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Wang G. A more holistic view of the logarithmic dose-response curve offers greater insights into insulin responses. J Biol Chem 2025; 301:108037. [PMID: 39617270 PMCID: PMC11731574 DOI: 10.1016/j.jbc.2024.108037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Revised: 11/19/2024] [Accepted: 11/25/2024] [Indexed: 12/23/2024] Open
Abstract
The stimulus-response curve is usually modeled by the Hill function due to its simplicity and clear molecular mechanisms (Michaelis-Menten type of kinetics). Unfortunately, the mechanisms do not explain why the stimulus is ubiquitously measured by logarithmic dose rather than the dose itself and why the log(dose)-response curve possesses such fine properties as symmetry and wide adjustability. Here, the dose-response is considered from a holistic perspective spanning multiple biological levels from molecules to the whole organism, which reveals that an appropriate model for log(dose) response is the cumulative normal distribution (CND) function, which had only statistical implication previously but now possess mechanistic-statistical duality. The present CND model establishes a connection between single-cell all-or-none responses and the graded response at the tissue/organism level, reveals the raison d'être of the logarithmic transformation, explains why log(dose)-response curve possesses many fine properties, and reveals new mechanisms of tissue/organism dose-response, including homogeneity-induced sensitivity. It also provides new insights into vital biological processes, such as the insulin dose-response.
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Affiliation(s)
- Guanyu Wang
- Laboratory of Biocomplexity and Engineering Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen, China; Futian Biomedical Innovation R&D Center, The Chinese University of Hong Kong, Shenzhen, China; Ciechanover Institute of Precision and Regenerative Medicine, School of Medicine, The Chinese University of Hong Kong, Shenzhen, China; Center for Endocrinology and Metabolic Diseases, Second Affiliated Hospital, The Chinese University of Hong Kong, Shenzhen, China.
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2
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Rebello CJ, Zhang D, Kirwan JP, Lowe AC, Emerson CJ, Kracht CL, Steib LC, Greenway FL, Johnson WD, Brown JC. Effect of exercise training on insulin-stimulated glucose disposal: a systematic review and meta-analysis of randomized controlled trials. Int J Obes (Lond) 2023; 47:348-357. [PMID: 36828899 PMCID: PMC10148910 DOI: 10.1038/s41366-023-01283-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 02/13/2023] [Accepted: 02/15/2023] [Indexed: 02/26/2023]
Abstract
BACKGROUND AND OBJECTIVE The effect of exercise training on whole-body insulin sensitivity has not been systematically summarized. We aimed to summarize the data from randomized controlled trials evaluating the effect of exercise training on insulin action, in adults. SUBJECTS MEDLINE, EMBASE, and CENTRAL databases were searched until January 2021. Randomized controlled trials lasting ≥4 weeks, including adults, and evaluating the effect of exercise on insulin-stimulated glucose disposal measured using the hyperinsulinemic euglycemic clamp, were included. METHODS Three reviewers extracted summary data from published trials. The primary outcome was insulin-stimulated glucose disposal. Standardized weighted mean differences (SMD) in glucose disposal between intervention and control were compared. The PEDro scale was used to assess risk of bias. RESULTS We included 25 trials (36 interventions, N = 851). Exercise increased insulin-stimulated glucose disposal relative to control, SMD = 0.52 (95% confidence interval [CI]: 0.39, 0.65; p < 0.001; I2 = 47%) without significantly suppressing hepatic glucose production. In trials without isotopic tracers, exercise increased glucose disposal (SMD = 0.63; 95% CI: 0.48, 0.77; p < 0.001, I2 = 55%). In trials with isotopic tracers, exercise increased glucose disposal only when tracers were added to the exogenous glucose used for clamping (SMD = 0.34; 95% CI: 0.03, 0.66, p = 0.034. I2 = 0%). In a meta-regression model including aerobic exercise, weight change, and tracer technique, only percent weight change explained between trial heterogeneity (β = 0.069; 95% CI: 0.005, 0.013). The PEDro rating indicated relatively low risk of bias (5.8 ± 0.22). CONCLUSIONS Exercise training for at least four weeks significantly increases insulin-stimulated glucose disposal. Weight loss maximizes the effect and may be needed to improve hepatic insulin sensitivity. Differences in tracer methodology contribute to divergent outcomes and should be considered when assessing conclusions from research examining the effect of exercise on insulin action. REGISTRATION PROSPERO (CRD42019124381).
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Affiliation(s)
- Candida J Rebello
- Nutrition and Chronic Disease, Pennington Biomedical Research Center, Baton Rouge, LA, USA.
| | - Dachuan Zhang
- Biostatistics, Pennington Biomedical Research Center, Baton Rouge, LA, USA
| | - John P Kirwan
- Integrated Physiology and Molecular Medicine, Pennington Biomedical Research Center, Baton Rouge, LA, USA
| | - Adam C Lowe
- Interventional Resources, Pennington Biomedical Research Center, Baton Rouge, LA, USA
| | - Carlante J Emerson
- Interventional Resources, Pennington Biomedical Research Center, Baton Rouge, LA, USA
| | - Chelsea L Kracht
- Clinical Science, Pennington Biomedical Research Center, Baton Rouge, LA, USA
| | - Lori C Steib
- Library and Information Center, Pennington Biomedical Research Center, Baton Rouge, LA, USA
| | - Frank L Greenway
- Clinical Trials Unit, Pennington Biomedical Research Center, Baton Rouge, LA, USA
| | - William D Johnson
- Biostatistics, Pennington Biomedical Research Center, Baton Rouge, LA, USA
| | - Justin C Brown
- Cancer Metabolism Program, Pennington Biomedical Research Center, Baton Rouge, LA, USA
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3
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Interactions between insulin and exercise. Biochem J 2021; 478:3827-3846. [PMID: 34751700 DOI: 10.1042/bcj20210185] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 10/11/2021] [Accepted: 10/13/2021] [Indexed: 02/06/2023]
Abstract
The interaction between insulin and exercise is an example of balancing and modifying the effects of two opposing metabolic regulatory forces under varying conditions. While insulin is secreted after food intake and is the primary hormone increasing glucose storage as glycogen and fatty acid storage as triglycerides, exercise is a condition where fuel stores need to be mobilized and oxidized. Thus, during physical activity the fuel storage effects of insulin need to be suppressed. This is done primarily by inhibiting insulin secretion during exercise as well as activating local and systemic fuel mobilizing processes. In contrast, following exercise there is a need for refilling the fuel depots mobilized during exercise, particularly the glycogen stores in muscle. This process is facilitated by an increase in insulin sensitivity of the muscles previously engaged in physical activity which directs glucose to glycogen resynthesis. In physically trained individuals, insulin sensitivity is also higher than in untrained individuals due to adaptations in the vasculature, skeletal muscle and adipose tissue. In this paper, we review the interactions between insulin and exercise during and after exercise, as well as the effects of regular exercise training on insulin action.
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O'Reilly CL, Uranga S, Fluckey JD. Culprits or consequences: Understanding the metabolic dysregulation of muscle in diabetes. World J Biol Chem 2021; 12:70-86. [PMID: 34630911 PMCID: PMC8473417 DOI: 10.4331/wjbc.v12.i5.70] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 06/21/2021] [Accepted: 08/03/2021] [Indexed: 02/06/2023] Open
Abstract
The prevalence of type 2 diabetes (T2D) continues to rise despite the amount of research dedicated to finding the culprits of this debilitating disease. Skeletal muscle is arguably the most important contributor to glucose disposal making it a clear target in insulin resistance and T2D research. Within skeletal muscle there is a clear link to metabolic dysregulation during the progression of T2D but the determination of culprits vs consequences of the disease has been elusive. Emerging evidence in skeletal muscle implicates influential cross talk between a key anabolic regulatory protein, the mammalian target of rapamycin (mTOR) and its associated complexes (mTORC1 and mTORC2), and the well-described canonical signaling for insulin-stimulated glucose uptake. This new understanding of cellular signaling crosstalk has blurred the lines of what is a culprit and what is a consequence with regard to insulin resistance. Here, we briefly review the most recent understanding of insulin signaling in skeletal muscle, and how anabolic responses favoring anabolism directly impact cellular glucose disposal. This review highlights key cross-over interactions between protein and glucose regulatory pathways and the implications this may have for the design of new therapeutic targets for the control of glucoregulatory function in skeletal muscle.
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Affiliation(s)
| | - Selina Uranga
- Health and Kinesiology, Texas A&M University, TX 77843, United States
| | - James D Fluckey
- Health and Kinesiology, Texas A&M University, TX 77843, United States
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5
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Abstract
As the principal tissue for insulin-stimulated glucose disposal, skeletal muscle is a primary driver of whole-body glycemic control. Skeletal muscle also uniquely responds to muscle contraction or exercise with increased sensitivity to subsequent insulin stimulation. Insulin's dominating control of glucose metabolism is orchestrated by complex and highly regulated signaling cascades that elicit diverse and unique effects on skeletal muscle. We discuss the discoveries that have led to our current understanding of how insulin promotes glucose uptake in muscle. We also touch upon insulin access to muscle, and insulin signaling toward glycogen, lipid, and protein metabolism. We draw from human and rodent studies in vivo, isolated muscle preparations, and muscle cell cultures to home in on the molecular, biophysical, and structural elements mediating these responses. Finally, we offer some perspective on molecular defects that potentially underlie the failure of muscle to take up glucose efficiently during obesity and type 2 diabetes.
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6
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Exercise-A Panacea of Metabolic Dysregulation in Cancer: Physiological and Molecular Insights. Int J Mol Sci 2021; 22:ijms22073469. [PMID: 33801684 PMCID: PMC8037630 DOI: 10.3390/ijms22073469] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 03/21/2021] [Accepted: 03/24/2021] [Indexed: 12/14/2022] Open
Abstract
Metabolic dysfunction is a comorbidity of many types of cancers. Disruption of glucose metabolism is of concern, as it is associated with higher cancer recurrence rates and reduced survival. Current evidence suggests many health benefits from exercise during and after cancer treatment, yet only a limited number of studies have addressed the effect of exercise on cancer-associated disruption of metabolism. In this review, we draw on studies in cells, rodents, and humans to describe the metabolic dysfunctions observed in cancer and the tissues involved. We discuss how the known effects of acute exercise and exercise training observed in healthy subjects could have a positive outcome on mechanisms in people with cancer, namely: insulin resistance, hyperlipidemia, mitochondrial dysfunction, inflammation, and cachexia. Finally, we compile the current limited knowledge of how exercise corrects metabolic control in cancer and identify unanswered questions for future research.
