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Background & Aims: The liver is inaccessible to organ balance measurements in humans. To validate [(18)F]fluorodeoxyglucose ([(18)F]FDG) positron emission tomography (PET) in the quantification of hepatic glucose uptake (HGU), we determined [(18)F]FDG modeling parameters, lumped constant (LC), and input functions (single arterial versus dual)., Methods: Anesthetized pigs were studied during fasting (n = 6), physiologic (n = 4), and supraphysiologic (n = 4) hyperinsulinemia. PET was performed with C(15)O (blood pool) and [(18)F]FDG (glucose uptake). 6,6-Deuterated glucose ([(2)H]G) was coinjected with [(18)F]FDG and blood collected from the carotid artery and portal and hepatic veins to compute LC as ratio between tracers fractional extraction. HGU was estimated from PET images and ex vivo from high-performance liquid chromatography measurements of liver [(18)F]FDG versus [(18)F]FDG-6-phosphate and [(18)F]-glycogen. Endogenous glucose production was measured with [(2)H]G and hepatic blood flow by flowmeters., Results: HGU was increased in hyperinsulinemia versus fasting (P < .05). Fractional extraction of [(18)F]FDG and [(2)H]G was similar (not significant), intercorrelated (r = 0.98, P < .0001), and equally higher during hyperinsulinemia than fasting (P 0.95, P < .0001), with a modest underestimation of HGU by the former., Conclusions: [(18)F]FDG-PET-derived parameters provide accurate quantification of HGU and estimates of liver perfusion and glucose production. In the liver, LC of [(18)F]FDG is nearly unitary. Using a single arterial input introduces only a small error in estimation of HGU.

Unlabelled: The glucose analog (18)F-FDG is commonly used to quantify regional glucose uptake in vivo. The aim of this study was to test whether the analysis of plasma (18)F-FDG kinetics could be used to estimate endogenous glucose production (EGP) and the total rate of appearance (Ra), total rate of disappearance (Rd), and the metabolic clearance rate (MCR) of glucose., Methods: Fourteen pigs were coinjected with (18)F-FDG and 6,6-(2)H-glucose ((2)H-G) during fasting (n = 6) and during physiologic (1.0 mU.kg(-1).min(-1), n = 4) and supraphysiologic (5.0 mU.kg(-1).min(-1), n = 4) euglycemic hyperinsulinemia. Arterial plasma was sampled for 180 min to quantify the parameters for the 2 tracers., Results: Fasting Rd((2))(H-G) and Rd(FDG) were 12.3 +/- 2.1 and 13.3 +/- 1.3 micromol.kg(-1).min(-1) (difference not statistically significant [NS]). M values were more than doubled between the 2 clamp studies (P < 0.0001). Rd((2))(H-G) and Rd(FDG) were dose-dependently higher during the hyperinsulinemic state (19.8 +/- 3.7 vs. 18.9 +/- 1.1 and 31.4 +/- 4.1 vs. 31.9 +/- 2.3 in 1.0 and 5.0 mU.kg(-1).min(-1) studies, respectively; difference between tracers NS) than during the fasting state, with a parallel suppression of EGP((2))(H-G) and EGP(FDG). Parameters estimated by (18)F-FDG and (2)H-G were equivalent in all groups; their agreement was confirmed by Bland-Altman examination. Total Rd(FDG) correlated with Rd((2))(H-G) (r = 0.74; P = 0.003), M (r = 0.92; P = 0.001), MCR((2))(H-G) (r = 0.52; P = 0.037), and EGP((2))(H-G) (r = -0.71; P = 0.004). EGP(FDG) correlated with EGP((2))(H-G) (r = 0.62; P = 0.018), Rd((2))(H-G) (r = -0.78; P = 0.001), and MCR((2))(H-G) (r = -0.67; P = 0.008). The (18)F-FDG mean transit time correlated inversely with the M and Rd values and positively with EGP., Conclusion: The glucose analog (18)F-FDG can be used in the simultaneous estimation of whole-body glucose turnover and production and regional (18)F-FDG PET measurements under both fasting and insulin-stimulated conditions.

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 (2)H(2)O technique) and EGP (with 3-(3)H-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/m(2) or greater) or nonobese (body mass index < 30 kg/m(2)); diabetic subjects were further subdivided according to the severity of fasting hyperglycemia [fasting plasma glucose (FPG) < 9 mm or >or= 9 mm]. EGP was similar in nondiabetic controls and T2DM with FPG less than 9 mm but was increased in T2DM with FPG >or= 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

OBJECTIVE -- Diabetic hyperglycemia results from insulin resistance of peripheral tissues and glucose overproduction due to increased gluconeogenesis (GNG). Thiazolidinediones (TZDs) improve peripheral insulin sensitivity, but the effect on the liver is less clear. The goal of this study was to examine the effect of TZDs on GNG. RESEARCH DESIGN AND METHODS -- Twenty sulfonylurea-treated type 2 diabetic subjects were randomly assigned (double-blind study) to receive pioglitazone (PIO group; 45 mg/day) or placebo (Plc group) for 4 months to assess endogenous glucose production (EGP) (3-³H-glucose infusion), GNG (D2O technique), and insulin sensitivity by two-step hyperinsulinemic-euglycemic clamp (240 and 960 pmol/min per m²). RESULTS -- Fasting plasma glucose (FPG) (10.0 ± 0.8 to 7.7 ± 0.7 mmol/l) and HbA1c (9.0 ± 0.4 to 7.3 ± 0.6%) decreased in the PIO and increased in Plc group (P < 0.05 PIO vs. Plc). Insulin sensitivity increased ∼40% during high insulin clamp after pioglitazone (P < 0.01) and remained unchanged in the Plc group (P < 0.05 PIO vs. Plc). EGP did not change, while GNG decreased in the PIO group (9.6 ± 0.7 to 8.7 ± 0.6 µmol ⋅ min[sup -1]. kgffm-1) and increased in the Plc group (8.0 ± 0.5 to 9.6 ± 0.8) (P < 0.05 PIO vs. Plc). Change in FPG correlated with change in GNG flux (r = 0.63, P < 0.003) and in insulin sensitivity (r = 0.59, P < 0.01). Plasma adiponectin increased after pioglitazone (P < 0.001) and correlated with ΔFPG (r = -0.54, P < 0.03), ΔGNG flux (r = -0.47, P < 0.05), and Δinsulin sensitivity (r = 0.65, P < 0.005). Plasma free fatty acids decreased after pioglitazone and correlated with ΔGNG flux (r = 0.54, P < 0.02). From stepwise regression analysis, the strongest determinant of change in FPG was change in GNG flux. CONCLUSIONS -- Pioglitazone improves FPG, primarily by reducing GNG flux in type 2 diabetic subjects. [ABSTRACT FROM AUTHOR]