|
1
|
Amerkamp J, Benli S, Isenmann E, Brinkmann C. Optimizing the lifestyle of patients with type 2 diabetes mellitus - Systematic review on the effects of combined diet-and-exercise interventions. Nutr Metab Cardiovasc Dis 2025; 35:103746. [PMID: 39490277 DOI: 10.1016/j.numecd.2024.09.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 08/07/2024] [Accepted: 09/17/2024] [Indexed: 11/05/2024]
Abstract
AIM To investigate the effects of combined diet-and-exercise interventions in patients with type 2 diabetes mellitus (T2DM). DATA SYNTHESIS A systematic literature search was conducted on PubMed, Web of Science, SPORTDiscus and BISp Surf databases (latest update in June 2024). A total of 14706 records was identified. After screening procedures, 11 randomized controlled trials (n = 24 reports) were included. The included studies compared either the effects of a) a combined intervention versus a diet-only intervention or b) different combinations of diet and exercise. The overall quality of the included study reports was moderate (evaluated with the Risk of Bias 2 (RoB2) tool). Effects of adding exercise to a (calorie-restricted) diet were primarily reflected in increased physical fitness/performance. In far fewer cases, additional beneficial effects on glycemic control, number of subjects taking medication, body weight, body composition, or lipid profile were reported. Combined with regular exercise, an energy-restricted low-carbohydrate (LC) diet with either high-fat (HF) or high-protein (HP) contents showed superior effects compared with an energy-matched conventional (CONV) diet in terms of improvements in medication use (HF-LC versus CONV diet), lipids (HF-LC or HP-LC versus CONV diet) or wellbeing (HP-LC versus CONV diet) in some studies. CONCLUSIONS Complementing a dietary intervention with regular exercise can have additional health benefits in T2DM, specifically improved physical fitness/performance. LC diets might be superior to other diets when combined with regular exercise. Other diet-and-exercise combinations than those analyzed in this review need to be investigated. REVIEW REGISTRATION NUMBER CRD42023458830.
Collapse
Affiliation(s)
- Jessica Amerkamp
- Department of Preventive and Rehabilitative Sport Medicine, Institute of Cardiovascular Research and Sport Medicine, German Sport University Cologne, Am Sportpark Müngersdorf 6, 50933, Cologne, Germany
| | - Süleyman Benli
- IST University of Applied Sciences, Erkrather Straße 220, 40233, Düsseldorf, Germany
| | - Eduard Isenmann
- IST University of Applied Sciences, Erkrather Straße 220, 40233, Düsseldorf, Germany; Department of Molecular and Cellular Sport Medicine, Institute of Cardiovascular Research and Sport Medicine, German Sport University Cologne, Am Sportpark Müngersdorf 6, 50933, Cologne, Germany
| | - Christian Brinkmann
- Department of Preventive and Rehabilitative Sport Medicine, Institute of Cardiovascular Research and Sport Medicine, German Sport University Cologne, Am Sportpark Müngersdorf 6, 50933, Cologne, Germany; IST University of Applied Sciences, Erkrather Straße 220, 40233, Düsseldorf, Germany.
| |
Collapse
|
|
2
|
Gunaseelan V, Selvarajan S, Kamalanathan S, Kadhiravan T, Venkatraman S. Effect of metformin on exercise capacity in treatment naïve type 2 diabetes patients. Drug Metab Pers Ther 2025; 40:35-41. [PMID: 39679445 DOI: 10.1515/dmpt-2024-0049] [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: 04/24/2024] [Accepted: 10/24/2024] [Indexed: 12/17/2024]
Abstract
OBJECTIVES Exercise capacity is decreased in diabetes mellitus due to impaired insulin sensitivity, endothelial dysfunction and mitochondrial dysfunction. The aim of the study was to evaluate the effect of metformin on exercise capacity in treatment naïve patients with type 2 diabetes mellitus. METHODS Newly diagnosed type 2 diabetes mellitus patients were tested for baseline insulin resistance and exercise capacity, before starting on metformin. Exercise capacity was measured by incremental exercise testing in treadmill (ZAN 600 CPET system) using modified Bruce protocol at baseline, 6 weeks and 12 weeks following metformin therapy. RESULTS A total of 33 treatment naïve type 2 diabetes patients were enrolled of which 19 patients completed the study. There was no significant change in any of the exercise capacity parameters at the end of 12 weeks of metformin. Nevertheless, there was a significant improvement in VO2/kg among those with insulin resistance as compared to those without insulin resistance. CONCLUSIONS Metformin monotherapy did not produce any change in exercise capacity in treatment naïve type 2 diabetes patients. However, a significant fall in exercise capacity (VO2/kg) was observed in patients without insulin resistance as compared to those with insulin resistance at the end of 12 weeks of metformin therapy.