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7
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Dynamic changes in DICER levels in adipose tissue control metabolic adaptations to exercise. Proc Natl Acad Sci U S A 2020; 117:23932-23941. [PMID: 32900951 DOI: 10.1073/pnas.2011243117] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
DICER is a key enzyme in microRNA (miRNA) biogenesis. Here we show that aerobic exercise training up-regulates DICER in adipose tissue of mice and humans. This can be mimicked by infusion of serum from exercised mice into sedentary mice and depends on AMPK-mediated signaling in both muscle and adipocytes. Adipocyte DICER is required for whole-body metabolic adaptations to aerobic exercise training, in part, by allowing controlled substrate utilization in adipose tissue, which, in turn, supports skeletal muscle function. Exercise training increases overall miRNA expression in adipose tissue, and up-regulation of miR-203-3p limits glycolysis in adipose under conditions of metabolic stress. We propose that exercise training-induced DICER-miR-203-3p up-regulation in adipocytes is a key adaptive response that coordinates signals from working muscle to promote whole-body metabolic adaptations.
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8
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Sylow L, Kleinert M, Richter EA, Jensen TE. Exercise-stimulated glucose uptake - regulation and implications for glycaemic control. Nat Rev Endocrinol 2017; 13:133-148. [PMID: 27739515 DOI: 10.1038/nrendo.2016.162] [Citation(s) in RCA: 293] [Impact Index Per Article: 36.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Skeletal muscle extracts glucose from the blood to maintain demand for carbohydrates as an energy source during exercise. Such uptake involves complex molecular signalling processes that are distinct from those activated by insulin. Exercise-stimulated glucose uptake is preserved in insulin-resistant muscle, emphasizing exercise as a therapeutic cornerstone among patients with metabolic diseases such as diabetes mellitus. Exercise increases uptake of glucose by up to 50-fold through the simultaneous stimulation of three key steps: delivery, transport across the muscle membrane and intracellular flux through metabolic processes (glycolysis and glucose oxidation). The available data suggest that no single signal transduction pathway can fully account for the regulation of any of these key steps, owing to redundancy in the signalling pathways that mediate glucose uptake to ensure maintenance of muscle energy supply during physical activity. Here, we review the molecular mechanisms that regulate the movement of glucose from the capillary bed into the muscle cell and discuss what is known about their integrated regulation during exercise. Novel developments within the field of mass spectrometry-based proteomics indicate that the known regulators of glucose uptake are only the tip of the iceberg. Consequently, many exciting discoveries clearly lie ahead.
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Affiliation(s)
- Lykke Sylow
- Molecular Physiology Group, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - Maximilian Kleinert
- Molecular Physiology Group, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
- Institute for Diabetes and Obesity, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Erik A Richter
- Molecular Physiology Group, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - Thomas E Jensen
- Molecular Physiology Group, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
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Simmonds MJ, Sabapathy S, Serre KR, Haseler LJ, Gass GC, Marshall-Gradisnik SM, Minahan CL. Regular walking improves plasma protein concentrations that promote blood hyperviscosity in women 65–74 yr with type 2 diabetes. Clin Hemorheol Microcirc 2016; 64:189-198. [DOI: 10.3233/ch-162061] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Affiliation(s)
- Michael J. Simmonds
- Menzies Health Institute Queensland, Gold Coast, QLD, Australia
- School of Allied Health Sciences, Griffith University, Gold Coast, QLD, Australia
| | - Surendran Sabapathy
- Menzies Health Institute Queensland, Gold Coast, QLD, Australia
- School of Allied Health Sciences, Griffith University, Gold Coast, QLD, Australia
| | - Kevin R. Serre
- Faculty of Health Sciences and Medicine, Bond University, Gold Coast, QLD, Australia
| | - Luke J. Haseler
- Menzies Health Institute Queensland, Gold Coast, QLD, Australia
- School of Allied Health Sciences, Griffith University, Gold Coast, QLD, Australia
| | - Gregory C. Gass
- Faculty of Health Sciences and Medicine, Bond University, Gold Coast, QLD, Australia
| | | | - Clare L. Minahan
- Menzies Health Institute Queensland, Gold Coast, QLD, Australia
- School of Allied Health Sciences, Griffith University, Gold Coast, QLD, Australia
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10
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Way KL, Hackett DA, Baker MK, Johnson NA. The Effect of Regular Exercise on Insulin Sensitivity in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis. Diabetes Metab J 2016; 40:253-71. [PMID: 27535644 PMCID: PMC4995180 DOI: 10.4093/dmj.2016.40.4.253] [Citation(s) in RCA: 112] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Accepted: 06/21/2016] [Indexed: 01/25/2023] Open
Abstract
The purpose of this study was to examine the effect of regular exercise training on insulin sensitivity in adults with type 2 diabetes mellitus (T2DM) using the pooled data available from randomised controlled trials. In addition, we sought to determine whether short-term periods of physical inactivity diminish the exercise-induced improvement in insulin sensitivity. Eligible trials included exercise interventions that involved ≥3 exercise sessions, and reported a dynamic measurement of insulin sensitivity. There was a significant pooled effect size (ES) for the effect of exercise on insulin sensitivity (ES, -0.588; 95% confidence interval [CI], -0.816 to -0.359; P<0.001). Of the 14 studies included for meta-analyses, nine studies reported the time of data collection from the last exercise bout. There was a significant improvement in insulin sensitivity in favour of exercise versus control between 48 and 72 hours after exercise (ES, -0.702; 95% CI, -1.392 to -0.012; P=0.046); and this persisted when insulin sensitivity was measured more than 72 hours after the last exercise session (ES, -0.890; 95% CI, -1.675 to -0.105; P=0.026). Regular exercise has a significant benefit on insulin sensitivity in adults with T2DM and this may persist beyond 72 hours after the last exercise session.
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Affiliation(s)
- Kimberley L Way
- University of Sydney Faculty of Health Sciences, Lidcombe, Australia
- Charles Perkins Centre, University of Sydney, Camperdown, Australia
- Boden Institute of Obesity, Nutrition, Exercise and Eating Disorders, Sydney Medical School University of Sydney, Camperdown, Australia.
| | - Daniel A Hackett
- University of Sydney Faculty of Health Sciences, Lidcombe, Australia
| | - Michael K Baker
- Boden Institute of Obesity, Nutrition, Exercise and Eating Disorders, Sydney Medical School University of Sydney, Camperdown, Australia
- Australian Catholic University School of Exercise Science, Strathfield, Australia
| | - Nathan A Johnson
- University of Sydney Faculty of Health Sciences, Lidcombe, Australia
- Charles Perkins Centre, University of Sydney, Camperdown, Australia
- Boden Institute of Obesity, Nutrition, Exercise and Eating Disorders, Sydney Medical School University of Sydney, Camperdown, Australia.
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11
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Blaauw B, Schiaffino S, Reggiani C. Mechanisms modulating skeletal muscle phenotype. Compr Physiol 2014; 3:1645-87. [PMID: 24265241 DOI: 10.1002/cphy.c130009] [Citation(s) in RCA: 187] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Mammalian skeletal muscles are composed of a variety of highly specialized fibers whose selective recruitment allows muscles to fulfill their diverse functional tasks. In addition, skeletal muscle fibers can change their structural and functional properties to perform new tasks or respond to new conditions. The adaptive changes of muscle fibers can occur in response to variations in the pattern of neural stimulation, loading conditions, availability of substrates, and hormonal signals. The new conditions can be detected by multiple sensors, from membrane receptors for hormones and cytokines, to metabolic sensors, which detect high-energy phosphate concentration, oxygen and oxygen free radicals, to calcium binding proteins, which sense variations in intracellular calcium induced by nerve activity, to load sensors located in the sarcomeric and sarcolemmal cytoskeleton. These sensors trigger cascades of signaling pathways which may ultimately lead to changes in fiber size and fiber type. Changes in fiber size reflect an imbalance in protein turnover with either protein accumulation, leading to muscle hypertrophy, or protein loss, with consequent muscle atrophy. Changes in fiber type reflect a reprogramming of gene transcription leading to a remodeling of fiber contractile properties (slow-fast transitions) or metabolic profile (glycolytic-oxidative transitions). While myonuclei are in postmitotic state, satellite cells represent a reserve of new nuclei and can be involved in the adaptive response.
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Affiliation(s)
- Bert Blaauw
- Department of Biomedical Sciences, University of Padova, Padova, Italy
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12
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Roberts CK, Hevener AL, Barnard RJ. Metabolic syndrome and insulin resistance: underlying causes and modification by exercise training. Compr Physiol 2013; 3:1-58. [PMID: 23720280 DOI: 10.1002/cphy.c110062] [Citation(s) in RCA: 315] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Metabolic syndrome (MS) is a collection of cardiometabolic risk factors that includes obesity, insulin resistance, hypertension, and dyslipidemia. Although there has been significant debate regarding the criteria and concept of the syndrome, this clustering of risk factors is unequivocally linked to an increased risk of developing type 2 diabetes and cardiovascular disease. Regardless of the true definition, based on current population estimates, nearly 100 million have MS. It is often characterized by insulin resistance, which some have suggested is a major underpinning link between physical inactivity and MS. The purpose of this review is to: (i) provide an overview of the history, causes and clinical aspects of MS, (ii) review the molecular mechanisms of insulin action and the causes of insulin resistance, and (iii) discuss the epidemiological and intervention data on the effects of exercise on MS and insulin sensitivity.
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Affiliation(s)
- Christian K Roberts
- Exercise and Metabolic Disease Research Laboratory, Translational Sciences Section, School of Nursing, University of California at Los Angeles, Los Angeles, California, USA.
