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The effect of oral glutathione (GSH) supplementation was studied in obese subjects with and without type 2 diabetes (T2DM) on measures of glucose homeostasis and markers of oxidative stress. Twenty subjects (10 patients with T2DM and 10 obese subjects) were recruited for the study, and randomized in a double-blinded placebo-controlled manner to consume either 1000 mg GSH per day or placebo for 3 weeks. Before and after the 3 weeks insulin sensitivity was measured with the hyperinsulinemic-euglycemic clamp and a muscle biopsy was obtained to measure GSH and skeletal muscle mitochondrial hydrogen peroxide (H 2 O 2 ) emission rate. Whole body insulin sensitivity increased significantly in the GSH group. Skeletal muscle GSH was numerically increased (∼19%) in the GSH group; no change was seen in GSH to glutathione disulfide ratio. Skeletal muscle mitochondrial H 2 O 2 emission rate did not change in response to the intervention and neither did the urinary excretion of the RNA oxidation product 8-oxo-7,8-dihydroguanosine or the DNA oxidation product 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), although 8-oxodG decreased as a main effect of time. Oral GSH supplementation improves insulin sensitivity in obese subjects with and without T2DM, although it does not alter markers of oxidative stress. The study has been registered in clinicaltrials.gov (NCT02948673). Novelty: Reduced glutathione supplementation increases insulin sensitivity in obese subjects with and without T2DM. H 2 O 2 emission rate from skeletal muscle mitochondria was not affected by GSH supplementation.

Key Points: This is the first long-term human clinical trial to report on effects of nicotinamide riboside (NR) on skeletal muscle mitochondrial function, content and morphology. NR supplementation decreases nicotinamide phosphoribosyltransferase (NAMPT) protein abundance in skeletal muscle. NR supplementation does not affect NAD metabolite concentrations in skeletal muscle. Respiration, distribution and quantity of muscle mitochondria are unaffected by NR. NAMPT in skeletal muscle correlates positively with oxidative phosphorylation Complex I, sirtuin 3 and succinate dehydrogenase., Abstract: Preclinical evidence suggests that the nicotinamide adenine dinucleotide (NAD + ) precursor nicotinamide riboside (NR) boosts NAD + levels and improves diseases associated with mitochondrial dysfunction. We aimed to determine if dietary NR supplementation in middle-aged, obese, insulin-resistant men affects mitochondrial respiration, content and morphology in skeletal muscle. In a randomized, placebo-controlled clinical trial, 40 participants received 1000 mg NR or placebo twice daily for 12 weeks. Skeletal muscle biopsies were collected before and after the intervention. Mitochondrial respiratory capacity was determined by high-resolution respirometry on single muscle fibres. Protein abundance and mRNA expression were measured by Western blot and quantitative PCR analyses, respectively, and in a subset of the participants (placebo n = 8; NR n = 8) we quantified mitochondrial fractional area and mitochondrial morphology by laser scanning confocal microscopy. Protein levels of nicotinamide phosphoribosyltransferase (NAMPT), an essential NAD + biosynthetic enzyme in skeletal muscle, decreased by 14% with NR. However, steady-state NAD + levels as well as gene expression and protein abundance of other NAD + biosynthetic enzymes remained unchanged. Neither respiratory capacity of skeletal muscle mitochondria nor abundance of mitochondrial associated proteins were affected by NR. Moreover, no changes in mitochondrial fractional area or network morphology were observed. Our data do not support the hypothesis that dietary NR supplementation has significant impact on skeletal muscle mitochondria in obese and insulin-resistant men. Future studies on the effects of NR on human skeletal muscle may include both sexes and potentially provide comparisons between young and older people., (© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.)