Collapse
|
|
3
|
Lewis C, Rafi E, Dobbs B, Barton T, Hatipoglu B, Malin SK. Tailoring Exercise Prescription for Effective Diabetes Glucose Management. J Clin Endocrinol Metab 2025; 110:S118-S130. [PMID: 39836084 PMCID: PMC12054731 DOI: 10.1210/clinem/dgae908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Indexed: 01/22/2025]
Abstract
CONTEXT Physical activity, exercise, or both are a staple of lifestyle management approaches both for type 1 diabetes mellitus (T1DM) and type 2 diabetes (T2DM). While the current literature supports both physical activity and exercise for improving glycemic control, reducing cardiovascular risk, maintaining proper weight, and enhancing overall well-being, the optimal prescription regimen remains debated. EVIDENCE ACQUISITION We searched PubMed and Google Scholar databases for relevant studies on exercise, insulin sensitivity, and glycemic control in people with T1DM and T2DM. EVIDENCE SYNTHESIS In patients with T1DM, exercise generally improves cardiovascular fitness, muscle strength, and glucose levels. However, limited work has evaluated the effect of aerobic plus resistance exercise compared to either exercise type alone on glycemic outcomes. Moreover, less research has evaluated breaks in sedentary behavior with physical activity. When considering the factors that may cause hypoglycemic effects during exercise in T1DM, we found that insulin therapy, meal timing, and neuroendocrine regulation of glucose homeostasis are all important. In T2DM, physical activity is a recommended therapy independent of weight loss. Contemporary consideration of timing of exercise relative to meals and time of day, potential medication interactions, and breaks in sedentary behavior have gained recognition as potentially novel approaches that enhance glucose management. CONCLUSION Physical activity or exercise is, overall, an effective treatment for glycemia in people with diabetes independent of weight loss. However, additional research surrounding exercise is needed to maximize the health benefit, particularly in "free-living" settings.
Collapse
Affiliation(s)
- Claudia Lewis
- Department of Endocrinology, University Hospitals Diabetes and Metabolic Care Center, Cleveland, OH 44106, USA
| | - Ebne Rafi
- Department of Endocrinology, University Hospitals Diabetes and Metabolic Care Center, Cleveland, OH 44106, USA
| | - Brandi Dobbs
- Department of Endocrinology, University Hospitals Diabetes and Metabolic Care Center, Cleveland, OH 44106, USA
| | - Tanner Barton
- Department of Athletics, John Carroll University, University Heights, OH 44118, USA
| | - Betul Hatipoglu
- Department of Endocrinology, University Hospitals Diabetes and Metabolic Care Center, Cleveland, OH 44106, USA
- Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Steven K Malin
- Department of Kinesiology and Health, Rutgers University, New Brunswick, NJ 08901, USA
- Division of Endocrinology, Metabolism & Nutrition; Rutgers University, New Brunswick, NJ 08901, USA
- New Jersey Institute for Food, Nutrition and Health, Rutgers University, New Brunswick, NJ 08901, USA
- Institute of Translational Medicine and Science, Rutgers University, New Brunswick, NJ 08901, USA
| |
Collapse
|
|
4
|
Zhang S, Wang N, Gao Z, Gao J, Wang X, Xie H, Wang CY, Zhang S. Reductive stress: The key pathway in metabolic disorders induced by overnutrition. J Adv Res 2025:S2090-1232(25)00031-1. [PMID: 39805424 DOI: 10.1016/j.jare.2025.01.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Revised: 12/04/2024] [Accepted: 01/05/2025] [Indexed: 01/16/2025] Open
Abstract
