L-carnitine infusion does not alleviate lipid-induced insulin resistance and metabolic inflexibility.

BACKGROUND: Low carnitine status may underlie the development of insulin resistance and metabolic inflexibility. Intravenous lipid infusion elevates plasma free fatty acid (FFA) concentration and is a model for simulating insulin resistance and metabolic inflexibility in healthy, insulin sensitive volunteers. Here, we hypothesized that co-infusion of L-carnitine may alleviate lipid-induced insulin resistance and metabolic inflexibility. METHODS: In a randomized crossover trial, eight young healthy volunteers underwent hyperinsulinemic-euglycemic clamps (40mU/m2/min) with simultaneous infusion of saline (CON), Intralipid (20%, 90mL/h) (LIPID), or Intralipid (20%, 90mL/h) combined with L-carnitine infusion (28mg/kg) (LIPID+CAR). Ten volunteers were randomized for the intervention arms (CON, LIPID and LIPID+CAR), but two dropped-out during the study. Therefore, eight volunteers participated in all three intervention arms and were included for analysis. RESULTS: L-carnitine infusion elevated plasma free carnitine availability and resulted in a more pronounced increase in plasma acetylcarnitine, short-, medium-, and long-chain acylcarnitines compared to lipid infusion, however no differences in skeletal muscle free carnitine or acetylcarnitine were found. Peripheral insulin sensitivity and metabolic flexibility were blunted upon lipid infusion compared to CON but L-carnitine infusion did not alleviate this. CONCLUSION: Acute L-carnitine infusion could not alleviated lipid-induced insulin resistance and metabolic inflexibility and did not alter skeletal muscle carnitine availability. Possibly, lipid-induced insulin resistance may also have affected carnitine uptake and may have blunted the insulin-induced carnitine storage in muscle. Future studies are needed to investigate this.

Passive exposure to heat improves glucose metabolism in overweight humans.

AIM: Heat exposure has been indicated to positively affect glucose metabolism. An involvement of heat shock protein 72 (HSP72) in the enhancement of insulin sensitivity upon heat exposure has been previously suggested. Here, we performed an intervention study exploring the effect of passive heat acclimation (PHA) on glucose metabolism and intracellular (a) HSP72 concentrations in overweight humans. METHODS: Eleven non-diabetic overweight (BMI 27-35 kg/m2 ) participants underwent 10 consecutive days of PHA (4-6 h/day, 34.4 ± 0.2°C, 22.8 ± 2.7%RH). Before and after PHA, whole-body insulin sensitivity was assessed using a one-step hyperinsulinaemic-euglycaemic clamp, skeletal muscle biopsies were taken to measure intracellular iHSP72, energy expenditure and substrate oxidation were measured using indirect calorimetry and blood samples were drawn to assess markers of metabolic health. Thermophysiological adaptations were measured during a temperature ramp protocol before and after PHA. RESULTS: Despite a lack of change in iHSP72, 10 days of PHA reduced basal (9.7 ± 1.4 pre- vs 8.4 ± 2.1 µmol · kg-1 · min-1 post-PHA, P = .038) and insulin-stimulated (2.1 ± 0.9 pre- vs 1.5 ± 0.8 µmol · kg-1 · min-1 post-PHA, P = .005) endogenous glucose production (EGP) and increased insulin suppression of EGP (78.5 ± 9.7% pre- vs 83.0 ± 7.9% post-PHA, P = .028). Consistently, fasting plasma glucose (6.0 ± 0.5 pre- vs 5.8 ± 0.4 mmol/L post-PHA, P = .013) and insulin concentrations (97 ± 55 pre- vs 84 ± 49 pmol/L post-PHA, P = .026) decreased significantly. Moreover, fat oxidation increased, and free fatty acids as well as cholesterol concentrations and mean arterial pressure decreased after PHA. CONCLUSION: Our results show that PHA for 10 days improves glucose metabolism and enhances fat metabolism, without changes in iHSP72. Further exploration of the therapeutic role of heat in cardio-metabolic disorders should be considered.

Nicotinamide riboside supplementation alters body composition and skeletal muscle acetylcarnitine concentrations in healthy obese humans.

BACKGROUND: Nicotinamide riboside (NR) is an NAD+ precursor that boosts cellular NAD+ concentrations. Preclinical studies have shown profound metabolic health effects after NR supplementation. OBJECTIVES: We aimed to investigate the effects of 6 wk NR supplementation on insulin sensitivity, mitochondrial function, and other metabolic health parameters in overweight and obese volunteers. METHODS: A randomized, double-blinded, placebo-controlled, crossover intervention study was conducted in 13 healthy overweight or obese men and women. Participants received 6 wk NR (1000 mg/d) and placebo supplementation, followed by broad metabolic phenotyping, including hyperinsulinemic-euglycemic clamps, magnetic resonance spectroscopy, muscle biopsies, and assessment of ex vivo mitochondrial function and in vivo energy metabolism. RESULTS: Markers of increased NAD+ synthesis-nicotinic acid adenine dinucleotide and methyl nicotinamide-were elevated in skeletal muscle after NR compared with placebo. NR increased body fat-free mass (62.65% ± 2.49% compared with 61.32% ± 2.58% in NR and placebo, respectively; change: 1.34% ± 0.50%, P = 0.02) and increased sleeping metabolic rate. Interestingly, acetylcarnitine concentrations in skeletal muscle were increased upon NR (4558 ± 749 compared with 3025 ± 316 pmol/mg dry weight in NR and placebo, respectively; change: 1533 ± 683 pmol/mg dry weight, P = 0.04) and the capacity to form acetylcarnitine upon exercise was higher in NR than in placebo (2.99 ± 0.30 compared with 2.40 ± 0.33 mmol/kg wet weight; change: 0.53 ± 0.21 mmol/kg wet weight, P = 0.01). However, no effects of NR were found on insulin sensitivity, mitochondrial function, hepatic and intramyocellular lipid accumulation, cardiac energy status, cardiac ejection fraction, ambulatory blood pressure, plasma markers of inflammation, or energy metabolism. CONCLUSIONS: NR supplementation of 1000 mg/d for 6 wk in healthy overweight or obese men and women increased skeletal muscle NAD+ metabolites, affected skeletal muscle acetylcarnitine metabolism, and induced minor changes in body composition and sleeping metabolic rate. However, no other metabolic health effects were observed.This trial was registered at clinicaltrials.gov as NCT02835664.

