty acid and glucose concentrations (all P 
0.02). We conclude that obesity per se, and visceral fat accumulation in particular, as well as poorly controlled diabetes are potent stimuli to augment gluconeogenic flux.
This work was supported by National Institutes of Health Grant DK-24092, General Clinical Research Center Grant M01-RR-01346, a Veterans Affairs Merit Award, and funds from the Veterans Administration Medical Research Service.
Abbreviations: BMI, Body mass index; C5, carbon 5; 2DM, type 2 diabetes; EGP, endogenous glucose production; FFA, free fatty acid; FFM, fat-free mass; FM, fat mass; FPG, fasting plasma glucose; GNG, gluconeogenesis; HbA1c, glycosylated hemoglobin; MRI, magnetic response imaging; Rd, glucose disappearance; T2DM, type 2 diabetes; VF, visceral fat.
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