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13
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Li Y, Meng L, Miao Q, Sato Y. Association between physical activity and serum C-peptide levels among the elderly. Geriatr Gerontol Int 2013; 14:647-53. [DOI: 10.1111/ggi.12152] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/04/2013] [Indexed: 01/09/2023]
Affiliation(s)
- Ying Li
- Department of Social Medicine; School of Public Health; Zhejiang University; Hangzhou China
| | - Lu Meng
- Department of Social Medicine; School of Public Health; Zhejiang University; Hangzhou China
| | - QianQian Miao
- Department of Social Medicine; School of Public Health; Zhejiang University; Hangzhou China
| | - Yasuto Sato
- Department of Hygiene and Public Health II; Tokyo Women's Medical University; Tokyo Japan
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Manabe Y, Gollisch KSC, Holton L, Kim YB, Brandauer J, Fujii NL, Hirshman MF, Goodyear LJ. Exercise training-induced adaptations associated with increases in skeletal muscle glycogen content. FEBS J 2013. [PMID: 23206309 DOI: 10.1111/febs.12085] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
Chronic exercise training results in numerous skeletal muscle adaptations, including increases in insulin sensitivity and glycogen content. To understand the mechanism leading to increased muscle glycogen, we studied the effects of exercise training on glycogen regulatory proteins in rat skeletal muscle. Female Sprague Dawley rats performed voluntary wheel running for 1, 4 or 7 weeks. After 7 weeks of training, insulin-stimulated glucose uptake was increased in epitrochlearis muscle. As compared with sedentary control rats, muscle glycogen did not change after 1 week of training, but increased significantly after 4 and 7 weeks. The increases in muscle glycogen were accompanied by elevated glycogen synthase activity and protein expression. To assess the regulation of glycogen synthase, we examined its major activator, protein phosphatase 1 (PP1), and its major deactivator, glycogen synthase kinase (GSK)-3. Consistent with glycogen synthase activity, PP1 activity was unchanged after 1 week of training but significantly increased after 4 and 7 weeks of training. Protein expression of R(GL)(G(M)), another regulatory PP1 subunit, significantly decreased after 4 and 7 weeks of training. Unlike PP1 activity, GSK-3 phosphorylation did not follow the pattern of glycogen synthase activity. The ~ 40% decrease in GSK-3α phosphorylation after 1 week of exercise training persisted until 7 weeks, and may function as a negative feedback mechanism in response to elevated glycogen. Our findings suggest that exercise training-induced increases in muscle glycogen content could be regulated by multiple mechanisms, including enhanced insulin sensitivity, glycogen synthase expression, allosteric activation of glycogen synthase, and PP1 activity.
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Affiliation(s)
- Yasuko Manabe
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, MA 02215, USA
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15
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Dubé JJ, Allison KF, Rousson V, Goodpaster BH, Amati F. Exercise dose and insulin sensitivity: relevance for diabetes prevention. Med Sci Sports Exerc 2012; 44:793-9. [PMID: 22051572 DOI: 10.1249/mss.0b013e31823f679f] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
PURPOSE Exercise improves insulin resistance and is a first line for the prevention and treatment of type 2 diabetes. The extent, however, to which these responses are dose dependent is not known. The purpose of this study was to examine whether exercise dose was associated with improvements in insulin sensitivity after 4 months of exercise training in previously sedentary adults. METHODS Fifty-five healthy volunteers participated in a 16-wk supervised endurance exercise intervention with a pre/postintervention design. Insulin sensitivity was assessed by euglycemic hyperinsulinemic clamp, peak oxygen uptake by a graded exercise test, and body composition by dual-energy x-ray absorptiometry. The exercise intervention consisted of three to five sessions per week with a minimum of three sessions supervised. A ramped exercise prescription protocol was used to achieve 75% of peak HR for 45 min per session. Exercise dose, expressed as average kilocalories expended per week, was computed as the product of exercise intensity, duration and frequency. RESULTS Improved insulin sensitivity was significantly related to exercise dose in a graded dose-response relationship. No evidence of threshold or maximal dose-response effect was observed. Age and gender did not influence this dose-response relationship. Exercise intensity was also significantly related to improvements in insulin sensitivity, whereas frequency was not. CONCLUSIONS This study identifies a graded dose-response relationship between exercise dose and improvements in insulin sensitivity. The implication of this observation is of importance for the adaptation of exercise prescription in clinical situations.
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Affiliation(s)
- John J Dubé
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
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16
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Jensen J, Rustad PI, Kolnes AJ, Lai YC. The role of skeletal muscle glycogen breakdown for regulation of insulin sensitivity by exercise. Front Physiol 2011; 2:112. [PMID: 22232606 PMCID: PMC3248697 DOI: 10.3389/fphys.2011.00112] [Citation(s) in RCA: 265] [Impact Index Per Article: 18.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2011] [Accepted: 12/09/2011] [Indexed: 12/12/2022] Open
Abstract
Glycogen is the storage form of carbohydrates in mammals. In humans the majority of glycogen is stored in skeletal muscles (∼500 g) and the liver (∼100 g). Food is supplied in larger meals, but the blood glucose concentration has to be kept within narrow limits to survive and stay healthy. Therefore, the body has to cope with periods of excess carbohydrates and periods without supplementation. Healthy persons remove blood glucose rapidly when glucose is in excess, but insulin-stimulated glucose disposal is reduced in insulin resistant and type 2 diabetic subjects. During a hyperinsulinemic euglycemic clamp, 70-90% of glucose disposal will be stored as muscle glycogen in healthy subjects. The glycogen stores in skeletal muscles are limited because an efficient feedback-mediated inhibition of glycogen synthase prevents accumulation. De novo lipid synthesis can contribute to glucose disposal when glycogen stores are filled. Exercise physiologists normally consider glycogen's main function as energy substrate. Glycogen is the main energy substrate during exercise intensity above 70% of maximal oxygen uptake ([Formula: see text]) and fatigue develops when the glycogen stores are depleted in the active muscles. After exercise, the rate of glycogen synthesis is increased to replete glycogen stores, and blood glucose is the substrate. Indeed insulin-stimulated glucose uptake and glycogen synthesis is elevated after exercise, which, from an evolutional point of view, will favor glycogen repletion and preparation for new "fight or flight" events. In the modern society, the reduced glycogen stores in skeletal muscles after exercise allows carbohydrates to be stored as muscle glycogen and prevents that glucose is channeled to de novo lipid synthesis, which over time will causes ectopic fat accumulation and insulin resistance. The reduction of skeletal muscle glycogen after exercise allows a healthy storage of carbohydrates after meals and prevents development of type 2 diabetes.
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Affiliation(s)
- Jørgen Jensen
- Department of Physical Performance, Norwegian School of Sport Sciences Oslo, Norway
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LINDEN KELLYC, WADLEY GLENND, GARNHAM ANDREWP, MCCONELL GLENNK. Effect of l-Arginine Infusion on Glucose Disposal during Exercise in Humans. Med Sci Sports Exerc 2011; 43:1626-34. [DOI: 10.1249/mss.0b013e318212a317] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
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Green JG, Johnson NA, Sachinwalla T, Cunningham CW, Thompson MW, Stannard SR. Moderate-intensity endurance exercise prevents short-term starvation-induced intramyocellular lipid accumulation but not insulin resistance. Metabolism 2011; 60:1051-7. [PMID: 21353260 DOI: 10.1016/j.metabol.2011.01.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2010] [Revised: 01/07/2011] [Accepted: 01/10/2011] [Indexed: 12/25/2022]
Abstract
Exercise has the potential to alleviate the resistance to insulin-mediated glucose uptake precipitated by elevated circulating free fatty acids (FFAs) in conditions such as obesity, lipid infusion, and starvation. In this study, 6 lean healthy men underwent two 3-day periods of starvation with either no exercise or daily endurance exercise (80 min d(-1) at 50% maximal rate of oxygen consumption) and a 3-day mixed diet without exercise. Insulin sensitivity was determined by intravenous glucose tolerance test, and intramyocellular lipid (IMCL) concentration was measured by (1)H magnetic resonance spectroscopy. In both starvation conditions, fasting plasma FFAs were significantly elevated, whereas plasma glucose and whole-body insulin sensitivity were significantly reduced. Vastus lateralis IMCL to water ratio was significantly elevated after starvation without exercise compared with that after starvation with exercise or that after mixed diet. Intramyocellular lipid to water ratio was not different between starvation with exercise and mixed diet. In healthy lean men, exercise during starvation prevents the accumulation of IMCL yet does not affect the starvation-induced changes in FFAs and insulin sensitivity. Unlike during lipid infusion or obesity-induced insulin resistance, exercise cannot overcome the reduction in insulin action caused by starvation. We propose that carbohydrate availability is a key modulator of the combined effects of exercise and circulating FFAs on insulin sensitivity.
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Affiliation(s)
- Jackson G Green
- Research Centre for Maori Health and Development, Massey University, Palmerston North, New Zealand.
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Wasserman DH, Cherrington AD. Regulation of Extramuscular Fuel Sources During Exercise. Compr Physiol 2011. [DOI: 10.1002/cphy.cp120123] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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Kreiner F, Galbo H. Insulin sensitivity and related cytokines, chemokines, and adipokines in polymyalgia rheumatica. Scand J Rheumatol 2010; 39:402-8. [DOI: 10.3109/03009741003631479] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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Richards JC, Johnson TK, Kuzma JN, Lonac MC, Schweder MM, Voyles WF, Bell C. Short-term sprint interval training increases insulin sensitivity in healthy adults but does not affect the thermogenic response to beta-adrenergic stimulation. J Physiol 2010. [PMID: 20547683 DOI: 10.1113/jphysiol.2010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Sprint interval training (SIT) and traditional endurance training elicit similar physiological adaptations. From the perspective of metabolic function, superior glucose regulation is a common characteristic of endurance-trained adults. Accordingly, we have investigated the hypothesis that short-term SIT will increase insulin sensitivity in sedentary/recreationally active humans. Thirty one healthy adults were randomly assigned to one of three conditions: (1) SIT (n = 12): six sessions of repeated (4-7) 30 s bouts of very high-intensity cycle ergometer exercise over 14 days; (2) sedentary control (n = 10); (3) single-bout SIT (n = 9): one session of 4 x 30 s cycle ergometer sprints. Insulin sensitivity was determined (hyperinsulinaemic euglycaemic clamp) prior to and 72 h following each intervention. Compared with baseline, and sedentary and single-bout controls, SIT increased insulin sensitivity (glucose infusion rate: 6.3 +/- 0.6 vs. 8.0 +/- 0.8 mg kg(1) min(1); mean +/- s.e.m.; P = 0.04). In a separate study, we investigated the effect of SIT on the thermogenic response to beta-adrenergic receptor (beta-AR) stimulation, an important determinant of energy balance. Compared with baseline, and sedentary and single-bout control groups, SIT did not affect resting energy expenditure (EE: ventilated hood technique; 6274 +/- 226 vs. 6079 +/- 297 kJ day(1); P = 0.51) or the thermogenic response to isoproterenol (6, 12 and 24 ng (kg fat-free mass)(1) min(1): %EE 11 +/- 2, 14 +/- 3, 23 +/- 2 vs. 11 +/- 1, 16 +/- 2, 25 +/- 3; P = 0.79). Combined data from both studies revealed no effect of SIT on fasted circulating concentrations of glucose, insulin, adiponectin, pigment epithelial-derived factor, non-esterified fatty acids or noradrenaline (all P > 0.05). Sixteen minutes of high-intensity exercise over 14 days augments insulin sensitivity but does not affect the thermogenic response to beta-AR stimulation.
