Single nucleotide polymorphisms in the peroxisome proliferator-activated receptor delta gene are associated with skeletal muscle glucose uptake.

The peroxisome proliferator-activated receptors (PPARs) belong to a superfamily of nuclear receptors. It includes PPAR-delta, a key regulator of fatty acid oxidation and energy uncoupling, universally expressed in different tissues. The PPAR-delta gene (PPARD) maps to 6p21.2-p21.1 and has 11 exons and spans 35 kbp. We investigated the effects of single nucleotide polymorphisms (SNPs) of PPARD on whole-body, skeletal muscle, and subcutaneous adipose tissue glucose uptake in 129 healthy individuals using the hyperinsulinemic-euglycemic clamp technique combined with fluorine-18-labeled fluorodeoxyglucose ([18F]FDG) and positron emission tomography (PET). Three of six SNPs of PPARD and their haplogenotypes were significantly associated with whole-body insulin sensitivity. [18F]FDG-PET scanning indicated that SNPs of PPARD primarily affected insulin sensitivity by modifying glucose uptake in skeletal muscle but not in adipose tissue. Our results give evidence that SNPs of PPARD regulate insulin sensitivity particularly in skeletal muscle.

The effect of the Ala12 allele of the peroxisome proliferator-activated receptor-gamma2 gene on skeletal muscle glucose uptake depends on obesity: a positron emission tomography study.

CONTEXT: The Pro(12)Ala polymorphism of the peroxisome proliferator-activated receptor-gamma2 gene is associated with insulin sensitivity. Obesity is a major risk factor for insulin resistance, but the association of the Pro(12)Ala polymorphism with body weight has been controversial. Furthermore, obesity may modulate the effect of this polymorphism on insulin sensitivity. OBJECTIVE: The aim of our study was to investigate the effects of the Pro(12)Ala polymorphism on skeletal muscle and adipose tissue glucose uptake (GU) in nonobese and obese subjects. DESIGN: The design was a cross-sectional study. STUDY SUBJECTS: The rates of GU were investigated in 124 (72 nonobese and 52 obese; body mass index cutoff point, 27 kg/m(2)) healthy subjects with the euglycemic hyperinsulinemic clamp. Skeletal muscle and adipose tissue GU and skeletal muscle perfusion were measured using fluorine-18-labeled fluorodeoxyglucose, [(15)O]H(2)O, and positron emission tomography. RESULTS: The rates of skeletal muscle GU were higher in nonobese subjects carrying the Ala(12) allele than in subjects carrying the Pro(12)Pro genotype (P = 0.004), whereas no differences were found in skeletal muscle perfusion between the groups. In contrast, in obese subjects the rates of skeletal muscle GU did not differ between carriers of the Ala(12) allele and carriers of the Pro(12)Pro genotype. No difference in adipose tissue GU was found in either nonobese or obese subjects according to Pro(12)Ala polymorphism. CONCLUSIONS: We conclude that the Pro(12)Ala polymorphism modulates skeletal muscle GU differently in nonobese and obese subjects.

Insulin- and exercise-stimulated skeletal muscle blood flow and glucose uptake in obese men.

OBJECTIVE: Insulin resistance in obese subjects results in the impaired use of glucose by insulin-sensitive tissues, e.g., skeletal muscle. In the present study, we determined whether insulin resistance in obesity is associated with an impaired ability of exercise to stimulate muscle blood flow, oxygen delivery, or glucose uptake. RESEARCH METHODS AND PROCEDURES: Nine obese (body mass index = 36 +/- 2 kg/m(2)) and 11 age-matched nonobese men (body mass index = 22 +/- 1 kg/m(2)) performed one-legged isometric exercise during hyperinsulinemia. Rates of femoral muscle blood flow, oxygen consumption, and glucose uptake were measured simultaneously in both legs using [(15)O]H(2)O, [(15)O]O(2), [(18)F]fluoro-deoxy-glucose, and positron emission tomography. RESULTS: The obese subjects exhibited resistance to insulin stimulation of glucose uptake in resting muscle, regardless of whether glucose uptake was expressed per kilogram of femoral muscle mass (p = 0.001) or per the total mass of quadriceps femoris muscle. At similar workloads, oxygen consumption, blood flow, and glucose uptake were lower in the obese than the nonobese subjects when expressed per kilogram of muscle, but similar when expressed per quadriceps femoris muscle mass. DISCUSSION: We conclude that obesity is characterized by insulin resistance of glucose uptake in resting skeletal muscle regardless of how glucose uptake is expressed. When compared with nonobese individuals at similar absolute workloads and under identical hyperinsulinemic conditions, the ability of exercise to increase muscle oxygen uptake, blood flow, and glucose uptake per muscle mass is blunted in obese insulin-resistant subjects. However, these defects are compensated for by an increase in muscle mass.