BACKGROUND The balance of redox states is crucial for maintaining physiological homeostasis. For decades, the focus has been mainly on the concept of oxidative stress, which is involved in the mechanism of almost all diseases. However, robust evidence has highlighted that reductive stress, the other side of the redox spectrum, plays a pivotal role in the development of various diseases, particularly those related to metabolism and cardiovascular health. AIM OF REVIEW In this review, we present an extensive array of evidence for the occurrence of reductive stress and its significant implications mainly in metabolic and cardiovascular diseases. KEY SCIENTIFIC CONCEPTS OF REVIEW Reductive stress is defined as a shift in the cellular redox balance towards a more reduced state, characterized by an excess of endogenous reductants (such as NADH, NADPH, and GSH) over their oxidized counterparts (NAD+, NADP+, and GSSG). While oxidative stress has been the predominant mechanism studied in obesity, metabolic disorders, and cardiovascular diseases, growing evidence underscores the critical role of reductive stress. This review discusses how reductive stress contributes to metabolic and cardiovascular pathologies, emphasizing its effects on key cellular processes. For example, excessive NADH accumulation can disrupt mitochondrial function by impairing the electron transport chain, leading to decreased ATP production and increased production of reactive oxygen species. In the endoplasmic reticulum (ER), an excess of reductive equivalents hampers protein folding, triggering ER stress and activating the unfolded protein response, which can lead to insulin resistance and compromised cellular homeostasis. Furthermore, we explore how excessive antioxidant supplementation can exacerbate reductive stress by further shifting the redox balance, potentially undermining the beneficial effects of exercise, impairing cardiovascular health, and aggravating metabolic disorders, particularly in obese individuals. This growing body of evidence calls for a reevaluation of the role of reductive stress in disease pathogenesis and therapeutic interventions.
Collapse
Affiliation(s)
- Shiyi Zhang
- The Center for Biomedical Research, Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Na Wang
- The Center for Biomedical Research, Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhichao Gao
- The Center for Biomedical Research, Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jia Gao
- The Center for Biomedical Research, Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaohui Wang
- The Center for Biomedical Research, Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hao Xie
- Institute of Translational Medicine, Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
| | - Cong-Yi Wang
- The Center for Biomedical Research, Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Shu Zhang
- The Center for Biomedical Research, Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| |
Collapse
|
|
5
|
Carrillo BJP, Cope E, Gurel S, Traslosheros A, Kenny A, Michot‐Duval O, Mody N, Delibegovic M, Philip S, Thies F, Blana D, Gabriel BM. Morning exercise and pre-breakfast metformin interact to reduce glycaemia in people with type 2 diabetes: a randomized crossover trial. J Physiol 2024; 602:6491-6506. [PMID: 38522033 PMCID: PMC11607888 DOI: 10.1113/jp285722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 02/29/2024] [Indexed: 03/25/2024] Open
Abstract
Exercise is recommended in the treatment of type 2 diabetes and can improve insulin sensitivity. However, previous evidence suggests that exercise at different times of the day in people with type 2 diabetes may have opposing outcomes on glycaemia. Metformin is the most commonly prescribed initial pharmacological intervention in type 2 diabetes, and may alter adaptions to exercise. It is unknown if there is an interaction between metformin and diurnal exercise outcomes. We aimed to investigate glycaemic outcomes of moderate intensity morning vs. evening exercise in people with type 2 diabetes being prescribed metformin monotherapy. In this study, nine males and nine females with type 2 diabetes undergoing metformin monotherapy (age 61 ± 8.2 years, mean ± SD) completed a 16-week crossover trial including 2-week baseline recording, 6 weeks randomly assigned to a morning exercise (07.00-10.00 h) or evening exercise (16.00-19.00 h) and a 2-week wash-out period. Exercise arms consisted of 30 min of walking at 70% of estimated max heart rate every other day. Glucose levels were measured with continuous glucose monitors and activity measured by