Although IL-6 is a key modulator of immune function, it also plays a role in regulating substrate metabolism. To determine whether IL-6 affects lipid metabolism, 18 healthy men were infused for 3 h with saline (Con; n = 6) or a high dose (High-rhIL6; n = 6) or a low dose (Low-rhIL6; n = 6) of recombinant human IL-6 (rhIL-6). The IL-6 concentration during Con, Low-rhIL6, and High-rhIL6 was at a steady state after 30 min of infusion at approximately 4, 140, and 320 pg/ml, respectively. Either dose of rhIL-6 was associated with a similar increase in fatty acid (FA) concentration and endogenous FA rate of appearance (R_a) from 90 min after the start of the infusion. The FA concentration and FA R_a continued to increase until the cessation of rhIL-6 infusion, reaching levels approximately 50% greater than Con values. The elevated levels reached at the end of rhIL-6 infusion persisted at least 3 h postinfusion. Triacylglycerol concentrations were unchanged during rhIL-6 infusion, whereas whole body fat oxidation increased after the second hour of rhIL-6 infusion. Of note, during Low-rhIL6, the induced elevation in FA concentration and FA R_a occurred in the absence of any change in adrenaline, insulin, or glucagon, and no adverse side effects were observed. In conclusion, the data identify IL-6 as a potent modulator of fat metabolism in humans, increasing fat oxidation and FA reesterification without causing hypertriacylglyceridemia.

We investigated the importance of the two catalytic alpha-isoforms of the 5'-AMP-activated protein kinase (AMPK) in 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR) and contraction-induced glucose uptake in skeletal muscle. Incubated soleus and EDL muscle from whole-body alpha2- or alpha1-AMPK knockout (KO) and wild type (WT) mice were incubated with 2.0 mm AICAR or electrically stimulated to contraction. Both AICAR and contraction increased 2DG uptake in WT muscles. KO of alpha2, but not alpha1, abolished AICAR-induced glucose uptake, whereas neither KO affected contraction-induced glucose uptake. AICAR and contraction increased alpha2- and alpha1-AMPK activity in wild type (WT) muscles. During AICAR stimulation, the remaining AMPK activity in KO muscles increased to the same level as in WT. During contraction, the remaining AMPK activity in alpha2-KO muscles was elevated by 100% probably explained by a 2-3-fold increase in alpha1-protein. In alpha1-KO muscles, alpha2-AMPK activity increased to similar levels as in WT. Both interventions increased total AMPK activity, as expressed by AMPK-P and ACCbeta-P, in WT muscles. During AICAR stimulation, this was dramatically reduced in alpha2-KO but not in alpha1-KO, whereas during contraction, both measurements were essentially similar to WT in both KO-muscles. The results show that alpha2-AMPK is the main donor of basal and AICAR-stimulated AMPK activity and is responsible for AICAR-induced glucose uptake. In contrast, during contraction, the two alpha-isoforms seem to substitute for each other in terms of activity, which may explain the normal glucose uptake despite the lack of either alpha2- or alpha1-AMPK. Alternatively, neither alpha-isoform of AMPK is involved in contraction-induced muscle glucose uptake.

Insulin resistance and type 2 diabetes are associated with mitochondrial dysfunction. The aim of the present study was to test the hypothesis that oxidative phosphorylation and electron transport capacity are diminished in the skeletal muscle of type 2 diabetic subjects, as a result of a reduction in the mitochondrial content. The O₂ flux capacity of permeabilised muscle fibres from biopsies of the quadriceps in healthy subjects (n = 8; age 58 ± 2 years [mean±SEM]; BMI 28 ± 1 kg/m²; fasting plasma glucose 5.4 ± 0.2 mmol/l) and patients with type 2 diabetes (n = 11; age 62 ± 2 years; BMI 32 ± 2 kg/m²; fasting plasma glucose 9.0 ± 0.8 mmol/l) was measured by high-resolution respirometry. O₂ flux expressed per mg of muscle (fresh weight) during ADP-stimulated state 3 respiration was lower (p < 0.05) in patients with type 2 diabetes in the presence of complex I substrate (glutamate) (31 ± 2 vs 43 ± 3 pmol O₂ s⁻¹ mg⁻¹) and in response to glutamate + succinate (parallel electron input from complexes I and II) (63 ± 3 vs 85 ± 6 pmol s⁻¹ mg⁻¹). Further increases in O₂ flux capacity were observed in response to uncoupling by FCCP, but were again lower (p < 0.05) in type 2 diabetic patients than in healthy control subjects (86 ± 4 vs 109 ± 8 pmol s⁻¹ mg⁻¹). However, when O₂ flux was normalised for mitochondrial DNA content or citrate synthase activity, there were no differences in oxidative phosphorylation or electron transport capacity between patients with type 2 diabetes and healthy control subjects. Mitochondrial function is normal in type 2 diabetes. Blunting of coupled and uncoupled respiration in type 2 diabetic patients can be attributed to lower mitochondrial content.