Various modeling strategies have been developed to convert regional [(18)F]fluorodeoxyglucose ([(18)F]FDG) concentration measured by positron emission tomography (PET) to a measurement of physiological parameters. However, all the proposed models have been developed and tested mostly for brain studies. The purpose of the present study is to select the most accurate model for describing [(18)F]FDG kinetics in human skeletal muscle. The database consists of basal and hyperinsulinemic-euglycemic studies performed in normal subjects. PET data were first analyzed by an input-output modeling technique (often called spectral analysis). These results provided guidelines for developing a compartmental model. A new model with four compartments and five rate constants (5K model) emerged as the best. By accounting for plasma and extracellular and intracellular kinetics, this model allows, for the first time, PET assessment of the individual steps of [(18)F]FDG kinetics in human skeletal muscle, from plasma to extracellular space to transmembrane transport into the cell to intracellular phosphorylation. Insulin is shown to affect transport and phosphorylation but not extracellular kinetics, with the transport step becoming the main site of control. The 5K model also allows definition of the domain of validity of the classic three-compartment three- or four-rate-constant models. These models are candidates for an investigative tool to quantitatively assess insulin control on individual metabolic steps in human muscle in normal and physiopathological states.

The effect of age on human striatal dopamine D2 receptors was investigated with positron emission tomography (PET) using [11C]raclopride as a radioligand. Twenty-one healthy volunteers aged from 20 to 81 years were studied. An equilibrium method was applied and two separate PET scans with different specific activities of [11C]raclopride were performed. The maximal number of receptors (Bmax) and their dissociation constant (Kd) were calculated using Scatchard analysis. There was an age-dependent decline in the Bmax (r = -0.49; p = 0.02) of striatal D2 receptors while the Kd remained unchanged. The results show that there is an age-related loss of striatal D2 receptors, which, together with other changes in the brain nigrostriatal dopaminergic system, may contribute to extrapyramidal symptoms associated with aging.

OBJECTIVE -Impaired insulin-mediated hepatic glucose uptake (HGU) has been implicated in the hyperglycemia of type 2 diabetes. We examined the effects of metformin (2 g/day) and rosiglitazone (8 mg/day) monotherapy on HGU and its relation to subcutaneous fat, visceral fat (VF), and whole-body insulin-mediated glucose metabolism in type 2 diabetic patients.RESEARCH DESIGN AND METHODS -Glucose uptake was measured before and after 26 weeks of treatment using positron emission tomography with [18 F]2-fluoro-2-deoxyglucose during euglycemic hyperinsulinemia; fat depots were quantified by magnetic resonance imaging.RESULTS -Fasting plasma glucose levels were significantly decreased after either rosiglitazone (Ϫ0.9 Ϯ 0.5 mmol/l) or metformin treatment (Ϫ1.1 Ϯ 0.5 mmol/l) in comparison with placebo; only metformin was associated with weight loss (P Ͻ 0.02 vs. placebo). When controlling for the latter, the placebo-subtracted change in whole-body glucose uptake averaged Ϫ1 Ϯ 4 mol ⅐ min Ϫ1 ⅐ kg Ϫ1 in metformin-treated patients (NS) and ϩ9 Ϯ 3 mol ⅐ min Ϫ1 ⅐ kg Ϫ1 in rosiglitazone-treated patients (P ϭ 0.01). Both rosiglitazone and metformin treatment were associated with an increase in HGU; versus placebo, the change reached statistical significance when controlling for sex (placebo-subtracted values ϭ ϩ0.008 Ϯ 0.004 mol ⅐ min Ϫ1 ⅐ kg Ϫ1 ⅐ pmol/l Ϫ1 , P Ͻ 0.03, for metformin; and ϩ0.007 Ϯ 0.004, P Ͻ 0.07, for rosiglitazone). After treatment with either drug, insulin-mediated VF glucose uptake (VFGU) was higher than with placebo. In the whole dataset, changes in HGU were negatively related to changes in HbA 1c (r ϭ 0.43, P ϭ 0.01) and positively associated with changes in VFGU (r ϭ 0.48, P Ͻ 0.01).CONCLUSIONS -We conclude that both metformin and rosiglitazone monotherapy increase HGU in type 2 diabetes; direct drug actions, better glycemic control, and enhanced VF insulin sensitivity are likely determinants of this phenomenon. Diabetes Care 26:2069 -2074, 2003T he ability of insulin to stimulate hepatic glucose uptake (HGU) is impaired in patients with type 2 diabetes (1), contributing to the development of hyperglycemia. The defect appears to involve the first steps of glucose uptake and metabolism in the liver, eventually leading to decreased glycogen synthesis (1). These findings are in line with the notion that glucokinase is ratelimiting for glucose entry into the liver (2) and that genetic defects of glucokinase activity associated with human maturityonset diabetes of young (MODY-2) lead to decreased HGU and glycogen synthesis (3). In acquired forms of diabetes, hepatic glucokinase activity was decreased in liver biopsies obtained from obese type 2 diabetic individuals (4), and the direct HGUmediated pathway of glycogen synthesis was reduced in poorly controlled type 1 diabetic individuals (5) and in modestly hyperglycemic type 2 diabetic patients (1). The mechanisms underlying these findings are not completely understood. Insulin has been hypothesized to be the main regulator of these enzymatic steps (1,6). Therefor...

Quantitative 2-[(18)F]fluoro-2-deoxy-D-glucose ([(18)F]FDG) positron emission tomography (PET) has been widely used to calculate glucose utilization in skeletal muscle. FDG-PET results depend partly on the lumped constant (LC), which accounts for the differences in the transport and phosphorylation between [(18)F]FDG and glucose. In this study, we estimated the LC for [(18)F]FDG directly in normal and in insulin-resistant obese subjects by combining FDG PET with the microdialysis technique. Eight obese [age 29.4 +/- 1.0 yr, body mass index (BMI) 33.6 +/- 1.0 kg/m(2)] and eight nonobese (age 25.0 +/- 1.0 yr, BMI 23.1 +/- 1.0 kg/m(2)) males were studied during euglycemic hyperinsulinemia (1 mU. kg(-1).min(-1) for 150 min). Muscle blood flow was measured using (15)O-labeled water and PET. Muscle [(18)F]FDG uptake (rGU(FDG)) was calculated with Patlak graphic analysis. Interstitial glucose concentration of the quadriceps femoris muscle was measured simultaneously with [(18)F]FDG scanning using microdialysis. Muscle glucose uptake (by microdialysis, rGU(MD)) was calculated by multiplying glucose extraction by regional muscle blood flow. A significant correlation was found between rGU(MD) and rGU(FDG) (r = 0.78, P < 0.01). The LC was determined as the ratio of the rGU(FDG) to the rGU(MD). The LC averaged 1.16 +/- 0.16 and was similar in the obese and nonobese subjects (1.15 +/- 0.11 vs. 1.16 +/- 0.07, respectively, not significant). In conclusion, the microdialysis technique can be reliably combined with FDG PET to measure glucose uptake in skeletal muscle. Direct measurements with these two independent techniques suggest an LC value of 1.2 for [(18)F]FDG in human skeletal muscle during insulin stimulation, and the LC appears not to be sensitive to insulin resistance.