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1.
Effects of chronic decaffeinated green tea extract supplementation on lipolysis and substrate utilization during upper body exercise.
Blicher, S, Bartholomae, E, Kressler, J
Journal of sport and health science. 2021;(2):237-242
Abstract
BACKGROUND Decaffeinated green tea extract (dGTE) can increase fat oxidation during leg exercise, but dGTE is unsuitable for many people (e.g., those with injuries/disabilities), and its effects on arm exercise and women are unknown. METHODS Eight adults (23-37 years old, 4 women) performed an incremental arm cycle test to measure peak oxygen uptake (VO2peak), followed by four 1-h trials at 50% VO2peak. Subjects were randomly assigned to 650 mg of dGTE or placebo (PLA) for 4 weeks followed by a 4-week washout and crossover trial. Blood samples were obtained pre-exercise and post-exercise for glycerol and free fatty acid analysis. Respiratory gases were collected continuously. RESULTS VO2 showed no differences across trials ((0.83-0.89) ± (0.19-0.25) L/min, p = 0.460), neither did energy expenditure ((264-266) ± (59-77) kcal, p = 0.420) nor fat oxidation (dGTE = 0.11 to 0.12 g/min vs. PLA = 0.10 to 0.09 g/min, p = 0.220). Fat oxidation as percentage of energy expenditure was not different for dGTE vs. PLA (23% ± 12% to 25% ± 11% vs. 23% ± 10% to 21% ± 9%, p = 0.532). Glycerol concentration increased post-exercise in all trials, independent of treatments (pre = (3.4-5.1) ± (0.6-2.6) mg/dL vs. post = (7.9-9.8) ± (2.6-3.7) mg/dL, p = 0.867, η2 = 0.005 for interaction), as did free fatty acid ((3.5-4.8) ± (1.4-2.2) mg/dL vs. (7.2-9.1) ± (2.6-4.5) mg/dL, p = 0.981, η2 = 0.000). CONCLUSION Chronic dGTE supplementation had no effect on lipolysis and fat oxidation during arm cycle exercise in men and women.
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2.
Liver-Oriented Acute Metabolic Effects of A Low Dose of L-Carnitine under Fat-Mobilizing Conditions: Pilot Human Clinical Trial.
Odo, S, Tanabe, K, Yohda, M, Yamauchi, M
Journal of nutritional science and vitaminology. 2020;(2):136-149
Abstract
The acute metabolic effect of low dosages of L-carnitine under fat-mobilizing conditions was investigated. Healthy subjects (Study 1: n=5; Study 2: n=6) were asked to fast overnight. Then, 30 min of aerobic exercise on a cycle ergometer was performed after supplementation, followed by a 3.5-h sedentary recovery phase. The following ingestion patterns were used: Study 1 (i) noningestion, (ii) 750 mg of L-carnitine (LC), and (iii) 750 mg of LC+50 g of carbohydrate (CHO); Study 2 (iv) noningestion, (v) 500 mg of LC, (vi) 30 mg of CoQ10, and (vii) 500 mg of LC+30 mg of CoQ10. The energy expenditure (EE) and nonprotein respiratory quotient (npRQ) were measured during the pre-exercise, postexercise, and recovery periods. Serum free carnitine, acetylcarnitine, total carnitine (Study 1 and 2), and ketone bodies (Study 2) were measured. The 750 mg LC treatment significantly facilitated fat oxidation during the recovery phases (p<0.05) without elevating EE. The higher fat oxidation associated with LC was completely suppressed by CHO. CoQ10 affected neither npRQ nor EE. npRQ was significantly correlated with the serum total ketone bodies (R=-0.68, p<0.001) and acetylcarnitine (R=-0.61--0.70, p<0.001). The highest correlation was found between acetylcarnitine and total ketone bodies immediately after exercise (R=0.85, p<0.001). In conclusion, LC enhanced liver fat utilization and ketogenesis in an acute manner without stimulating EE under fat-mobilizing conditions.
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3.
Growth and differentiation factor 15 is secreted by skeletal muscle during exercise and promotes lipolysis in humans.
