Exercise Response Variations in Skeletal Muscle PCr Recovery Rate and Insulin Sensitivity Relate to Muscle Epigenomic Profiles in Individuals With Type 2 Diabetes

Abstract Aims/hypothesis Mitochondria operate in networks, adapting to external stresses and changes in cellular metabolic demand and are subject to various quality control mechanisms. On the basis of these traits, we here hypothesise that the regulation of mitochondrial networks in skeletal muscle is hampered in humans with compromised oxidative capacity and insulin sensitivity. Methods In a cross-sectional design, we compared four groups of participants (selected from previous studies) ranging in aerobic capacity and insulin sensitivity, i.e. participants with type 2 diabetes (n = 11), obese participants without diabetes (n = 12), lean individuals (n = 10) and endurance-trained athletes (n = 12); basal, overnight fasted muscle biopsies were newly analysed for the current study and we compared the levels of essential mitochondrial dynamics and quality control regulatory proteins in skeletal muscle tissue. Results Type 2 diabetes patients and obese participants were older than lean participants and athletes (58.6 ± 4.0 and 56.7 ± 7.2 vs 21.8 ± 2.5 and 25.1 ± 4.3 years, p < 0.001, respectively) and displayed a higher BMI (32.4 ± 3.7 and 31.0 ± 3.7 vs 22.1 ± 1.8 and 21.0 ± 1.5 kg/m2, p < 0.001, respectively) than lean individuals and endurance-trained athletes. Fission protein 1 (FIS1) and optic atrophy protein 1 (OPA1) protein content was highest in muscle from athletes and lowest in participants with type 2 diabetes and obesity, respectively (FIS1: 1.86 ± 0.79 vs 0.79 ± 0.51 AU, p = 0.002; and OPA1: 1.55 ± 0.64 vs 0.76 ± 0.52 AU, p = 0.014), which coincided with mitochondrial network fragmentation in individuals with type 2 diabetes, as assessed by confocal microscopy in a subset of type 2 diabetes patients vs endurance-trained athletes (n = 6). Furthermore, lean individuals and athletes displayed a mitonuclear protein balance that was different from obese participants and those with type 2 diabetes. Mitonuclear protein balance also associated with heat shock protein 60 (HSP60) protein levels, which were higher in athletes when compared with participants with obesity (p = 0.048) and type 2 diabetes (p = 0.002), indicative for activation of the mitochondrial unfolded protein response. Finally, OPA1, FIS1 and HSP60 correlated positively with aerobic capacity (r = 0.48, p = 0.0001; r = 0.55, p < 0.001 and r = 0.61, p < 0.0001, respectively) and insulin sensitivity (r = 0.40, p = 0.008; r = 0.44, p = 0.003 and r = 0.48, p = 0.001, respectively). Conclusions/interpretation Collectively, our data suggest that mitochondrial dynamics and quality control in skeletal muscle are linked to oxidative capacity in humans, which may play a role in the maintenance of muscle insulin sensitivity. Clinical Trial registry numbers NCT00943059, NCT01298375 and NL1888

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Hypoglycaemic effect of catalpol in a mouse model of high-fat diet-induced prediabetes

Applied Physiology Nutrition and Metabolism ◽

10.1139/apnm-2020-0075 ◽

2020 ◽

Vol 45 (10) ◽

pp. 1127-1137 ◽

Cited By ~ 1

Author(s):

Dengqiu Xu ◽

Xiaofei Huang ◽

Hozeifa M. Hassan ◽

Lu Wang ◽

Sijia Li ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Skeletal Muscle ◽

Type 2 Diabetes Mellitus ◽

Insulin Sensitivity ◽

Glucose Tolerance ◽

Mouse Model ◽

Fasting Glucose ◽

Hypoglycaemic Effect

Type 2 diabetes mellitus is a major health problem and a societal burden. Individuals with prediabetes are at increased risk of type 2 diabetes mellitus. Catalpol, an iridoid glycoside, has been reported to exert a hypoglycaemic effect in db/db mice, but its effect on the progression of prediabetes is unclear. In this study, we established a mouse model of prediabetes and examined the hypoglycaemic effect, and the mechanism of any such effect, of catalpol. Catalpol (200 mg/(kg·day)) had no effect on glucose tolerance or the serum lipid level in a mouse model of impaired glucose tolerance-stage prediabetes. However, catalpol (200 mg/(kg·day)) increased insulin sensitivity and decreased the fasting glucose level in a mouse model of impaired fasting glucose/impaired glucose tolerance-stage prediabetes. Moreover, catalpol increased the mitochondrial membrane potential (1.52-fold) and adenosine triphosphate content (1.87-fold) in skeletal muscle and improved skeletal muscle function. These effects were mediated by activation of the insulin receptor-1/glucose transporter type 4 (IRS-1/GLUT4) signalling pathway in skeletal muscle. Our findings will facilitate the development of a novel approach to suppressing the progression of diabetes at an early stage. Novelty Catalpol prevents the progression of prediabetes in a mouse model of prediabetes. Catalpol improves insulin sensitivity in skeletal muscle. The effects of catalpol are mediated by activation of the IRS-1/GLUT4 signalling pathway.