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Affiliation(s)
- Jennifer C Richards
- Department of Health and Exercise Science, Colorado State University, Fort Collins, CO 80523-1582, USA
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Richards JC, Johnson TK, Kuzma JN, Lonac MC, Schweder MM, Voyles WF, Bell C. Short-term sprint interval training increases insulin sensitivity in healthy adults but does not affect the thermogenic response to beta-adrenergic stimulation. J Physiol 2010; 588:2961-72. [PMID: 20547683 DOI: 10.1113/jphysiol.2010.189886] [Citation(s) in RCA: 129] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Sprint interval training (SIT) and traditional endurance training elicit similar physiological adaptations. From the perspective of metabolic function, superior glucose regulation is a common characteristic of endurance-trained adults. Accordingly, we have investigated the hypothesis that short-term SIT will increase insulin sensitivity in sedentary/recreationally active humans. Thirty one healthy adults were randomly assigned to one of three conditions: (1) SIT (n = 12): six sessions of repeated (4-7) 30 s bouts of very high-intensity cycle ergometer exercise over 14 days; (2) sedentary control (n = 10); (3) single-bout SIT (n = 9): one session of 4 x 30 s cycle ergometer sprints. Insulin sensitivity was determined (hyperinsulinaemic euglycaemic clamp) prior to and 72 h following each intervention. Compared with baseline, and sedentary and single-bout controls, SIT increased insulin sensitivity (glucose infusion rate: 6.3 +/- 0.6 vs. 8.0 +/- 0.8 mg kg(1) min(1); mean +/- s.e.m.; P = 0.04). In a separate study, we investigated the effect of SIT on the thermogenic response to beta-adrenergic receptor (beta-AR) stimulation, an important determinant of energy balance. Compared with baseline, and sedentary and single-bout control groups, SIT did not affect resting energy expenditure (EE: ventilated hood technique; 6274 +/- 226 vs. 6079 +/- 297 kJ day(1); P = 0.51) or the thermogenic response to isoproterenol (6, 12 and 24 ng (kg fat-free mass)(1) min(1): %EE 11 +/- 2, 14 +/- 3, 23 +/- 2 vs. 11 +/- 1, 16 +/- 2, 25 +/- 3; P = 0.79). Combined data from both studies revealed no effect of SIT on fasted circulating concentrations of glucose, insulin, adiponectin, pigment epithelial-derived factor, non-esterified fatty acids or noradrenaline (all P > 0.05). Sixteen minutes of high-intensity exercise over 14 days augments insulin sensitivity but does not affect the thermogenic response to beta-AR stimulation.
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Affiliation(s)
- Jennifer C Richards
- Department of Health and Exercise Science, Colorado State University, Fort Collins, CO 80523-1582, USA
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Kostyak JC, Kris-Etherton P, Bagshaw D, DeLany JP, Farrell PA. Relative fat oxidation is higher in children than adults. Nutr J 2007; 6:19. [PMID: 17705825 PMCID: PMC2014754 DOI: 10.1186/1475-2891-6-19] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2006] [Accepted: 08/16/2007] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND Prepubescent children may oxidize fatty acids more readily than adults. Therefore, dietary fat needs would be higher for children compared with adults. The dietary fat recommendations are higher for children 4 to 18 yrs (i.e., 25 to 35% of energy) compared with adults (i.e., 20 to 35% of energy). Despite this, many parents and children restrict dietary fat for health reasons. METHODS This study assessed whether rates of fat oxidation are similar between prepubescent children and adults. Ten children (8.7 +/- 1.4 yr, 33 +/- 13 kg mean +/- SD) in Tanner stage 1 and 10 adults (41.6 +/- 8 yr, 74 +/- 13 kg) were fed a weight maintenance diet for three days to maintain body weight and to establish a consistent background for metabolic rate measurements (all foods provided). Metabolic rate was measured on three separate occasions before and immediately after breakfast and for 9 hrs using a hood system (twice) or a room calorimeter (once) where continuous metabolic measurements were taken. RESULTS During all three sessions whole body fat oxidation was higher in children (lower RQ) compared to adults (mean RQ= 0.84 +/- .016 for children and 0.87 +/- .02, for adults, p < 0.02). Although, total grams of fat oxidized was similar in children (62.7 +/- 20 g/24 hrs) compared to adults (51.4 +/- 19 g/24 hrs), the grams of fat oxidized relative to calorie expenditure was higher in children (0.047 +/- .01 g/kcal, compared to adults (0.032 +/- .01 p < 0.02). Females oxidized more fat relative to calorie expenditure than males of a similar age. A two way ANOVA showed no interaction between gender and age in terms of fat oxidation. CONCLUSION These data suggest that fat oxidation relative to total calorie expenditure is higher in prepubescent children than in adults. Consistent with current dietary guidelines, a moderate fat diet is appropriate for children within the context of a diet that meets their energy and nutrient needs.
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Affiliation(s)
- John C Kostyak
- Department of Biology, University of Delaware, 305 Wolf Hall, Newark, Delaware, 9716, USA
| | - Penny Kris-Etherton
- Department of Nutritional Sciences, The Pennsylvania State University, S-126 Henderson Bldg., University Park, Pennsylvania, 16802, USA
| | - Deborah Bagshaw
- Department of Nutritional Sciences, The Pennsylvania State University, S-126 Henderson Bldg., University Park, Pennsylvania, 16802, USA
| | - James P DeLany
- Department of Medicine, University of Pittsburgh, BSTWR E1140, Pittsburgh, Pennsylvania, 15261, USA
| | - Peter A Farrell
- Department of Exercise & Sport Science, East Carolina University, 176 Minges Academic Wing, Greenville, North Carolina, 27858, USA
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Wojtaszewski JFP, Richter EA. Effects of acute exercise and training on insulin action and sensitivity: focus on molecular mechanisms in muscle. Essays Biochem 2007; 42:31-46. [PMID: 17144878 DOI: 10.1042/bse0420031] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
A single bout of exercise increases insulin sensitivity for several hours and the effect is mainly restricted to the muscles recruited during exercise. When exercise is repeated over time, adaptations to physical training occur that include more long-lasting increases in insulin sensitivity. The present review explores the molecular mechanisms involved in both the acute and chronic effects of exercise on insulin sensitivity in skeletal muscle.
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Affiliation(s)
- Jørgen F P Wojtaszewski
- Copenhagen Muscle Research Centre, Institute of Exercise and Sport Sciences, University of Copenhagen, Denmark
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Giannini C, de Giorgis T, Mohn A, Chiarelli F. Role of physical exercise in children and adolescents with diabetes mellitus. J Pediatr Endocrinol Metab 2007; 20:173-84. [PMID: 17396433 DOI: 10.1515/jpem.2007.20.2.173] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
During the past 50 years several studies have underlined the central role of physical exercise in the management of patients with both type 1 and type 2 diabetes mellitus. The numerous benefits described in normal individuals who practise regular exercise have also been demonstrated in patients with diabetes who obtained significant physical and psychological advantages for the care of the underlying disease. Despite physical and psychological benefits, the occurrence of acute complications and some important effects on diabetes-related vascular complications may often discourage patients from participation in sports activities. However, even though adverse events may occur, exercise is still judged one of the most important components in the treatment of patients with diabetes. Thus, children, adolescents and young adults with diabetes must be educated on the metabolic changes occurring during physical activity in order to be able to acquire the ability to individually modulate their diet and insulin therapy before and after exercise. Appropriate education may allow a proper and correct approach to physical exercise.
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Abstract
PURPOSE OF REVIEW High levels of cardiorespiratory fitness and/or habitual physical activity are associated with reduced risk of cardiovascular disease. The responsible mechanisms are multifarious, but effects on insulin sensitivity are likely to play an important role. The purpose of this review is to highlight some recent evidence on the interrelationships between physical activity, fitness, obesity, genotype and insulin resistance. RECENT FINDINGS Effects on cardiorespiratory fitness and abdominal obesity are both likely to contribute to the insulin-sensitizing effects of regular physical activity. Recent data suggest that at least in older adults, the intensity of an exercise intervention may influence the magnitude of changes in insulin sensitivity, and emerging data suggest that individual changes in insulin sensitivity following an exercise programme may, in part, be influenced by genotype. SUMMARY Increasing physical activity reduces insulin resistance. As both intensity of exercise and genetic factors may modulate the magnitude of this effect, current physical activity for health guidelines that emphasize engagement in moderate-intensity physical activity in a 'one-size-fits-all' approach may need revision in the future to optimize the potential benefits accrued from individuals becoming more active.
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Affiliation(s)
- Jason M R Gill
- Institute of Diet, Exercise and Lifestyle (IDEAL), Institute of Biomedical and Life Sciences, University of Glasgow, UK.
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Sato Y, Miyao M, Watanabe T, Shimaoka K, Sakai E, Kumazawa A, Oshida Y. Follow-up studies of group behavior therapy for obese Japanese patients. Scand J Med Sci Sports 2007. [DOI: 10.1111/j.1600-0838.1992.tb00345.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Sari R, Balci MK, Balci N, Karayalcin U. Acute effect of exercise on plasma leptin level and insulin resistance in obese women with stable caloric intake. Endocr Res 2007; 32:9-17. [PMID: 18271502 DOI: 10.1080/07435800701670070] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
UNLABELLED Obese individuals are frequently hyperleptinemic and insulin resistant. Chronic exercise is associated with improvements in plasma leptin level and insulin sensitivity; however, little is known about the acute effect of exercise on these parameters. The aim of this study was to evaluate the acute effect of aerobic exercise on plasma leptin and insulin sensitivity in obese women with stable caloric intake. PATIENTS AND METHODS Twenty-three obese women (age 41.2 +/- 10.3 years, body mass index 40.7 +/- 6.7 kg/m2) were included to the study. All subjects were admitted to an exercise program (45-minute walking sessions at 60-80% of maximum heart rate) every day except weekends for four weeks (total 20 exercise sessions). Insulin resistance was evaluated by HOMA model. Plasma glucose, insulin and leptin levels were determined at baseline and at the end of the first, seventh, and twentieth exercise session. RESULTS Baseline and at the end of the first, seventh, and twentieth exercise session plasma leptin levels were 59.1 +/- 20.1, 58.5 +/- 21.0, 53.4 +/- 21.9, and 51.2 +/- 20.5 ng/ml and HOMA-r were 2.75 +/- 1.47, 1.77 +/- 0.71, 1.73 +/- 0.89, 1.62 +/- 0. 70, respectively. Compared to baseline, at the end of the seventh (p = 0.021) and twentieth exercise session (p = 0.003), plasma leptin levels were significantly low. Plasma leptin level did not change significantly at the end of the first exercise session (p > 0.05). At the end of the first exercise session (p = 0.005), end of the seventh (p = 0.003) and twentieth exercise session (p = 0.007) HOMA-r was lower than baseline. There was no correlation between weight loss during exercise period and the change of leptin, and HOMA-r. Fasting plasma glucose, insulin and leptin levels were determined at baseline and at the end of the first, seventh, and twentieth exercise session. CONCLUSION Our study suggests that acute exercise decreases insulin resistance at the first exercise session with no effect on leptin levels. Significant leptin decrement was evident at the first week and lasted during the entire four weeks exercise session.