Background: Statins are widely used to lower cholesterol concentrations in both primary and secondary prevention of cardiovascular disease. The treatment increases the risk of muscle pain (myalgia) and of type 2 diabetes. However, the underlying mechanisms remain disputed., Methods: We investigated whether statin induced myalgia is coupled to impaired glucose homeostasis using oral glucose tolerance test (OGTT), intravenous glucose tolerance test (IVGTT), and the hyperinsulinemic euglycemic clamp. We performed a cross-sectional study of statin users without CVD (primary prevention) stratified into a statin myalgic (M; n = 25) and a non-myalgic (NM; n = 39) group as well as a control group (C; n = 20) consisting of non-statin users., Results: A reduction in the insulin secretion rate during the OGTT was observed in the myalgic group compared with the non-myalgic group (AUC ISR OGTT , C: 1032 (683 - 1500); M: 922 (678 - 1091); NM: 1089 (933 - 1391) pmol·L -1 ·min (median with 25%-75% percentiles), but no other measurements indicated impaired β-cell function. We found no other differences between the three groups for other measurements in the OGTT, IVGTT, and euglycemic clamp. Muscle protein content of GLUT4 and hexokinase II was similar between the three groups., Conclusions: We conclude that statin users in primary prevention experiencing myalgia do not have impaired glucose homeostasis compared with other statin users or non-users. We consider this an important aspect in the dialogue between physician and patient regarding statin treatment and adverse effects., (© 2018 John Wiley & Sons, Ltd.)

Background: A prevalent side-effect of simvastatin is attenuated glucose homeostasis. The underlying mechanism is unknown, but impaired lipid metabolism may provide the link. The aim of this study was to investigate whether simvastatin-treated patients had a lower capacity to oxidize lipids and reduced expression of the major proteins regulating lipid uptake, synthesis, lipolysis, and storage in skeletal muscle than matched controls., Materials and Methods: Ten men were treated with simvastatin (HbA1c: 5.7 ± 0.1%), and 10 healthy men (HbA1c: 5.2 ± 0.1%) underwent an oral glucose tolerance test and a muscle biopsy was obtained. Fat oxidation rates were measured at rest and during exercise. Western blotting was used to assess protein content., Results: Patients treated with simvastatin had impaired glucose tolerance compared with control subjects, but fat oxidation at rest and during exercise was compatible. Skeletal muscle protein content of CD36, lipoprotein lipase (LPL), and diacylglycerol acyltransferase (DGAT) 1 were lower, and DGAT 2 tended to be lower in patients treated with simvastatin., Conclusions: Patients treated with simvastatin had a reduced capacity to synthesize FA and diacylglycerol (DAG) into triacylglycerol in skeletal muscle compared to matched controls. Decreased lipid synthesis capacity may lead to accumulation of lipotoxic intermediates (FA and DAG) and hence impair glucose tolerance.

Skeletal muscles play an essential role in whole-body glucose homeostasis. They are a key organ system engaged in the development of insulin resistance, and also a crucial tissue mediating the beneficial metabolic effects of physical activity. However, molecular mechanisms underlying both these processes in skeletal muscle remain unclear. The aim of our study was to compare metabolomic profiles in skeletal muscle of patients at different stages of dysglycemia, from normoglycemia through prediabetes to T2D, and its changes under a mixed-mode (strength and endurance) exercise intervention. We performed targeted metabolomics comprising several major metabolite classes, including amino acids, biogenic amines and lipid subgroups in skeletal muscles of male patients. Dysglycemic groups differed significantly at baseline in lysophosphatidylcholines, phosphatidylcholines, sphingomyelins, glutamine, ornithine, and carnosine. Following the exercise intervention, we detected significant changes in lipids and metabolites related to lipid metabolism, including in ceramides and acylcarnitines. With their larger and more significant change over the intervention and among dysglycemic groups, these findings suggest that lipid species may play a predominant role in both the pathogenesis of type 2 diabetes and its protection by exercise. Simultaneously, we demonstrated that amino acid metabolism, especially glutamate dysregulation, is correlated to the development of insulin resistance and parallels disturbances in lipid metabolites. [ABSTRACT FROM AUTHOR]