Amino acid uptake in the skeletal muscle measured using [11C]methylaminoisobutyrate (MEAIB) and PET.

An amino acid analogue, [(11)C]MeAIB, recently introduced for oncological positron emission tomography (PET) studies, is a highly selective substrate for insulin-sensitive amino acid transport system A. The aim of this study was to study the uptake kinetics of [(11)C]MeAIB in skeletal muscle in the fasting state and during insulin stimulation. Two dynamic PET studies were carried out in 11 healthy subjects, once in the fasting state and once during euglycaemic hyperinsulinaemia (serum insulin 67+/-12 mU l(-1)). Graphical analysis was used to calculate the fractional [(11)C]MeAIB uptake rate ( K(i)). Amino acid uptake was estimated by multiplying K(i) by the serum amino acid concentration. After tracer injection, rapid uptake in muscle tissue was detected both in the fasting state and during insulin stimulation and femoral muscles were clearly visualised in both studies. In the graphical analysis, the volume of distribution of [(11)C]MeAIB plotted against normalised plasma time yielded a linear curve (the slope of which = K(i)). The fractional [(11)C]MeAIB uptake rate ( K(i)) in the femoral muscle regions increased from 0.0070+/-0.0018 min(-1) (mean+/-SD) in the fasting state to 0.0079+/-0.0020 min(-1) ( P<0.05) during insulin stimulation. When compared with the fasting state, serum total amino acid concentration decreased from 2.49+/-0.22 to 2.16+/-0.18 mmol l(-1) ( P<0.0001) and the serum concentration of six amino acids typically using system A for their transport decreased from 0.72+/-0.1 to 0.63+/-0.07 mmol l(-1) ( P=0.0001) during hyperinsulinaemia. The calculated skeletal muscle total amino acid uptake and the uptake of the six amino acids typically using system A were similar in the fasting state and during insulin clamp (17.1+/-3.2 vs 17.7+/-3.7 micro mol kg(-1) min(-1), NS, and 5.0+/-1.3 vs 5.0+/-1.4 micro mol kg(-1) min(-1), NS, respectively). The uptake rates correlated with perfusion both in the fasting state and during hyperinsulinaemia ( P<0.05). [(11)C]MeAIB PET appears to be a feasible method for measurement of amino acid uptake in human skeletal muscle. As a tracer that is not metabolised in the tissues, [(11)C]MeAIB provides simple modelling and robust data analysis and thus provides a means to investigate amino acid uptake into muscle tissue in various disease conditions known to affect protein metabolism.

Glucose uptake and perfusion in subcutaneous and visceral adipose tissue during insulin stimulation in nonobese and obese humans.

To elucidate the role of adipose tissue glucose uptake in whole-body metabolism, sc and visceral adipose tissue glucose uptake and perfusion were measured in 10 nonobese and 10 age-matched obese men with positron emission tomography using [(18)F]-2-fluoro-2-deoxy-D-glucose, and [(15)O]-labeled water during normoglycemic hyperinsulinemia. Whole-body and skeletal muscle glucose uptake rates per kilogram were lower in obese than in nonobese subjects (P < 0.01). Compared with nonobese, the obese subjects had 67% lower abdominal sc and 58% lower visceral adipose tissue glucose uptake per kilogram of fat. In both groups, insulin stimulated glucose uptake per kilogram fat was significantly higher in visceral fat depots than in sc regions (P < 0.01). Both sc and visceral adipose tissue blood flow expressed per kilogram and minute was impaired in the obese subjects, compared with the nonobese (P < 0.05). Fat masses measured with magnetic resonance images were higher in obese than in nonobese individuals. If regional glucose uptake rates were expressed as per total fat mass, total glucose uptake rates per depot were similar in obese and nonobese subjects and represented 4.1% of whole-body glucose uptake in obese and 2.6% in nonobese subjects (P < 0.02 between the groups). In conclusion, insulin-stimulated glucose uptake per kilogram fat is higher in visceral than in sc adipose tissue. Glucose uptake and blood flow in adipose tissue exhibit insulin resistance in obesity, but because of the larger fat mass, adipose tissue does not seem to contribute substantially to the reduced insulin stimulated whole-body glucose uptake in obesity.