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Affiliation(s)
- Ramazan Sari
- Division of Endocrinology and Metabolism, Akdeniz University, School of Medicine, Antalya, Turkey.
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Wadley GD, Konstantopoulos N, Macaulay L, Howlett KF, Garnham A, Hargreaves M, Cameron-Smith D. Increased insulin-stimulated Akt pSer473 and cytosolic SHP2 protein abundance in human skeletal muscle following acute exercise and short-term training. J Appl Physiol (1985) 2006; 102:1624-31. [PMID: 17185494 DOI: 10.1152/japplphysiol.00821.2006] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The purpose of the present study was to determine in human skeletal muscle whether a single exercise bout and 7 days of consecutive endurance (cycling) training 1) increased insulin-stimulated Akt pSer(473) and 2) altered the abundance of the protein tyrosine phosphatases (PTPases), PTP1B and SHP2. In healthy, untrained men (n = 8; 24 +/- 1 yr), glucose infusion rate during a hyperinsulinemic euglycemic clamp, when compared with untrained values, was not improved 24 h following a single 60-min bout of endurance cycling but was significantly increased ( approximately 30%; P < 0.05) 24 h following completion of 7 days of exercise training. Insulin-stimulated Akt pSer(473) was approximately 50% higher (P < 0.05) 24 h following the acute bout of exercise, with this effect remaining after 7 days of training (P < 0.05). Insulin-stimulated insulin receptor and insulin receptor substrate-1 tyrosine phosphorylation were not altered 24 h after acute exercise and short-term training. Insulin did not acutely regulate the localization of the PTPases, PTP1B or SHP2, although cytosolic protein abundance of SHP2 was increased (P < 0.05; main effect) 24 h following acute exercise and short-term training. In conclusion, insulin-sensitive Akt pSer(473) and cytosolic SHP2 protein abundance are higher after acute exercise and short-term training, and this effect appears largely due to the residual effects of the last bout of prior exercise. The significance of exercise-induced alterations in cytosolic SHP2 and insulin-stimulated Akt pSer(473) on the improvement in insulin sensitivity requires further elucidation.
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Affiliation(s)
- Glenn D Wadley
- 1School of Exercise and Nutrition Sciences, Deakin University, Burwood, Victoria, Australia.
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Gill JMR, Malkova D. Physical activity, fitness and cardiovascular disease risk in adults: interactions with insulin resistance and obesity. Clin Sci (Lond) 2006; 110:409-25. [PMID: 16526946 DOI: 10.1042/cs20050207] [Citation(s) in RCA: 95] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
There is a considerable body of evidence gathered from studies over the past half a century indicating that a high level of physical activity and a moderately high or high degree of cardiorespiratory fitness reduces the risk of CVD (cardiovascular disease). Recent data suggest that high levels of physical activity or fitness may be particularly beneficial to individuals with insulin-resistant conditions, such as the metabolic syndrome, Type II diabetes or obesity. These individuals, if unfit and sedentary, exhibit increased CVD risk, but their dose-response relationship for physical activity/fitness appears to be particularly steep such that, when they undertake high levels of activity (or have high fitness), their level of risk becomes closer to that of their normal weight or nondiabetic peers. This may be due to effects of physical activity in normalizing the metabolic dysfunction particularly associated with insulin-resistant conditions.
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Affiliation(s)
- Jason M R Gill
- Institute of Diet, Exercise and Lifestyle (IDEAL), Institute of Biomedical and Life Sciences, West Medical Building, University of Glasgow, UK.
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Colombo M, Gregersen S, Kruhoeffer M, Agger A, Xiao J, Jeppesen PB, Orntoft T, Ploug T, Galbo H, Hermansen K. Prevention of hyperglycemia in Zucker diabetic fatty rats by exercise training: effects on gene expression in insulin-sensitive tissues determined by high-density oligonucleotide microarray analysis. Metabolism 2005; 54:1571-81. [PMID: 16311088 DOI: 10.1016/j.metabol.2005.06.003] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2004] [Accepted: 06/13/2005] [Indexed: 11/17/2022]
Abstract
Exercise training (ET) causes metabolic improvement in the prediabetic and diabetic states. However, only little information exists on the changes to ET at the transcriptional level in insulin-sensitive tissues. We have investigated the gene expression changes in skeletal muscle, liver, fat, and pancreatic islets after ET in male Zucker diabetic fatty (ZDF) rats. Eighteen ZDF rats (7 weeks old) were divided in a control and ET group. Exercise was performed using a motorized treadmill (20 m/min 1 hour daily for 6 days a week). Blood glucose, weight, and food intake were measured weekly. After 5 weeks, blood samples, soleus muscle, liver, visceral fat (epididymal fat pads), and islet tissue were collected. Gene expression was quantified with Affymetrix RG-U34A array (16 chips). Exercise training ameliorates the development of hyperglycemia and reduces plasma free fatty acid and the level of glucagon-insulin ratio (P < .05). In skeletal muscle, the expression of 302 genes increased, whereas that of 119 genes decreased. These changes involved genes related to skeletal muscle plasticity, Ca(2+) signals, energy metabolism (eg, glucose transporter 1, phosphorylase kinase), and other signaling pathways as well as genes with unknown functions (expressed sequence tags). In the liver, expression of 148 genes increased, whereas that of 199 genes decreased. These were primarily genes involved in lipogenesis and detoxification. Genes coding for transcription factors were changed in parallel in skeletal muscle and liver tissue. Training did not markedly influence the gene expression in islets. In conclusion, ET changes the expression of multiple genes in the soleus muscle and liver tissue and counteracts the development of diabetes, indicating that ET-induced changes in gene transcription may play an important role en the prevention of diabetes.
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Affiliation(s)
- Michele Colombo
- Department of Endocrinology and Metabolism C, Aarhus Sygehus THG, Aarhus University Hospital, Tage Hansens Gade 2, Aarhus, Denmark.
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Phillips SM, Stewart BG, Mahoney DJ, Hicks AL, McCartney N, Tang JE, Wilkinson SB, Armstrong D, Tarnopolsky MA. Body-weight-support treadmill training improves blood glucose regulation in persons with incomplete spinal cord injury. J Appl Physiol (1985) 2004; 97:716-24. [PMID: 15107410 DOI: 10.1152/japplphysiol.00167.2004] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The impact of a 6-mo body-weight-supported treadmill training program on glucose homeostasis and muscle metabolic characteristics was investigated. Nine individuals (31 ± 3 yr, 8.1 ± 2.5 yr postinjury; means ± SE) with incomplete spinal cord injury trained three times weekly for a total of 6 mo. Training session duration and intensity (velocity) increased by 54 ± 10% ( P < 0.01) and 135 ± 20%, respectively. Muscle biopsies and a modified glucose tolerance test (100 g glucose with [U-13C]glucose) were performed before (Pre) and after training (Post). Training resulted in a reduction in area under the curve of glucose × time (−15 ± 4%) and insulin × time (−33 ± 8%; both P < 0.05). Oxidation of exogenous (ingested) glucose increased as a result of training (Pre = 4.4 ± 0.7 g/h, Post = 7.4 ± 0.6 g/h; P < 0.05), as did oxidation of endogenous (liver) glucose (Pre = 3.8 ± 0.3 g/h, Post = 5.2 ± 0.3 g/h; P < 0.05). Training resulted in increased muscle glycogen (80 ± 23%; P < 0.05) and GLUT-4 content and hexokinase II enzyme activity (126 ± 34 and 49 ± 4%, respectively, both P < 0.01). Resting muscle phosphocreatine content also increased after training (Pre = 62.1 ± 4.3, Post = 78.7 ± 3.8, both mmol/kg dry wt and P < 0.05). Six months of thrice-weekly body-weight-supported treadmill training in persons with an incomplete spinal cord injury improved blood glucose regulation by increasing oxidation and storage of an oral glucose load. Increases in the capacity for transport and phosphorylation glucose in skeletal muscle likely play a role in these adaptations.
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Affiliation(s)
- Stuart M Phillips
- Department of Kinesiology, Exercise and Metabolism Research Group, Centre for Health Promotion and Rehabilitation, McMaster University, 1280 Main St. West, Hamilton, ON, Canada L8S 4K1.
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Ueda H, Urano Y, Sakurai T, Kizaki T, Hitomi Y, Ohno H, Izawa T. Enhanced expression of neuronal nitric oxide synthase in islets of exercise-trained rats. Biochem Biophys Res Commun 2004; 312:794-800. [PMID: 14680835 DOI: 10.1016/j.bbrc.2003.10.189] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2003] [Indexed: 10/26/2022]
Abstract
It is well known that glucose-stimulated insulin secretion (GSIS) decreases after exercise training. In the present study, we investigated the effects of exercise training (9 weeks of running) on the activity of glucokinase (GK), the production of nitric oxide (NO), and the protein expressions of both glucose transporter-2 (GLUT-2) and NO synthase (NOS) in rat pancreatic islets. Exercise training significantly reduced GSIS, with decreases in GK activity and GLUT-2 protein expression. The NO releases and cGMP contents were higher in the islets of trained rats than in those of control rats. Exercise training enhanced cNOS activity, the protein expression of both neuronal nitric oxide synthase (nNOS) and calmodulin, and NADPH-cytochrome c reductase activity in the homogenates of islets. Thus, exercise training-induced reduction of GSIS would result from, at least in part, decreases in both glucose entry and the first step in glycolytic utilization of glucose. Moreover, exercise training could enhance the protein expression of nNOS, which in turn enhances two catalytic activities of nNOS, an NO production and a cytochrome c reductase activity.