Laurens, C, Parmar, A, Murphy, E, Carper, D, Lair, B, Maes, P, Vion, J, Boulet, N, Fontaine, C, Marquès, M, et al
JCI insight. 2020;(6)
Abstract
We hypothesized that skeletal muscle contraction produces a cellular stress signal, triggering adipose tissue lipolysis to sustain fuel availability during exercise. The present study aimed at identifying exercise-regulated myokines, also known as exerkines, able to promote lipolysis. Human primary myotubes from lean healthy volunteers were submitted to electrical pulse stimulation (EPS) to mimic either acute intense or chronic moderate exercise. Conditioned media (CM) experiments with human adipocytes were performed. CM and human plasma samples were analyzed using unbiased proteomic screening and/or ELISA. Real-time qPCR was performed in cultured myotubes and muscle biopsy samples. CM from both acute intense and chronic moderate exercise increased basal lipolysis in human adipocytes. Growth and differentiation factor 15 (GDF15) gene expression and secretion increased rapidly upon skeletal muscle contraction. GDF15 protein was upregulated in CM from both acute and chronic exercise-stimulated myotubes. We further showed that physiological concentrations of recombinant GDF15 protein increased lipolysis in human adipose tissue, while blocking GDF15 with a neutralizing antibody abrogated EPS CM-mediated lipolysis. We herein provide the first evidence to our knowledge that GDF15 is a potentially novel exerkine produced by skeletal muscle contraction and able to target human adipose tissue to promote lipolysis.
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4.
Attenuation of Weight Loss Through Improved Antilipolytic Effect in Adipose Tissue Via the SGLT2 Inhibitor Tofogliflozin.
Yoshida, A, Matsubayashi, Y, Nojima, T, Suganami, H, Abe, T, Ishizawa, M, Fujihara, K, Tanaka, S, Kaku, K, Sone, H
The Journal of clinical endocrinology and metabolism. 2019;(9):3647-3660
Abstract
CONTEXT Although calorie loss from increased urinary glucose excretion continues after long-term treatment with sodium-glucose cotransporter 2 inhibitors (SGLT2is), the mechanisms of the attenuated weight loss due to SGLT2is are not well known. OBJECTIVE To examine the mechanism of the attenuated weight loss during long-term treatment with an SGLT2i, tofogliflozin, focusing on the antilipolytic effect of insulin on adipose tissue. DESIGN AND PARTICIPANTS An integrated analysis was performed using data from two phase 3 studies of 52 weeks of tofogliflozin administration. The antilipolytic effect was evaluated using adipose tissue insulin resistance (Adipo-IR) calculated from the product of the levels of fasting insulin (f-IRI) and fasting free fatty acids (f-FFAs). RESULTS Data from 774 patients with type 2 diabetes (mean age, 58.5 years; glycosylated hemoglobin, 8.1%; body mass index, 25.6 kg/m2; estimated glomerular filtration rate, 83.9 mL/min/1.73m2; 66% men) were analyzed. Weight loss plateaued between weeks 24 and 52 after decreasing significantly. f-IRI levels decreased significantly from baseline to week 24, and the decrease was maintained until Week 52. f-FFA levels significantly increased, peaked at week 24, then declined from weeks 24 to 52. Adipo-IR levels declined progressively throughout the 52 weeks (-3.6 mmol/L·pmol/L and -6.2 mmol/L·pmol/L at weeks 24 and 52, respectively; P < 0.001 baseline vs weeks 24 and 52 and week 24 vs week 52). Higher baseline Adipo-IR levels were independently associated with greater weight loss at week 52. CONCLUSION The improved antilipolytic effect in adipose tissue may attenuate progressive lipolysis, leading to attenuating future weight loss induced by an SGLT2i in patients with type 2 diabetes.
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Basal insulin peglispro increases lipid oxidation, metabolic flexibility, thermogenesis and ketone bodies compared to insulin glargine in subjects with type 1 diabetes mellitus.