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Leptin Enhances Insulin Sensitivity by Direct and Sympathetic Nervous System Regulation of Muscle IGFBP-2 Expression: Evidence From Nonrodent Models

Endocrinology ◽

10.1210/en.2013-2099 ◽

2014 ◽

Vol 155 (6) ◽

pp. 2133-2143 ◽

Cited By ~ 31

Author(s):

Steven W. Yau ◽

Belinda A. Henry ◽

Vincenzo C. Russo ◽

Glenn K. McConell ◽

Iain J. Clarke ◽

...

Keyword(s):

Type 2 Diabetes ◽

Skeletal Muscle ◽

Nervous System ◽

Insulin Sensitivity ◽

Sympathetic Nervous System ◽

Insulin Signaling ◽

In Vivo Experiments ◽

Sympathetic Nervous

Leptin is produced from white adipose tissue and acts primarily to regulate energy balance. Obesity is associated with leptin resistance and increased circulating levels of leptin. Leptin has recently been shown to influence levels of IGF binding protein-2 (IGFBP-2), a protein that is reduced in obesity and type 2 diabetes. Overexpression of IGFBP-2 protects against obesity and type 2 diabetes. As such, IGFBP-2 signaling may represent a novel pathway by which leptin regulates insulin sensitivity. We sought to investigate how leptin regulates skeletal muscle IGFBP-2 levels and to assess the impact of this on insulin signaling and glucose uptake. In vitro experiments were undertaken in cultured human skeletal myotubes, whereas in vivo experiments assessed the effect of intracerebroventricular leptin on peripheral skeletal muscle IGFBP-2 expression and insulin sensitivity in sheep. Leptin directly increased IGFBP-2 mRNA and protein in human skeletal muscle through both signal transducer and activator of transcription-3 and phosphatidylinositol 3-kinase signaling, in parallel with enhanced insulin signaling. Silencing IGFBP-2 lowered leptin- and insulin-stimulated protein kinase B phosphorylation and glucose uptake. In in vivo experiments, intracerebroventricular leptin significantly increased hind-limb skeletal muscle IGFBP-2, an effect completely blocked by concurrent peripheral infusion of a β-adrenergic blocking agent. Sheep receiving central leptin showed improvements in glucose tolerance and circulating insulin levels after an iv glucose load. In summary, leptin regulates skeletal muscle IGFBP-2 by both direct peripheral and central (via the sympathetic nervous system) mechanisms, and these likely impact on peripheral insulin sensitivity and glucose metabolism.

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Impact of Endurance and Resistance Training on Skeletal Muscle Glucose Metabolism in Older Adults

Nutrients ◽

10.3390/nu11112636 ◽

2019 ◽

Vol 11 (11) ◽

pp. 2636 ◽

Cited By ~ 3

Author(s):

Leslie A. Consitt ◽

Courtney Dudley ◽

Gunjan Saxena

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Older Adults ◽

Skeletal Muscle ◽

Insulin Sensitivity ◽

Resistance Training ◽

Glucose Metabolism ◽

Age Related ◽

Age Related Changes

Aging is associated with insulin resistance and the development of type 2 diabetes. While this process is multifaceted, age-related changes to skeletal muscle are expected to contribute to impaired glucose metabolism. Some of these changes include sarcopenia, impaired insulin signaling, and imbalances in glucose utilization. Endurance and resistance exercise training have been endorsed as interventions to improve glucose tolerance and whole-body insulin sensitivity in the elderly. While both types of exercise generally increase insulin sensitivity in older adults, the metabolic pathways through which this occurs can differ and can be dependent on preexisting conditions including obesity and type 2 diabetes. In this review, we will first highlight age-related changes to skeletal muscle which can contribute to insulin resistance, followed by a comparison of endurance and resistance training adaptations to insulin-stimulated glucose metabolism in older adults.

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The Effects of Rosiglitazone on Insulin Sensitivity, Lipolysis, and Hepatic and Skeletal Muscle Triglyceride Content in Patients With Type 2 Diabetes

Diabetes ◽

10.2337/diabetes.51.3.797 ◽

2002 ◽

Vol 51 (3) ◽

pp. 797-802 ◽

Cited By ~ 473

Author(s):

A. B. Mayerson ◽

R. S. Hundal ◽

S. Dufour ◽

V. Lebon ◽

D. Befroy ◽

...