wrist-worn monitors. Food-intake was recorded by 4-day food diaries during baseline, first and last 2 weeks of each exercise arm. There was no difference in exercise intensity, total caloric intake or total physical activity between morning and evening arms. As primary outcomes, acute (24 h) glucose area under the curve (AUC), was lower (P = 0.02) after acute morning exercise (180.6 ± 68.4 mmol/l) compared to baseline (210.3 ± 76.7 mmol/l); and there were no differences identified for glucose (mmol/l) between baseline, morning and evening exercise at any specific time point when data were analysed with two-way ANOVA. As secondary outcomes, acute glucose AUC was significantly lower (P = 0.01) in participants taking metformin before breakfast (152.5 ± 29.95 mmol/l) compared with participants taking metformin after breakfast (227.2 ± 61.51 mmol/l) only during the morning exercise arm; and during weeks 5-6 of the exercise protocol, glucose AUC was significantly lower (P = 0.04) for participants taking metformin before breakfast (168.8 ± 15.8 mmol/l), rather than after breakfast (224.5 ± 52.0 mmol/l), only during morning exercise. Our data reveal morning moderate exercise acutely lowers glucose levels in people with type 2 diabetes being prescribed metformin. This difference appears to be driven by individuals that consumed metformin prior to breakfast rather than after breakfast. This beneficial effect upon glucose levels of combined morning exercise and pre-breakfast metformin persisted through the final 2 weeks of the trial. Our findings suggest that morning moderate intensity exercise combined with pre-breakfast metformin intake may benefit the management of glycaemia in people with type 2 diabetes. KEY POINTS: Morning moderate exercise acutely lowers glucose levels in people with type 2 diabetes being prescribed metformin. This difference appears to be driven by individuals that consumed metformin prior to breakfast rather than after breakfast. Morning exercise combined with pre-breakfast metformin persistently reduced glucose compared to morning exercise combined with post-breakfast metformin through the final week (week 6) of the intervention. Our study suggests it may be possible to make simple changes to the time that people with type 2 diabetes take metformin and perform exercise to improve their blood glucose.
Collapse
Affiliation(s)
- Brenda J. Peña Carrillo
- Aberdeen Cardiovascular and Diabetes Centre, School of Medicine, Medical Sciences & NutritionUniversity of AberdeenAberdeenUK
- The Rowett Institute, School of Medicine, Medical Sciences & NutritionUniversity of AberdeenAberdeenUK
| | - Emily Cope
- Aberdeen Cardiovascular and Diabetes Centre, School of Medicine, Medical Sciences & NutritionUniversity of AberdeenAberdeenUK
- The Rowett Institute, School of Medicine, Medical Sciences & NutritionUniversity of AberdeenAberdeenUK
| | - Sati Gurel
- The Rowett Institute, School of Medicine, Medical Sciences & NutritionUniversity of AberdeenAberdeenUK
| | - Andres Traslosheros
- The Rowett Institute, School of Medicine, Medical Sciences & NutritionUniversity of AberdeenAberdeenUK
| | - Amber Kenny
- Aberdeen Cardiovascular and Diabetes Centre, School of Medicine, Medical Sciences & NutritionUniversity of AberdeenAberdeenUK
- The Rowett Institute, School of Medicine, Medical Sciences & NutritionUniversity of AberdeenAberdeenUK
| | - Oscar Michot‐Duval
- The Rowett Institute, School of Medicine, Medical Sciences & NutritionUniversity of AberdeenAberdeenUK
| | - Nimesh Mody
- Aberdeen Cardiovascular and Diabetes Centre, School of Medicine, Medical Sciences & NutritionUniversity of AberdeenAberdeenUK
| | - Mirela Delibegovic
- Aberdeen Cardiovascular and Diabetes Centre, School of Medicine, Medical Sciences & NutritionUniversity of AberdeenAberdeenUK
| | - Sam Philip
- NHS Grampian Diabetes Research Unit, Diabetes CentreAberdeen Royal InfirmaryAberdeenUK
| | - Frank Thies
- The Rowett Institute, School of Medicine, Medical Sciences & NutritionUniversity of AberdeenAberdeenUK
| | - Dimitra Blana