Porksen, NK, Linnebjerg, H, Lam, ECQ, Garhyan, P, Pachori, A, Pratley, RE, Smith, SR
Diabetes, obesity & metabolism. 2018;(5):1193-1201
Abstract
AIMS: When treated with basal insulin peglispro (BIL), patients with type 1 diabetes mellitus (T1DM) exhibit weight loss and lower prandial insulin requirements versus insulin glargine (GL), while total insulin requirements remain similar. One possible explanation is enhanced lipid oxidation and improved ability to switch between glucose and lipid metabolism with BIL. This study compared the effects of BIL and GL on glucose and lipid metabolism in subjects with T1DM. MATERIALS AND METHODS Fifteen subjects with T1DM were enrolled into this open-label, randomised, crossover study, and received once-daily stable, individualised, subcutaneous doses of BIL and GL for 4 weeks each. Respiratory quotient (RQ) was measured using whole-room calorimetry, and energy expenditure (EE) and concentrations of ketone bodies (3-hydroxybutyrate) and acylcarnitines were assessed. RESULTS Mean sleep RQ was lower during the BIL (0.822) than the GL (0.846) treatment period, indicating greater lipid metabolism during the post-absorptive period with BIL. Increases in carbohydrate oxidation following breakfast were greater during BIL than GL treatment (mean change in RQ following breakfast 0.111 for BIL, 0.063 for GL). Furthermore, BIL treatment increased total daily EE versus GL (2215.9 kcal/d for BIL, 2135.5 kcal/d for GL). Concentrations of ketone bodies and acylcarnitines appeared to be higher following BIL than GL treatment. CONCLUSIONS BIL increased sleeping fat oxidation, EE, ketone bodies, acylcarnitines and post-prandial glucose metabolism when switching from conventional insulin, thus, restoring metabolic flexibility and increasing thermogenesis. These changes may explain the previously observed weight loss with BIL versus GL.
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Effects of Diazoxide-Mediated Insulin Suppression on Glucose and Lipid Metabolism in Nondiabetic Obese Men.
Loves, S, van Groningen, L, Filius, M, Mekking, M, Brandon, T, Tack, CJ, Hermus, A, de Boer, H
The Journal of clinical endocrinology and metabolism. 2018;(6):2346-2353
Abstract
CONTEXT It has been suggested that stimulation of lipolysis by diazoxide (DZX)-mediated insulin suppression may be useful in treating obesity. However, the optimal dose to promote lipolysis without causing hyperglycemia is unknown. OBJECTIVE To assess the effects of DZX in nondiabetic obese men on lipid and glucose metabolism. DESIGN Double-blind, placebo (PL)-controlled, 6-month trial in men with a body mass index of 30 to 37.5 kg/m2 treated with a combination of caloric restriction, a standardized exercise program, and DZX or PL dose escalation. RESULTS The mean maximal tolerated dose of DZX was 422 ± 44 mg/d (range, 200 to 700 mg/d). Dose-limiting events were edema (n = 11), hyperglycemia (n = 6), and nausea (n = 2). After dose reduction to a level free of clinical side effects, DZX treatment was associated with a markedly greater decrease in fasting insulin levels than PL (-72.3 ± 3.5% vs -23.0 ± 12.6%; P < 0.001) and a significant improvement of blood pressure and plasma lipid levels. The decline in insulin levels occurred at the cost of a small increase in plasma glucose (0.6 ± 0.2 mmol/L vs -0.1 ± 0.1 mmol/L; P = 0.04) and hemoglobin A1C (0.2 ± 0.1% vs 0.0 ± 0.1%; P = 0.17). CONCLUSION In nondiabetic obese men, insulin levels can be reduced up to 70% without major metabolic side effects. The marked intersubject variation in maximal tolerated dose indicates that DZX dose titration needs to be individualized.
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7.
Effect of exenatide on postprandial glucose fluxes, lipolysis, and ß-cell function in non-diabetic, morbidly obese patients.
Camastra, S, Astiarraga, B, Tura, A, Frascerra, S, Ciociaro, D, Mari, A, Gastaldelli, A, Ferrannini, E
Diabetes, obesity & metabolism. 2017;(3):412-420
Abstract
AIMS: To investigate the effect of exenatide on glucose disposal, insulin secretion, ß-cell function, lipolysis and hormone concentrations in non-diabetic, morbidly obese subjects under physiological conditions. MATERIALS AND METHODS Patients were assigned to exenatide 10 µg twice daily (EXE, n = 15) or control (CT, n = 15) for 3 months. Patients received a meal test/tracer study (MTT) to measure endogenous glucose production (EGP), rate of oral glucose appearance (RaO), insulin secretion rate (ISR), ß-cell function, hepatic insulin resistance (HIR) and adipose tissue insulin resistance (AT-IR) and insulin sensitivity (IS). RESULTS Post treatment, the EXE group showed a significant reduction in body weight ( P < .001). The postmeal time-course of glucose, insulin and ISR showed a lower peak between 60 and 180 minutes in phase with a reduction in RaO ( P < .01). After an initial similar suppression, EGP resumed at higher rates between 60 and 180 minutes ( P = .02) in EXE vs CT, while total RaO and EGP were similar throughout the MTT. In EXE, the postmeal glucagon, GLP1 and GIP responses were reduced ( P < .05). Fasting and postprandial lipolysis and ß-cell function were unaltered by active treatment. HIR, AT-IR and IS were all improved after exenatide treatment ( P < .05). CONCLUSIONS In morbidly obese non-diabetic subjects, exenatide causes weight loss, decreased postprandial glycaemia and glucagon response without changes in ß-cell function. These effects are consequent upon delayed oral glucose appearance in the circulation. Exenatide treatment is also associated with an improvement in hepatic, adipose tissue and whole-body IS with no influence on postprandial lipolysis.