Keyword(s):

Type 2 Diabetes ◽

Skeletal Muscle ◽

Insulin Sensitivity ◽

Triglyceride Content ◽

Muscle Triglyceride

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16 SKELETAL-MUSCLE LIPOPROTEIN EXPRESSION IS REGULATED BY TRAINING AND TYPE 2 DIABETES IN HUMANS AND IMPROVES INSULIN SENSITIVITY IN OBESE MICE

Atherosclerosis Supplements ◽

10.1016/s1567-5688(11)70017-4 ◽

2011 ◽

Vol 12 (1) ◽

pp. 4

Author(s):

E. Bartels ◽

T. Ploug ◽

J. Størling ◽

T. Mandrup-Poulsen ◽

F. Dela ◽

...

Keyword(s):

Type 2 Diabetes ◽

Skeletal Muscle ◽

Insulin Sensitivity ◽

Obese Mice

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The effects of 3 weeks of oral glutathione supplementation on whole body insulin sensitivity in obese males with and without type 2 diabetes: A randomized trial

Applied Physiology Nutrition and Metabolism ◽

10.1139/apnm-2020-1099 ◽

2021 ◽

Author(s):

Stine D. Søndergård ◽

Ida Cintin ◽

Anja Birk Kuhlman ◽

Thomas Morville ◽

Marie Louise Bergmann ◽

...

Keyword(s):

Oxidative Stress ◽

Type 2 Diabetes ◽

Skeletal Muscle ◽

Insulin Sensitivity ◽

Oxidation Product ◽

Emission Rate ◽

Whole Body ◽

Markers Of Oxidative Stress ◽

Obese Subjects

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 1000mg GSH per day or placebo for three 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 (H2O2) emission rate. Whole body insulin sensitivity increased significantly in the GSH group. Skeletal muscle GSH was numerically increased (app. 19%) in the GSH group, no change was seen in GSH to glutathione disulfide (GSSG) ratio. Skeletal muscle mitochondrial H2O2 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 (8-oxoGuo) 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 bullets: • Reduced glutathione supplementation increases insulin sensitivity in obese subjects with and without type 2 diabetes • H2O2 emission rate from skeletal muscle mitochondria was not affected by glutathione supplementation

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Endurance training remodels skeletal muscle phospholipid composition and increases intrinsic mitochondrial respiration in men with Type 2 diabetes

Physiological Genomics ◽

10.1152/physiolgenomics.00014.2019 ◽

2019 ◽

Vol 51 (11) ◽

pp. 586-595 ◽

Cited By ~ 4

Author(s):

Maria F. Pino ◽

Natalie A. Stephens ◽

Alexey M. Eroshkin ◽

Fanchao Yi ◽

Andrew Hodges ◽

...

Keyword(s):

Type 2 Diabetes ◽

Skeletal Muscle ◽

Insulin Sensitivity ◽

Endurance Training ◽

Mitochondrial Function ◽

Mitochondrial Respiration ◽

Phospholipid Composition ◽

Rna Seq ◽

Mitochondrial Dna Copy Number

The effects of exercise training on the skeletal muscle (SKM) lipidome and mitochondrial function have not been thoroughly explored in individuals with Type 2 diabetes (T2D). We hypothesize that 10 wk of supervised endurance training improves SKM mitochondrial function and insulin sensitivity that are related to alterations in lipid signatures within SKM of T2D (males n = 8). We employed integrated multi-omics data analyses including ex vivo lipidomics (MS/MS-shotgun) and transcriptomics (RNA-Seq). From biopsies of SKM, tissue and primary myotubes mitochondrial respiration were quantified by high-resolution respirometry. We also performed hyperinsulinemic-euglycemic clamps and blood draws before and after the training. The lipidomics analysis revealed that endurance training (>95% compliance) increased monolysocardiolipin by 68.2% ( P ≤ 0.03), a putative marker of mitochondrial remodeling, and reduced total sphingomyelin by 44.8% ( P ≤ 0.05) and phosphatidylserine by 39.7% ( P ≤ 0.04) and tended to reduce ceramide lipid content by 19.8%. Endurance training also improved intrinsic mitochondrial respiration in SKM of T2D without alterations in mitochondrial DNA copy number or cardiolipin content. RNA-Seq revealed 71 transcripts in SKM of T2D that were differentially regulated. Insulin sensitivity was unaffected, and HbA1c levels moderately increased by 7.3% despite an improvement in cardiorespiratory fitness (V̇o2peak) following the training intervention. In summary, endurance training improves intrinsic and cell-autonomous SKM mitochondrial function and modifies lipid composition in men with T2D independently of alterations in insulin sensitivity and glycemic control.

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