Impaired free fatty acid uptake in skeletal muscle but not in myocardium in patients with impaired glucose tolerance: studies with PET and 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid.

Abstract

Free fatty acids (FFAs) are an important substrate for myocardial and skeletal muscle metabolism, and increased availability and oxidation of FFA are suggested to be associated with insulin resistance. This study was undertaken to assess whether myocardial or muscle uptake of FFA is altered in patients with impaired glucose tolerance (IGT). Eight healthy men (control group; age 48+/-1 years, BMI 25+/-1 kg/m2, mean +/- SE) and eight men with IGT (glucose-intolerant group; age 49+/-1 years, BMI 29+/-1 kg/m2) were studied in the fasting state. Myocardial oxygen consumption and blood flow and myocardial and femoral muscle FFA uptake rates were measured with positron emission tomography (PET) and [15O]O2, [15O]H2O, [15O]CO, and 14(R, S)-[18F]fluoro-6-thia-heptadecanoic acid ([18F]FTHA), a fatty acid tracer trapped into the cell after undergoing initial steps of beta-oxidation. Serum glucose and insulin concentrations were higher in the glucose-intolerant group during the PET study, but FFA concentrations were comparable between the groups. No differences between the groups were observed in the myocardial blood flow, oxygen consumption, fractional FTHA uptake rates, or FFA uptake indices (5.6+/-0.4 vs. 5.2+/-0.4 pmol x 100 g(-1) x min(-1), glucose-intolerant versus control, NS). In the femoral muscle, fractional FTHA uptake (0.0062+/-0.0003 vs. 0.0072+/-0.0003 min(-1), P = 0.044) and FFA uptake indices (0.30+/-0.02 vs. 0.43+/-0.04 min(-1), P = 0.020) were significantly lower in the glucose-intolerant group than in the control group. In conclusion, when studied at the fasting state and normal serum FFA concentrations, subjects with IGT have similar myocardial but lowered femoral muscle FFA uptake. This finding argues against the hypothesis that an increased oxidation of serum FFA, via the competition of glucose and FFA as fuel sources, is the primary cause for impaired peripheral glucose utilization and insulin resistance commonly observed in IGT.

Reduced Lipid Oxidation in Skeletal Muscle From Type 2 Diabetic Subjects May Be of Genetic Origin

“…Moreover, subjects with impaired glucose tolerance express a reduced fatty acid uptake (5,32). However, lipid uptake did not seem to be primarily affected under basal conditions or acute insulin stimulation in our study, indicating that lipid uptake in vivo was decreased as an adaptive reaction.…”

Effect of Obesity and Insulin Resistance on Myocardial Substrate Metabolism and Efficiency in Young Women

“…36 Therefore, it is possible that the alterations in fatty acid metabolism observed in young obese women in the present study may not apply to men studied previously by other investigators. 34,35 We found that MGU tended to be inversely associated with BMI and plasma glucose AUC, but the relationship was not statistically significant even though MFAUp, MFAU, and MFAO correlated significantly with BMI, plasma glucose AUC, or both. This pattern of substrate metabolism parallels that seen in obese animals that are studied early in the course of their progression from insulin resistance to type II diabetes and in isolated working rat heart models that are infused with leptin.…”

“…In those studies, MFAUp and MFAO were not different between normal volunteers and subjects with impaired glucose tolerance. 34,35 However, differences in study subject sex, age, and endogenous myocardial fat content and the choice of tracers between studies may have affected the results. Data from studies conducted in experimental animals suggest that estrogens increase MFAO.…”

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

“…Despite increased adipose tissue lipolysis, skeletal muscle lipid clearance is decreased in obese, type 2 diabetics (Kelley & Simoneau 1994, Turpeinen et al 1999, Blaak et al 2000, Blaak 2003, Goossens et al 2016. The combination of increased fatty acid release from adipose tissue and decreased clearance by skeletal muscle results in hyperlipidemia and increased reliance on the liver to clear fatty acids (Lewis et al 2002, Jonkers et al 2013, Janssens et al 2015.…”