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Affiliation(s)
- Hiroshi Ueda
- Department of Kinesiology, Graduate School of Science, Tokyo Metropolitan University, 1-1, Minami-ohsawa, Hachioji, Tokyo 192-0397, Japan
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Pereira LO, Lancha AH. Effect of insulin and contraction up on glucose transport in skeletal muscle. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2004; 84:1-27. [PMID: 14642866 DOI: 10.1016/s0079-6107(03)00055-5] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The major glucose transporter protein expressed in skeletal muscle is GLUT4. Both muscle contraction and insulin induce translocation of GLUT4 from the intracellular pool to the plasma membrane. The intracellular pathways that lead to contraction- and insulin-stimulated GLUT4 translocation seem to be different, allowing the attainment of a maximal effect when acting together. Insulin utilizes a phosphatidylinositol 3-kinase-dependent mechanism, whereas the exercise signal may be initiated by calcium release from the sarcoplasmic reticulum or from autocrine- or paracrine-mediated activation of glucose transport. During exercise skeletal muscle utilizes more glucose than when at rest. However, endurance training leads to decreased glucose utilization during sub-maximal exercise, in spite of a large increase in the total GLUT4 content associated with training. The mechanisms involved in this reduction have not been totally elucidated, but appear to cause the decrease of the amount of GLUT4 translocated to the plasma membrane by altering the exercise-induced enhancement of glucose transport capacity. On the other hand, the effect of resistance training is controversial. Recent studies, however, demonstrated the improvement in insulin sensitivity correlated with increasing muscle mass. New studies should be designed to define the molecular basis for these important adaptations to skeletal muscle. Since during exercise the muscle may utilize insulin-independent mechanisms to increase glucose uptake, the mechanisms involved should provide important knowledge to the understanding and managing peripheral insulin resistance.
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Affiliation(s)
- Luciana Oquendo Pereira
- Biochemistry Department, Biology Institute, Campinas State University, Campinas, São Paulo, Brazil
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Ahn CW, Song YD, Nam JH, Kim DM, Woo SO, Park SW, Cha BS, Lim SK, Kim KR, Lee JH, Lee HC, Huh KB. Insulin sensitivity in physically fit and unfit children of parents with Type 2 diabetes. Diabet Med 2004; 21:59-63. [PMID: 14706055 DOI: 10.1046/j.1464-5491.2003.01049.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
AIMS First-degree relatives of patients with Type 2 diabetes mellitus (T2DM) are often reported to be insulin resistant. We wanted to identify early metabolic abnormalities in this condition, and determine whether they are altered by regular physical training. METHODS We measured insulin sensitivity using the euglycaemic glucose clamp technique and insulin response to oral glucose in 10 unfit (did not participate in routine physical exercise) offspring of T2DM parents and 10 unfit control subjects, and compared them with six fit (routinely swam for 3 h/day 5 days/week) offspring of T2DM parents and six fit controls with no family history of T2DM. RESULTS Unfit offspring had a higher plasma glucose response than the other three groups. The mean area under the glucose curve was also significantly higher in unfit offspring than in the other three groups (12.6 +/- 0.6 vs. 10.4 +/- 0.4, 9.6 +/- 0.5, and 9.5 +/- 0.7 mmol/l per hour for the unfit controls, fit offspring and fit controls, respectively; P < 0.05). The corresponding insulin response of unfit offspring was significantly higher at 60 min in the oral glucose tolerance test (OGTT) that that of fit offspring or fit controls. In addition, the mean area under the insulin curve was significantly greater in unfit offspring than in either fit offspring or fit controls (868 +/- 172 vs. 294 +/- 71, 287 +/- 43 mmol/l per hour, respectively; P < 0.05). Moreover, the glucose disposal rate (GDR), measured using a euglycaemic clamp, was significantly lower in unfit and fit offspring than in unfit and fit controls (5.6 +/- 0.3 vs. 8.6 +/- 0.3 mg/kg per minute; P < 0.01 and 9.3 +/- 0.9 vs. 12.1 +/- 0.8 mg/kg per minute, respectively; P < 0.015), whereas the GDR was similar in unfit controls and fit offspring (8.6 +/- 0.4 vs. 9.3 +/- 0.9 mg/kg per minute; P > 0.05). CONCLUSION These results support the concept that early metabolic abnormalities, as reflected by a decreased GDR (insulin sensitivity) in the offspring of T2DM patients, may be improved by increased physical fitness.
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Affiliation(s)
- C W Ahn
- Department of Internal Medicine, College of Medicine, Yonsei University, Seoul, Korea
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Pedersen BK, Steensberg A, Keller P, Keller C, Fischer C, Hiscock N, van Hall G, Plomgaard P, Febbraio MA. Muscle-derived interleukin-6: lipolytic, anti-inflammatory and immune regulatory effects. Pflugers Arch 2003; 446:9-16. [PMID: 12690457 DOI: 10.1007/s00424-002-0981-z] [Citation(s) in RCA: 137] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Interleukin-6 (IL-6) is produced locally in working skeletal muscle and can account for the exercise-induced increase in plasma IL-6. The transcription rate for IL-6 in muscle nuclei isolated from muscle biopsies during exercise is very high and is enhanced further when muscle glycogen content is low. Furthermore, cultured human primary muscle cells can increase IL-6 mRNA when incubated with the calcium ionophore ionomycin and it is likely that myocytes produce IL-6 in response to muscle contraction. The biological roles of muscle-derived IL-6 have been investigated in studies in which human recombinant IL-6 was infused in healthy volunteers to mimic closely the IL-6 concentrations observed during prolonged exercise. Using stable isotopes, we have demonstrated that physiological concentrations of IL-6 induce lipolysis. Although we have yet to determine the precise biological action of muscle-derived IL-6, our data support the hypothesis that the role of IL-6 released from contracting muscle during exercise is to act in a hormone-like manner to mobilize extracellular substrates and/or augment substrate delivery during exercise. In addition, IL-6 inhibits low-level TNF-alpha production, and IL-6 produced during exercise probably inhibits TNF-alpha-induced insulin resistance in peripheral tissues. Hence, IL-6 produced by skeletal muscle during contraction may play an important role in the beneficial health effects of exercise
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Affiliation(s)
- Bente Klarlund Pedersen
- Dept. of Infectious Diseases, Rigshospitalet, Section 7641, University of Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark.
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Mohr T, Dela F, Handberg A, Biering-Sørensen F, Galbo H, Kjaer M. Insulin action and long-term electrically induced training in individuals with spinal cord injuries. Med Sci Sports Exerc 2001; 33:1247-52. [PMID: 11474322 DOI: 10.1097/00005768-200108000-00001] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
PURPOSE Individuals with spinal cord injuries (SCI) have an increased prevalence of insulin resistance and type 2 diabetes mellitus. In able-bodied individuals, training with large muscle groups increases insulin sensitivity and may prevent type 2 diabetes mellitus. However, individuals with SCI cannot voluntarily recruit major muscle groups, but by functional electrical stimulation (FES) they can now perform ergometer bicycle training. METHODS Ten subjects with SCI (35 +/- 2 yr (mean +/- SE), 73 +/- 5 kg, level of lesion C6--Th4, time since injury: 12 +/- 2 yr) performed 1 yr of FES cycling (30 min x d(-1), 3 d x wk(-1) (intensive training)). Seven subjects continued 6 months with reduced training (1 d x wk(-1) (reduced training)). A sequential, hyperinsulinemic (50 mU x min(-1) x m(-2) (step 1) and 480 mU x min(-1) x m(-2) (step 2)), euglycemic clamp, an oral glucose tolerance test (OGTT), and determination of GLUT 4 transporter protein in muscle biopsies were performed before and after training. RESULTS Insulin-stimulated glucose uptake rates increased after intensive training (from 4.9 +/- 0.5 mg x min(-1) x kg(-1) to 6.2 +/- 0.6 mg x min(-1) x kg(-1) (P < 0.008) (step 1) and from 9.0 +/- 0.8 mg x min(-1) x kg(-1) to 10.6 +/- 0.8 mg x min(-1) x kg(-1) (P = 0.103) (step 2)). With the reduction in training, insulin sensitivity decreased to a similar level as before training (P > 0.05). GLUT 4 increased by 105% after intense training and decreased again with the training reduction. The subjects had impaired glucose tolerance before and after training, and neither glucose tolerance nor insulin responses to OGTT were significantly altered by training. CONCLUSIONS Electrically induced bicycle training, performed three times per week increases insulin sensitivity and GLUT 4 content in skeletal muscle in subjects with SCI. A reduction in training to once per week is not sufficient to maintain these effects. FES training may have a role in the prevention of the insulin resistance syndrome in persons with SCI.
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Affiliation(s)
- T Mohr
- Department of Medical Physiology, The Panum Institute, University of Copenhagen, Copenhagen, Denmark.
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Youngren JF, Keen S, Kulp JL, Tanner CJ, Houmard JA, Goldfine ID. Enhanced muscle insulin receptor autophosphorylation with short-term aerobic exercise training. Am J Physiol Endocrinol Metab 2001; 280:E528-33. [PMID: 11171609 DOI: 10.1152/ajpendo.2001.280.3.e528] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Exercise training improves insulin action in skeletal muscle, but the mechanisms of this effect are not completely understood. In particular, the role of the insulin receptor (IR) is unclear. We examined the IR and an enzyme indicative of oxidative capacity in muscle in relation to improved insulin action in 20 previously sedentary individuals before and after a 7-day program of moderate-intensity cycle ergometry. After training, insulin sensitivity increased 33% (6.20 +/- 0.91 vs. 8.22 +/- 1.12 min. microU(-1). ml(-1) mean +/- SE, pre- vs. posttraining, respectively, P < 0.05). The mitochondrial marker enzyme cytochrome c oxidase (COX) increased in vastus lateralis biopsies by 21% (P < 0.05). After training, IR autophosphorylation, determined by ELISA, was significantly increased by approximately 40% at insulin concentrations from 1 to 100 nM (P < 0.05). The training-induced improvements in IR autophosphorylation were significantly correlated with changes in muscle COX content (r = 0.65, P < 0.05). These studies indicate that, in this model of increased physical activity, improvements in IR function are an early adaptation to exercise in humans, are correlated with increases in muscle oxidative capacity, and likely contribute to the beneficial effects of exercise training on insulin action.
