Effect of a Sustained Reduction in Plasma Free Fatty Acid Concentration on Intramuscular Long-Chain Fatty Acyl-CoAs and Insulin Action in Type 2 Diabetic Patients

Headnote

To investigate the effect of a sustained (7-day) decrease in plasma free fatty acid (FFA) concentrations on insulin action and intramyocellular long-chain fatty acyl-CoAs (LCFA-CoAs), we studied the effect of acipimox, a potent inhibitor of lipolysis, in seven type 2 diabetic patients (age 53 ± 3 years, BMI 30.2 ± 2.0 kg/m^sup 2^, fasting plasma glucose 8.5 ± 0.8 mmol/l, HbA^sub 1c^ 7.5 ± 0.4%). Subjects received an oral glucose tolerance test (OGTT) and 120-min euglycemic insulin (80 mU/m^sup 2^ per min) clamp with 3-[^sup 3^H]glucose/ vastus lateralis muscle biopsies to quantitate rates of insulin-mediated whole-body glucose disposal (R^sub d^) and intramyocellular LCFA-CoAs before and after acipimox (250 mg every 6 h for 7 days). Acipimox significantly reduced fasting plasma FFAs (from 563 ± 74 to 230 ± 33 µmol/l P < 0.01) and mean plasma FFAs during the OGTT (from 409 ± 44 to 184 ± 22 µmol/l; P < 0.01). After acipimox, decreases were seen in fasting plasma insulin (from 78 ± 18 to 42 ± 6 pmol/l; P < 0.05), fasting plasma glucose (from 8.5 ± 0.8 to 7.0 ± 0.5 mmol/l; P < 0.02), and mean plasma glucose during the OGTT (from 14.5 ± 0.8 to 13.0 ± 0.8 mmol/l; P < 0.05). After acipimox, insulin-stimulated R^sub d^ increased from 3.3 ± 0.4 to 4.4 ± 0.4 mg . kg^sup -1^ . min^sup -1^ (P < 0.03), whereas suppression of endogenous glucose production (EGP) was similar and virtually complete during both insulin clamp studies (0.16 ± 0.10 vs. 0.14 ± 0.10 mg . kg^sup -1^ . min^sup -1^; P > 0.05). Basal EGP did not change after acipimox (1.9 ± 0.2 vs. 1.9 ± 0.2 mg . kg^sup -1^ . min^sup -1^). Total muscle LCFA-CoA content decreased after acipimox treatment (from 7.26 ± 0.58 to 5.64 ± 0.79 nmol/g; P < 0.05). Decreases were also seen in muscle palmityl CoA (16:0; from 1.06 ± 0.10 to 0.75 ± 0.11 nmol/g; P < 0.05), palmitoleate CoA (16:1; from 0.48 ± 0.05 to 0.33 ± 0.05 nmol/g; P = 0.07), oleate CoA (18:1; from 2.60 ± 0.11 to 1.95 ± 0.31 nmol/g; P < 0.05), linoleate CoA (18:2; from 1.81 ± 0.26 to 1.38 ± 0.18 nmol/g; P = 0.13), and linolenate...