Context: The maximal fat oxidation rate (MFO) is higher in aerobically fit vs unfit young men, but this training-related increase in MFO is attenuated in middle-aged men. Further, it has also been found that unfit men with obesity may have an elevated MFO compared to unfit normal-weight men.Objective: Based hereupon, we aimed to investigate whether a fitness-related higher MFO were attenuated in middle-aged women compared to young women. Also, we aimed to investigate if unfit women with obesity have a higher MFO compared to unfit normal-weight women. We hypothesized that the training-related elevated MFO was attenuated in middle-aged women, but that unfit women with obesity would have an elevated MFO compared to unfit normal-weight women.Methods: We recruited 70 women stratified into 6 groups: young fit (n = 12), young unfit (n = 12) middle-aged fit (n = 12), middle-aged unfit (n = 12), unfit young women with obesity (n = 12), and unfit middle-aged women with obesity (n = 10). Body composition and resting blood samples were obtained and MFO was measured by a graded exercise test on a cycle ergometer via indirect calorimetry. Subsequently, a maximal exercise test was performed to establish peak oxygen uptake (V̇O2peak).Results: Young and middle-aged fit women had a higher MFO compared to age-matched unfit women, and young fit women had a higher MFO compared to fit middle-aged women. Unfit women with obesity, independent of age, had a higher MFO compared to their normal-weight and unfit counterparts.Conclusion: The training-related increase in MFO seems maintained in middle-aged women, and we find that unfit women with obesity, independent of age, have a higher MFO compared to unfit normal-weight women. [ABSTRACT FROM AUTHOR]

Background: Polycystic ovary syndrome (PCOS) and metabolic inflexibility are linked to insulin resistance, and women with PCOS appear to be metabolic inflexible in the rested, insulin-stimulated state. Exercise training is a primary lifestyle intervention in PCOS. Exercise training improves whole-body fat oxidation during submaximal exercise in healthy women, yet little is known about the effect on this outcome in women with PCOS. Methods: We measured whole-body fat oxidation rates during sub maximal exercise before and after 16 weeks of high-intensity interval training (HIT) in women with PCOS randomly allocated to either: low- or high-volume HIT (n = 41; low-volume HIT, 10 × 1 min work bouts at maximal, sustainable intensity and high-volume HIT, 4 × 4 min work bouts at 90–95% of maximal heart rate) or non-exercise control (n = 23), and in women without PCOS (Non-PCOS) allocated to low- or high volume HIT (n = 15). HIT was undertaken three times weekly. In a subset of women with and without PCOS, we measured mitochondrial respiration in abdominal and gluteal subcutaneous adipose tissue using high-resolution respirometry, as well as fat cell sizes in these tissues. Results: At baseline, women with PCOS had lower whole-body fat oxidation and mitochondrial respiration rates in abdominal adipose tissue compared to Non-PCOS. Peak oxygen uptake (mL/min/kg) increased in women with PCOS (~4%, p = 0.006) and Non-PCOS (~6%, p = 0.003) after 16 weeks of HIT. Whole-body fat oxidation only improved in Non-PCOS after HIT. No changes were observed in mitochondrial respiration and cell size in abdominal and gluteal adipose tissue after HIT in either group of women. Conclusion: We observed exercise-induced improvements in whole-body fat oxidation during submaximal exercise in Non-PCOS, but not in women with PCOS, after 16 weeks of HIT, suggesting metabolic inflexibility in women with PCOS. Clinical Trial Registration: www.clinicaltrials.gov, identifier NCT02419482 and NCT02943291. [ABSTRACT FROM AUTHOR]

Glucagon is believed to be a pancreas-specific hormone, and hyperglucagonemia has been shown to contribute significantly to the hyperglycemic state of patients with diabetes. This hyperglucagonemia has been thought to arise from α-cell insensitivity to suppressive effects of glucose and insulin combined with reduced insulin secretion. We hypothesized that postabsorptive hyperglucagonemia represents a gut-dependent phenomenon and subjected 10 totally pancreatectomized patients and 10 healthy control subjects to a 75-g oral glucose tolerance test and a corresponding isoglycemic intravenous glucose infusion. We applied novel analytical methods of plasma glucagon (sandwich ELISA and mass spectrometry-based proteomics) and show that 29-amino acid glucagon circulates in patients without a pancreas and that glucose stimulation of the gastrointestinal tract elicits significant hyperglucagonemia in these patients. These findings emphasize the existence of extrapancreatic glucagon (perhaps originating from the gut) in man and suggest that it may play a role in diabetes secondary to total pancreatectomy. [ABSTRACT FROM AUTHOR]