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Affiliation(s)
- J F Youngren
- Division of Diabetes and Endocrine Research, Department of Medicine, Mount Zion Medical Center, University of California-San Francisco, San Francisco, CA 94143, USA.
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Stallknecht B, Larsen JJ, Mikines KJ, Simonsen L, Bülow J, Galbo H. Effect of training on insulin sensitivity of glucose uptake and lipolysis in human adipose tissue. Am J Physiol Endocrinol Metab 2000; 279:E376-85. [PMID: 10913038 DOI: 10.1152/ajpendo.2000.279.2.e376] [Citation(s) in RCA: 61] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Training increases insulin sensitivity of both whole body and muscle in humans. To investigate whether training also increases insulin sensitivity of adipose tissue, we performed a three-step hyperinsulinemic, euglycemic clamp in eight endurance-trained (T) and eight sedentary (S) young men [insulin infusion rates: 10,000 (step I), 20,000 (step II), and 150,000 (step III) microU x min(-1) x m(-2)]. Glucose and glycerol concentrations were measured in arterial blood and also by microdialysis in interstitial fluid in periumbilical, subcutaneous adipose tissue and in quadriceps femoris muscle (glucose only). Adipose tissue blood flow was measured by (133)Xe washout. In the basal state, adipose tissue blood flow tended to be higher in T compared with S subjects, and in both groups blood flow was constant during the clamp. The change from basal in arterial-interstitial glucose concentration difference was increased in T during the clamp but not in S subjects in both adipose tissue and muscle [adipose tissue: step I (n = 8), 0.48 +/- 0.18 mM (T), 0.23 +/- 0.11 mM (S); step II (n = 8), 0.19 +/- 0.09 (T), -0.09 +/- 0.24 (S); step III (n = 5), 0.47 +/- 0.24 (T), 0.06 +/- 0.28 (S); (T: P < 0.001, S: P > 0.05); muscle: step I (n = 4), 1. 40 +/- 0.46 (T), 0.31 +/- 0.21 (S); step II (n = 4), 1.14 +/- 0.54 (T), -0.08 +/- 0.14 (S); step III (n = 4), 1.23 +/- 0.34 (T), 0.24 +/- 0.09 (S); (T: P < 0.01, S: P > 0.05)]. Interstitial glycerol concentration decreased faster in T than in S subjects [half-time: T, 44 +/- 9 min (n = 7); S, 102 +/- 23 min (n = 5); P < 0.05]. In conclusion, training enhances insulin sensitivity of glucose uptake in subcutaneous adipose tissue and in skeletal muscle. Furthermore, interstitial glycerol data suggest that training also increases insulin sensitivity of lipolysis in subcutaneous adipose tissue. Insulin per se does not influence subcutaneous adipose tissue blood flow.
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Affiliation(s)
- B Stallknecht
- Department of Medical Physiology, The Panum Institute, University of Copenhagen, DK-2200 Copenhagen N, Denmark.
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Kirwan JP, del Aguila LF, Hernandez JM, Williamson DL, O'Gorman DJ, Lewis R, Krishnan RK. Regular exercise enhances insulin activation of IRS-1-associated PI3-kinase in human skeletal muscle. J Appl Physiol (1985) 2000; 88:797-803. [PMID: 10658053 DOI: 10.1152/jappl.2000.88.2.797] [Citation(s) in RCA: 101] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Insulin action in skeletal muscle is enhanced by regular exercise. Whether insulin signaling in human skeletal muscle is affected by habitual exercise is not well understood. Phosphatidylinositol 3-kinase (PI3-kinase) activation is an important step in the insulin-signaling pathway and appears to regulate glucose metabolism via GLUT-4 translocation in skeletal muscle. To examine the effects of regular exercise on PI3-kinase activation, 2-h hyperinsulinemic (40 mU. m(-2). min(-1))-euglycemic (5.0 mM) clamps were performed on eight healthy exercise-trained [24 +/- 1 yr, 71.8 +/- 2.0 kg, maximal O(2) uptake (VO(2 max)) of 56.1 +/- 2.5 ml. kg(-1). min(-1)] and eight healthy sedentary men and women (24 +/- 1 yr, 64.7 +/- 4.4 kg, VO(2 max) of 44.4 +/- 2.7 ml. kg(-1). min(-1)). A [6, 6-(2)H]glucose tracer was used to measure hepatic glucose output. A muscle biopsy was obtained from the vastus lateralis muscle at basal and at 2 h of hyperinsulinemia to measure insulin receptor substrate-1(IRS-1)-associated PI3-kinase activation. Insulin concentrations during hyperinsulinemia were similar for both groups (293 +/- 22 and 311 +/- 22 pM for trained and sedentary, respectively). Insulin-mediated glucose disposal rates (GDR) were greater (P < 0.05) in the exercise-trained compared with the sedentary control group (9.22 +/- 0.95 vs. 6.36 +/- 0.57 mg. kg fat-free mass(-1). min(-1)). Insulin-stimulated PI3-kinase activation was also greater (P < 0.004) in the trained compared with the sedentary group (3.8 +/- 0.5- vs. 1.8 +/- 0.2-fold increase from basal). Endurance capacity (VO(2 max)) was positively correlated with PI3-kinase activation (r = 0.53, P < 0.04). There was no correlation between PI3-kinase and muscle morphology. However, increases in GDR were positively related to PI3-kinase activation (r = 0.60, P < 0.02). We conclude that regular exercise leads to greater insulin-stimulated IRS-1-associated PI3-kinase activation in human skeletal muscle, thus facilitating enhanced insulin-mediated glucose uptake.
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Affiliation(s)
- J P Kirwan
- Departments of Reproductive Biology and Nutrition, Case Western Reserve University School of Medicine at MetroHealth Medical Center, Cleveland, Ohio 44109, USA.
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Enevoldsen LH, Stallknecht B, Fluckey JD, Galbo H. Effect of exercise training on in vivo insulin-stimulated glucose uptake in intra-abdominal adipose tissue in rats. Am J Physiol Endocrinol Metab 2000; 278:E25-34. [PMID: 10644533 DOI: 10.1152/ajpendo.2000.278.1.e25] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Intra-abdominal obesity may be crucial in the pathogenesis of the insulin-resistance syndrome, and training may alleviate this condition. We compared insulin-mediated glucose uptake in vivo in three intra-abdominal adipose tissues (ATs; retroperitoneal, parametrial, and mesenteric) and in subcutaneous AT and also studied the effect of training. Rats were either swim trained (15 wk, n = 9) or sedentary (n = 16). While the rats were under anesthesia, a hyperinsulinemic ( approximately 900 pM), euglycemic clamp was carried out and local glucose uptake was measured by both the 2-deoxy-D-[(3)H]glucose and microdialysis techniques. Blood flow was measured by microspheres. Upon insulin stimulation, blood flow generally decreased in AT. Flow was higher in mesenteric tissue than in other ATs, whereas insulin-mediated glucose uptake did not differ between ATs. Training doubled the glucose infusion rate during hyperinsulinemia, in part, reflecting an effect in muscle. During hyperinsulinemia, interstitial glucose concentrations were lower, glucose uptake per 100 g of tissue was higher in AT in trained compared with sedentary rats, and training influenced glucose uptake identically in all ATs. In conclusion, differences between ATs in insulin sensitivity with respect to glucose uptake do not explain that insulin resistance is associated with intra-abdominal rather than subcutaneous obesity. Furthermore, training may be beneficial by enhancing insulin sensitivity in intra-abdominal fat depots.
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Affiliation(s)
- L H Enevoldsen
- Department of Medical Physiology, The Panum Institute, University of Copenhagen, Denmark
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Dela F, Mikines KJ, Larsen JJ, Galbo H. Glucose clearance in aged trained skeletal muscle during maximal insulin with superimposed exercise. J Appl Physiol (1985) 1999; 87:2059-67. [PMID: 10601150 DOI: 10.1152/jappl.1999.87.6.2059] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Insulin and muscle contractions are major stimuli for glucose uptake in skeletal muscle and have in young healthy people been shown to be additive. We studied the effect of superimposed exercise during a maximal insulin stimulus on glucose uptake and clearance in trained (T) (1-legged bicycle training, 30 min/day, 6 days/wk for 10 wk at approximately 70% of maximal O(2) uptake) and untrained (UT) legs of healthy men (H) [n = 6, age 60 +/- 2 (SE) yr] and patients with Type 2 diabetes mellitus (DM) (n = 4, age 56 +/- 3 yr) during a hyperinsulinemic ( approximately 16,000 pmol/l), isoglycemic clamp with a final 30 min of superimposed two-legged exercise at 70% of individual maximal heart rate. With superimposed exercise, leg glucose extraction decreased (P < 0.05), and leg blood flow and leg glucose clearance increased (P < 0.05), compared with hyperinsulinemia alone. During exercise, leg blood flow was similar in both groups of subjects and between T and UT legs, whereas glucose extraction was always higher (P < 0.05) in T compared with UT legs (15.8 +/- 1.2 vs. 14.6 +/- 1.8 and 11.9 +/- 0.8 vs. 8.8 +/- 1.8% for H and DM, respectively) and leg glucose clearance was higher in T (H: 73 +/- 8, DM: 70 +/- 10 ml. min(-1). kg leg(-1)) compared with UT (H: 63 +/- 8, DM: 45 +/- 7 ml. min(-1). kg leg(-1)) but not different between groups (P > 0.05). From these results it can be concluded that, in both diabetic and healthy aged muscle, exercise adds to a maximally insulin-stimulated glucose clearance and that glucose extraction and clearance are both enhanced by training.
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Affiliation(s)
- F Dela
- Department of Medical Physiology, The Panum Institute, University of Copenhagen, Rigshospitalet, DK-2200 N, Copenhagen, Denmark.