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8.
Effects of insulin-induced hypoglycaemia on lipolysis rate, lipid oxidation and adipose tissue signalling in human volunteers: a randomised clinical study.
Voss, TS, Vendelbo, MH, Kampmann, U, Pedersen, SB, Nielsen, TS, Johannsen, M, Svart, MV, Jessen, N, Møller, N
Diabetologia. 2017;(1):143-152
Abstract
AIMS/HYPOTHESIS The aims of this study were to determine the role of lipolysis in hypoglycaemia and define the underlying intracellular mechanisms. METHODS Nine healthy volunteers were randomised to treatment order of three different treatments (crossover design). Treatments were: (1) saline control; (2) hyperinsulinaemic hypoglycaemia (HH; i.v. bolus of 0.1 U/kg insulin); and (3) hyperinsulinaemic euglycaemia (HE; i.v. bolus of 0.1 U/kg insulin and 20% glucose). Inclusion criteria were that volunteers were healthy, aged >18 years, had a BMI between 19 and 26 kg/m2, and provided both written and oral informed consent. Exclusion criteria were the presence of a known chronic disease (including diabetes mellitus, epilepsy, ischaemic heart disease and cardiac arrhythmias) and regular use of prescription medication. The data was collected at the medical research facilities at Aarhus University Hospital, Denmark. The primary outcome was palmitic acid flux. Participants were blinded to intervention order, but caregivers were not. RESULTS Adrenaline (epinephrine) and glucagon concentrations were higher during HH than during both HE and control treatments. NEFA levels and lipid oxidation rates (determined by indirect calorimetry) returned to control levels after 105 min. Palmitate flux was increased to control levels during HH (p = NS) and was more than twofold higher than during HE (overall mean difference between HH vs HE, 114 [95% CI 64, 165 μmol/min]; p < 0.001). In subcutaneous adipose tissue biopsies, we found elevated levels of hormone-sensitive lipase (HSL) and perilipin-1 phosphorylation 30 min after insulin injection during HH compared with both control and HE. There were no changes in the levels of adipose triglyceride lipase (ATGL), comparative gene identification-58 (CGI-58) or G0/G1 switch gene 2 (G0S2) proteins. Insulin-stimulated phosphorylation of Akt and mTOR were unaffected by hypoglycaemia. Expression of the G0S2 gene increased during HE and HH compared with control, without changes in ATGL (also known as PNPLA2) or CGI-58 (also known as ABHD5) mRNA levels. CONCLUSIONS/INTERPRETATION These findings suggest that NEFAs become a major fuel source during insulin-induced hypoglycaemia and that lipolysis may be an important component of the counter-regulatory response. These effects appear to be mediated by rapid stimulation of protein kinase A (PKA) and HSL, compatible with activation of the β-adrenergic catecholamine signalling pathway. TRIAL REGISTRATION ClinicalTrials.gov NCT01919788 FUNDING : The study was funded by Aarhus University, the Novo Nordisk Foundation and the KETO Study Group/Danish Agency for Science Technology and Innovation (grant no. 0603-00479, to NM).
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9.
Adipose Tissue Free Fatty Acid Storage In Vivo: Effects of Insulin Versus Niacin as a Control for Suppression of Lipolysis.