Metformin is used as an anti-diabetic drug. Metformin ameliorates insulin resistance by improving insulin sensitivity in liver and skeletal muscle. Reduced mitochondrial content has been reported in type 2 diabetic muscles and it may contribute to decreased insulin sensitivity characteristic for diabetic muscles. The molecular mechanism behind the effect of metformin is not fully clarified but inhibition of complex I in the mitochondria and also activation of the 5'AMP activated protein kinase (AMPK) has been reported in muscle. Furthermore, both AMPK activation and metformin treatment have been associated with stimulation of mitochondrial function and biogenesis. However, a causal relationship in skeletal muscle has not been investigated. We hypothesized that potential effects of in vivo metformin treatment on mitochondrial function and protein expressions in skeletal muscle are dependent upon AMPK signaling. We investigated this by two weeks of oral metformin treatment of muscle specific kinase dead α2 (KD) AMPK mice and wild type (WT) littermates. We measured mitochondrial respiration and protein activity and expressions of key enzymes involved in mitochondrial carbohydrate and fat metabolism and oxidative phosphorylation. Mitochondrial respiration, HAD and CS activity, PDH and complex I-V and cytochrome c protein expression were all reduced in AMPK KD compared to WT tibialis anterior muscles. Surprisingly, metformin treatment only enhanced respiration in AMPK KD mice and thereby rescued the respiration defect compared to the WT mice. Metformin did not influence protein activities or expressions in either WT or AMPK KD mice. We conclude that two weeks of in vivo metformin treatment enhances mitochondrial respiration in the mitochondrial deficient AMPK KD but not WT mice. The improvement seems to be unrelated to AMPK, and does not involve changes in key mitochondrial proteins. [ABSTRACT FROM AUTHOR]

Glycemic responses to bariatric surgery are highly heterogeneous among patients and defining response types remains challenging. Recently developed data-driven clustering methods have uncovered subtle pathophysiologically informative patterns among patients without diabetes. This study aimed to explain responses among patients with and without diabetes to bariatric surgery with clusters of glucose concentration during oral glucose tolerance tests (OGTTs). We assessed 30 parameters at baseline and at four subsequent follow-up visits over one year on 154 participants in the Bialystok Bariatric Surgery Study. We applied latent trajectory classification to OGTTs and multinomial regression and generalized linear mixed models to explain differential responses among clusters. OGTT trajectories created four clusters representing increasing dysglycemias that were discordant from standard diabetes diagnosis criteria. The baseline OGTT cluster increased the predictive power of regression models by over 31% and aided in correctly predicting more than 83% of diabetes remissions. Principal component analysis showed that the glucose homeostasis response primarily occurred as improved insulin sensitivity concomitant with improved the OGTT cluster. In sum, OGTT clustering explained multiple, correlated responses to metabolic surgery. The OGTT is an intuitive and easy-to-implement index of improvement that stratifies patients into response types, a vital first step in personalizing diabetic care in obese subjects. [ABSTRACT FROM AUTHOR]

Ceramide and diacylglycerol are linked to insulin resistance in rodents, but in humans the data are inconsistent. Insulin resistance is frequently observed with aging, but the role of ceramide and diacylglycerol is not clarified. Training improves metabolic health and, therefore, we aimed to elucidate the influence of age and high-intensity interval training (HIIT) on ceramide and diacylglycerol content in muscle. Fourteen young (33 ± 1) and 22 older (63 ± 1) overweight to obese subjects performed 6 weeks HIIT three times a week. Maximal oxygen uptake and body composition were measured and muscle biopsies and fasting blood samples were obtained. Muscle ceramide and diacylglycerol were measured by gas-liquid chromatography and proteins in insulin signaling, lipid and glucose metabolism were measured by Western blotting. Content of ceramide and diacylglycerol total, saturated, C16:0 and C18:0 fatty acids and C18:1 ceramide were higher in older compared to young. HIIT reduced saturated and C18:0 ceramides, while the content of the proteins involved in glucose (GLUT4, glycogen synthase, hexokinase II, AKT) and lipid metabolism (adipose triglyceride lipase, fatty acid binding protein) were increased after HIIT. We demonstrate a higher content of saturated ceramide and diacylglycerol fatty acids in the muscle of older subjects compared to young. Moreover, the content of saturated ceramides was reduced and muscle glucose metabolism improved at protein level after HIIT. This study highlights an increased content of saturated ceramides in aging which could be speculated to influence insulin sensitivity. [ABSTRACT FROM AUTHOR]