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Kraus W. Insulin resistance syndrome and cardiovascular disease: genetics and connections to skeletal muscle function. Am Heart J 1999; 138:S413-6. [PMID: 10539806 DOI: 10.1016/s0002-8703(99)70044-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Affiliation(s)
- W Kraus
- Center for Living, Duke University Medical Center, Durham, NC, USA
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Thorell A, Hirshman MF, Nygren J, Jorfeldt L, Wojtaszewski JF, Dufresne SD, Horton ES, Ljungqvist O, Goodyear LJ. Exercise and insulin cause GLUT-4 translocation in human skeletal muscle. THE AMERICAN JOURNAL OF PHYSIOLOGY 1999; 277:E733-41. [PMID: 10516134 DOI: 10.1152/ajpendo.1999.277.4.e733] [Citation(s) in RCA: 89] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Studies in rodents have established that GLUT-4 translocation is the major mechanism by which insulin and exercise increase glucose uptake in skeletal muscle. In contrast, much less is known about the translocation phenomenon in human skeletal muscle. In the current study, nine healthy volunteers were studied on two different days. On one day, biopsies of vastus lateralis muscle were taken before and after a 2-h euglycemic-hyperinsulinemic clamp (0.8 mU. kg(-1). min(-1)). On another day, subjects exercised for 60 min at 70% of maximal oxygen consumption (VO(2 max)), a biopsy was obtained, and the same clamp and biopsy procedure was performed as that during the previous experiment. Compared with insulin treatment alone, glucose infusion rates were significantly increased during the postexercise clamp for the periods 0-30 min, 30-60 min, and 60-90 min, but not during the last 30 min of the clamp. Plasma membrane GLUT-4 content was significantly increased in response to physiological hyperinsulinemia (32% above rest), exercise (35%), and the combination of exercise plus insulin (44%). Phosphorylation of Akt, a putative signaling intermediary for GLUT-4 translocation, was increased in response to insulin (640% above rest), exercise (280%), and exercise plus insulin (1,000%). These data demonstrate that two normal physiological conditions, moderate intensity exercise and physiological hyperinsulinemia approximately 56 microU/ml, cause GLUT-4 translocation and Akt phosphorylation in human skeletal muscle.
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Affiliation(s)
- A Thorell
- Department of Surgery, Huddinge University Hospital, S-141 86 Huddinge,Sweden
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Hansen BF, Asp S, Kiens B, Richter EA. Glycogen concentration in human skeletal muscle: effect of prolonged insulin and glucose infusion. Scand J Med Sci Sports 1999; 9:209-13. [PMID: 10407928 DOI: 10.1111/j.1600-0838.1999.tb00235.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
To study the upper limit of glycogen storage in human muscle, two healthy male subjects were infused with glucose and insulin for 8 h reaching plasma concentrations of about 21 mM glucose and approximately 2000 microU/ml insulin. Prior to the infusion subjects performed for 1 h one-legged knee-extensor exercise at 75% of their maximum one-legged work capacity in order to lower muscle glycogen stores in one leg. During the 8-h hyperglycemic clamp procedure, glycogen concentrations increased and levelled off at 2- and 5-fold above the pre-infusion levels in the resting and the working leg, respectively. However, the absolute glycogen levels reached in both legs were quite similar, close to 4 g per 100 g wet muscle (about 1000 mumol/g d.w.), independent of prior exercise. Previous studies have shown that glycogen levels, after a bout of glycogen-depleting exercise and subsequent ingestion of a carbohydrate-rich diet for 3 days, can be increased to values around 3-4 g per 100 g wet muscle. It appears that the maximal attainable glycogen concentration in human muscle seems to be close 4 g per 100 g wet muscle. This glycogen level can thus be reached either by a prolonged infusion of supra-physiological concentrations of glucose and insulin or by glycogen-depleting exercise followed by ingestion of a carbohydrate-rich diet.
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Affiliation(s)
- B F Hansen
- Diabetes Biology, Novo Nordisk A/S, Bagsvaerd, Denmark
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Arciero PJ, Vukovich MD, Holloszy JO, Racette SB, Kohrt WM. Comparison of short-term diet and exercise on insulin action in individuals with abnormal glucose tolerance. J Appl Physiol (1985) 1999; 86:1930-5. [PMID: 10368358 DOI: 10.1152/jappl.1999.86.6.1930] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The effects of a 10-day low-calorie diet (LCD; n = 8) or exercise training (ET; n = 8) on insulin secretion and action were compared in obese men (n = 9) and women (n = 7), aged 53 +/- 1 yr, with abnormal glucose tolerance by using a hyperglycemic clamp with superimposed arginine infusion and a high-fat drink. Body mass (LCD, 115 +/- 5 vs. 110 +/- 5 kg; ET, 111 +/- 7 vs. 109 +/- 7 kg; P < 0. 01) and fasting plasma glucose (LCD, 115 +/- 10 vs. 99 +/- 4 mg/dl; ET, 112 +/- 4 vs. 101 +/- 5 mg/dl, P < 0.01) and insulin (LCD, 23.9 +/- 5.6 vs. 15.2 +/- 3.9 microU/ml; ET, 17.6 +/- 1.9 vs. 13.9 +/- 2. 4 microU/ml; P < 0.05) decreased in both groups. There was a 40% reduction in plasma insulin during hyperglycemia (0-45 min) after LCD (peak: 118 +/- 18 vs. 71 +/- 14 microU/ml; P < 0.05) and ET (69 +/- 14 vs. 41 +/- 7 microU/ml; P < 0.05) and trends for reductions during arginine infusion and a high-fat drink. The 56% increase in glucose uptake after ET (4.95 +/- 0.90 vs. 7.74 +/- 0.82 mg. min-1. kg fat-free mass-1; P < 0.01) was significantly (P < 0.01) greater than the 19% increase (5.72 +/- 1.12 vs. 6.80 +/- 0.94 mg. min-1. kg fat-free mass-1; P = not significant) that occurred after LCD. The marked increase in glucose disposal after ET, despite lower insulin levels, suggests that short-term exercise is more effective than diet in enhancing insulin action in individuals with abnormal glucose tolerance.
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Affiliation(s)
- P J Arciero
- Division of Geriatrics and Gerontology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA
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48
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Burelle Y, Péronnet F, Charpentier S, Lavoie C, Hillaire-Marcel C, Massicotte D. Oxidation of an oral [13C]glucose load at rest and prolonged exercise in trained and sedentary subjects. J Appl Physiol (1985) 1999; 86:52-60. [PMID: 9887112 DOI: 10.1152/jappl.1999.86.1.52] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The purpose of this study was to compare the oxidation of [13C]glucose (100 g) ingested at rest or during exercise in six trained (TS) and six sedentary (SS) male subjects. The oxidation of plasma glucose was also computed from the volume of 13CO2 and 13C/12C in plasma glucose to compute the oxidation rate of glucose released from the liver and from glycogen stores in periphery (mainly muscle glycogen stores during exercise). At rest, oxidative disposal of both exogenous (8.3 +/- 0.3 vs. 6.6 +/- 0.8 g/h) and liver glucose (4.4 +/- 0.5 vs. 2.6 +/- 0.4 g/h) was higher in TS than in SS. This could contribute to the better glucose tolerance observed at rest in TS. During exercise, for the same absolute workload [140 +/- 5 W: TS = 47 +/- 2.5; SS = 68 +/- 3 %maximal oxygen uptake (VO2 max)], [13C]glucose oxidation was higher in TS than in SS (39.0 +/- 2.6 vs. 33.6 +/- 1.2 g/h), whereas both liver glucose (16.8 +/- 2.4 vs. 24.0 +/- 1.8 g/h) and muscle glycogen oxidation (36.0 +/- 3.0 vs. 51.0 +/- 5.4 g/h) were lower. For the same relative workload (68 +/- 3% VO2 max: TS = 3.13 +/- 0.96; SS = 2.34 +/- 0.60 l O2/min), exogenous glucose (44.4 +/- 1.8 vs. 33.6 +/- 1.2 g/h) and muscle glycogen oxidation (73.8 +/- 7.2 vs. 51.0 +/- 5.4 g/h) were higher in TS. However, despite a higher energy expenditure in TS, liver glucose oxidation was similar in both groups (22.2 +/- 3.0 vs. 24.0 +/- 1.8 g/h). Thus exogenous glucose oxidation was selectively favored in TS during exercise, reducing both liver glucose and muscle glycogen oxidation.
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Affiliation(s)
- Y Burelle
- Département de Kinésiologie, Université de Montréal, Montréal, Québec, H3C 3J7, Canada H3C 3P8
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Abstract
Physical exercise can be an important adjunct in the treatment of both non-insulin-dependent diabetes mellitus and insulin-dependent diabetes mellitus. Over the past several years, considerable progress has been made in understanding the molecular basis for these clinically important effects of physical exercise. Similarly to insulin, a single bout of exercise increases the rate of glucose uptake into the contracting skeletal muscles, a process that is regulated by the translocation of GLUT4 glucose transporters to the plasma membrane and transverse tubules. Exercise and insulin utilize different signaling pathways, both of which lead to the activation of glucose transport, which perhaps explains why humans with insulin resistance can increase muscle glucose transport in response to an acute bout of exercise. Exercise training in humans results in numerous beneficial adaptations in skeletal muscles, including an increase in GLUT4 expression. The increase in muscle GLUT4 in trained individuals contributes to an increase in the responsiveness of muscle glucose uptake to insulin, although not all studies show that exercise training in patients with diabetes improves overall glucose control. However, there is now extensive epidemiological evidence demonstrating that long-term regular physical exercise can significantly reduce the risk of developing non-insulin-dependent diabetes mellitus.
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Affiliation(s)
- L J Goodyear
- Research Division, Joslin Diabetes Center, Brigham and Women's Hospital, Boston, Massachusetts, USA.
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Wojtaszewski JF, Richter EA. Glucose utilization during exercise: influence of endurance training. ACTA PHYSIOLOGICA SCANDINAVICA 1998; 162:351-8. [PMID: 9578381 DOI: 10.1046/j.1365-201x.1998.0322e.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
During exercise skeletal muscle glucose utilization is higher than at rest. This is due to the combined effect of an increase in glucose supply, increased surface membrane glucose transport capacity and increased muscle glucose metabolism during exercise. The kinetics of glucose utilization in skeletal muscle during exercise in humans show an apparent Km of approximately 10 mM, indicating that changes in the blood glucose concentration around the physiological level of approximately 5 mM almost linearly translate into changes in muscle glucose utilization. The signalling events responsible for increased glucose transport in contracting muscle are not well understood, although calcium seems to be involved. Contractions do not utilize the proximal part of the insulin signalling cascade to activate glucose transport, because contractions do not cause phosphorylation of insulin receptor substrate 1 or activation of phosphatidylinositol 3-kinase. Endurance training leads to a decrease in glucose utilization during submaximal exercise of a given absolute submaximal power output in spite of a large increase in the total muscle GLUT4 content. The molecular mechanism behind this decrease in glucose utilization seems to be blunted exercise-induced translocation of GLUT4 protein to the sarcolemma, in turn blunting the exercise-induced increase in sarcolemmal glucose transport capacity.
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Affiliation(s)
- J F Wojtaszewski
- Copenhagen Muscle Research Centre, August Krogh Institute, University of Copenhagen, Denmark
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