Ali, AH, Mundi, M, Koutsari, C, Bernlohr, DA, Jensen, MD
Diabetes. 2015;(8):2828-35
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Abstract
Insulin stimulates the translocation fatty acid transport protein 1 (FATP1) to plasma membrane, and thus greater free fatty acid (FFA) uptake, in adipocyte cell models. Whether insulin stimulates greater FFA clearance into adipose tissue in vivo is unknown. We tested this hypothesis by comparing direct FFA storage in subcutaneous adipose tissue during insulin versus niacin-medicated suppression of lipolysis. We measured direct FFA storage in abdominal and femoral subcutaneous fat in 10 and 11 adults, respectively, during euglycemic hyperinsulinemia or after oral niacin to suppress FFA compared with 11 saline control experiments. Direct palmitate storage was assessed using a [U-(13)C]palmitate infusion to measure palmitate kinetics and an intravenous palmitate radiotracer bolus/timed biopsy. Plasma palmitate concentrations and flux were suppressed to 23 ± 3 and 26 ± 5 µmol ⋅ L(-1) (P = 0.91) and 44 ± 4 and 39 ± 5 µmol ⋅ min(-1) (P = 0.41) in the insulin and niacin groups, respectively, much less (P < 0.001) than the saline control group (102 ± 8 and 104 ± 12 µmol ⋅ min(-1), respectively). In the insulin, niacin, and saline groups, abdominal palmitate storage rates were 0.25 ± 0.05 vs. 0.25 ± 0.07 vs. 0.32 ± 0.05 µmol ⋅ kg adipose lipid(-1) ⋅ min(-1), respectively (P = NS), and femoral adipose storage rates were 0.19 ± 0.06 vs. 0.20 ± 0.05 vs. 0.31 ± 0.05 µmol ⋅ kg adipose lipid(-1) ⋅ min(-1), respectively (P = NS). In conclusion, insulin does not increase FFA storage in adipose tissue compared with niacin, which suppresses lipolysis via a different pathway.
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Estimates of insulin sensitivity from the intravenous-glucose-modified-clamp test depend on suppression of lipolysis in type 2 diabetes: a randomised controlled trial.
Kahl, S, Nowotny, B, Piepel, S, Nowotny, PJ, Strassburger, K, Herder, C, Pacini, G, Roden, M
Diabetologia. 2014;(10):2094-102
Abstract
AIMS/HYPOTHESIS The combined IVGTT-hyperinsulinaemic-euglycaemic clamp (Botnia clamp) allows the assessment of insulin secretion and sensitivity in one experiment. It remains unclear whether this clamp yields results comparable with those of the standard hyperinsulinaemic-euglycaemic clamp (SHEC) in diabetes patients. We hypothesised that the IVGTT induces responses affecting insulin sensitivity assessment. METHODS Of 22 randomised diet- or metformin-treated patients with well-controlled type 2 diabetes, 19 randomly underwent a Botnia clamp and an SHEC, spaced by 2 weeks, in one clinical research centre in a crossover study. The main outcomes were whole-body and hepatic insulin sensitivity as measured by the clamp and [6,6-(2)H2]glucose. Substrate utilisation was assessed from indirect calorimetry and beta cell function from insulin dynamics during IVGTT. RESULTS The values of whole-body insulin sensitivity obtained from Botnia clamp and SHEC were correlated (r = 0.87, p < 0.001), but also revealed intra-individual variations. Hepatic insulin sensitivity did not differ between experiments during the clamp, but differed after IVGTT. The contribution of glucose oxidation to glucose disposal increased by 2.2 ± 0.3 and 1.2 ± 0.4 mg kg fat-free mass (FFM)(-1) min(-1) (Botnia and SHEC, p < 0.05), whereas lipid oxidation decreased by 0.8 ± 0.1 and 0.4 ± 0.1 mg kg FFM(-1) min(-1) (p < 0.05) from baseline. Differences in NEFA (r = -0.60, p < 0.01), but not C-peptide (r = -0.16, p = 0.52) or hepatic insulin sensitivity between IVGTT and placebo before the clamps correlated with individual variations of insulin sensitivity. CONCLUSIONS/INTERPRETATION The Botnia clamp provides similar estimates of insulin sensitivity as SHEC in patients with type 2 diabetes, but changes in NEFA during IVGTT may affect insulin sensitivity and thereby the discrimination between insulin-sensitive and insulin-resistant individuals. TRIAL REGISTRATION ClinicalTrials.gov NCT01397279 FUNDING The study was funded by the Ministry of Science and Research of the State of North Rhine-Westphalia and the German Federal Ministry of Health, and supported in part by grants from the Federal Ministry for Research to the Centers for Diabetes Research, Helmholtz Alliance Imaging and Curing Environmental Metabolic Diseases and the Schmutzler-Stiftung.