Carnitine supplementation improves metabolic flexibility and skeletal muscle acetylcarnitine formation in volunteers with impaired glucose tolerance: A randomised controlled trial.

BACKGROUND: Type 2 diabetes patients and individuals at risk of developing diabetes are characterized by metabolic inflexibility and disturbed glucose homeostasis. Low carnitine availability may contribute to metabolic inflexibility and impaired glucose tolerance. Here, we investigated whether carnitine supplementation improves metabolic flexibility and insulin sensitivity in impaired glucose tolerant (IGT) volunteers. METHODS: Eleven IGT- volunteers followed a 36-day placebo- and L-carnitine treatment (2 g/day) in a randomised, placebo-controlled, double blind crossover design. A hyperinsulinemic-euglycemic clamp (40 mU/m2/min), combined with indirect calorimetry (ventilated hood) was performed to determine insulin sensitivity and metabolic flexibility. Furthermore, metabolic flexibility was assessed in response to a high-energy meal. Skeletal muscle acetylcarnitine concentrations were measured in vivo using long echo time proton magnetic resonance spectroscopy (1H-MRS, TE=500 ms) in the resting state (7:00AM and 5:00PM) and after a 30-min cycling exercise. Twelve normal glucose tolerant (NGT) volunteers were included without any intervention as control group. RESULTS: Metabolic flexibility of IGT-subjects completely restored towards NGT control values upon carnitine supplementation, measured during a hyperinsulinemic-euglycemic clamp and meal test. In muscle, carnitine supplementation enhanced the increase in resting acetylcarnitine concentrations over the day (delta 7:00 AM versus 5:00 PM) in IGT-subjects. Furthermore, carnitine supplementation increased post-exercise acetylcarnitine concentrations and reduced long-chain acylcarnitine species in IGT-subjects, suggesting the stimulation of a more complete fat oxidation in muscle. Whole-body insulin sensitivity was not affected. CONCLUSION: Carnitine supplementation improves acetylcarnitine formation and rescues metabolic flexibility in IGT-subjects. Future research should investigate the potential of carnitine in prevention/treatment of type 2 diabetes.

High oxidative capacity due to chronic exercise training attenuates lipid-induced insulin resistance.

Fat accumulation in skeletal muscle combined with low mitochondrial oxidative capacity is associated with insulin resistance (IR). Endurance-trained athletes, characterized by a high oxidative capacity, have elevated intramyocellular lipids, yet are highly insulin sensitive. We tested the hypothesis that a high oxidative capacity could attenuate lipid-induced IR. Nine endurance-trained (age = 23.4 ± 0.9 years; BMI = 21.2 ± 0.6 kg/m(2)) and 10 untrained subjects (age = 21.9 ± 0.9 years; BMI = 22.8 ± 0.6 kg/m(2)) were included and underwent a clamp with either infusion of glycerol or intralipid. Muscle biopsies were taken to perform high-resolution respirometry and protein phosphorylation/expression. Trained subjects had ~32% higher mitochondrial capacity and ~22% higher insulin sensitivity (P < 0.05 for both). Lipid infusion reduced insulin-stimulated glucose uptake by 63% in untrained subjects (P < 0.05), whereas this effect was blunted in trained subjects (29%, P < 0.05). In untrained subjects, lipid infusion reduced oxidative and nonoxidative glucose disposal (NOGD), whereas trained subjects were completely protected against lipid-induced reduction in NOGD, supported by dephosphorylation of glycogen synthase. We conclude that chronic exercise training attenuates lipid-induced IR and specifically attenuates the lipid-induced reduction in NOGD. Signaling data support the notion that high glucose uptake in trained subjects is maintained by shuttling glucose toward storage as glycogen.

The role of metformin and thiazolidinediones in the regulation of hepatic glucose metabolism and its clinical impact.

Fasting hyperglycemia in type 2 diabetes mellitus (T2DM) results from elevated endogenous glucose production (EGP), which is mostly due to augmented hepatic gluconeogenesis. Insulin-resistant humans exhibit impaired insulin-dependent suppression of EGP and excessive hepatic lipid storage (steatosis), which relates to abnormal supply of free fatty acids (FFA) and energy metabolism. Only two glucose-lowering drug classes, the biguanide metformin and the thiazolidendiones (TZDs), exert insulin- and glucagon-independent hepatic effects. Preclinical studies suggest that metformin inhibits mitochondrial complex I. TZDs, as peroxisome proliferator-activated receptor (PPAR) γ-agonists, predominantly reduce the flux of FFA and cytokines from adipose tissue to the liver, but could also directly inhibit mitochondrial complex I. Although both metformin and TZDs improve fasting hyperglycemia and EGP in clinical trials, only TZDs decrease steatosis and peripheral insulin resistance. More studies are required to address their effects on hepatocellular energy metabolism with a view to identifying novel targets for the treatment of T2DM.