- Centre for Health Data Science, Institute of Applied Health SciencesUniversity of AberdeenAberdeenUK
| | - Brendan M. Gabriel
- Aberdeen Cardiovascular and Diabetes Centre, School of Medicine, Medical Sciences & NutritionUniversity of AberdeenAberdeenUK
- The Rowett Institute, School of Medicine, Medical Sciences & NutritionUniversity of AberdeenAberdeenUK
- Department of Physiology and Pharmacology, Integrative PhysiologyThe Karolinska InstituteStockholmSweden
| |
Collapse
|
|
6
|
Ni D, Kokkinos P, Nylen ES. Glucagon-Like Peptide-1 Receptor Agonists and Sodium Glucose Cotransporter-2 Inhibitors and Cardiorespiratory Fitness Interaction. Mil Med 2024; 189:2369-2373. [PMID: 38870042 DOI: 10.1093/milmed/usae311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 05/13/2024] [Accepted: 06/04/2024] [Indexed: 06/15/2024] Open
Abstract
INTRODUCTION Cardiorespiratory fitness (CRF) is a stronger predictor of mortality than traditional risk factors and is a neglected vital sign of health. Enhanced fitness is a cornerstone in diabetes management and is most often delivered concurrently with pharmacological agents, which can have an opposing impact, as has been reported with metformin. Considering the rapid evolution of diabetes medications with improved cardiovascular outcomes, such as glucagon-like peptide-1 receptor agonists and sodium glucose cotransporter-2 inhibitors, it is of importance to consider the influence of these vis-a-vis effects on CRF. MATERIALS AND METHODS Combining the words glucagon-like peptide-1 receptor agonists and sodium glucose cotransporter-2 inhibitors with cardiorespiratory fitness, an online search was done using PubMed, Embase, Scopus, Web of Science, Scientific Electronic Library Online, and Cochrane. RESULTS There were only a few randomized controlled studies that included CRF, and the results were mostly neutral. A handful of smaller studies detected improved CRF using sodium glucose cotransporter-2 inhibitors in patients with congestive heart failure. CONCLUSIONS Since CRF is a superior prognosticator for cardiovascular outcomes and both medications can cause lean muscle mass loss, the current review highlights the paucity of relevant interactive analysis.
Collapse
Affiliation(s)
- David Ni
- Department of Endocrinology, VAMC, Washington, DC 20422, USA
| | - Peter Kokkinos
- Department of Cardiology, VAMC, Washington, DC 20422, USA
- Department of Kinesiology and Health, School of Arts and Sciences, Rutgers University, Newark, NJ 07103, USA
- Department of Kinesiology, George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA
| | - Eric S Nylen
- Department of Endocrinology, VAMC, Washington, DC 20422, USA
| |
Collapse
|
|
7
|
Guo Z, Gao J, Liu L, Liu X. Quantitatively Predicting Effects of Exercise on Pharmacokinetics of Drugs Using a Physiologically Based Pharmacokinetic Model. Drug Metab Dispos 2024; 52:1271-1287. [PMID: 39251368 DOI: 10.1124/dmd.124.001809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 09/01/2024] [Accepted: 09/05/2024] [Indexed: 09/11/2024] Open
Abstract
Exercise significantly alters human physiological functions, such as increasing cardiac output and muscle blood flow and decreasing glomerular filtration rate (GFR) and liver blood flow, thereby altering the absorption, distribution, metabolism, and excretion of drugs. In this study, we aimed to establish a database of human physiological parameters during exercise and to construct equations for the relationship between changes in each physiological parameter and exercise intensity, including cardiac output, organ blood flow (e.g., muscle blood flow and kidney blood flow), oxygen uptake, plasma pH and GFR, etc. The polynomial equation P = ΣaiHRi was used for illustrating the relationship between the physiological parameters (P) and heart rate (HR), which served as an index of exercise intensity. The pharmacokinetics of midazolam, quinidine, digoxin, and lidocaine during exercise were predicted by a whole-body physiologically based pharmacokinetic (WB-PBPK) model and the developed database of physiological parameters following administration to 100 virtual subjects. The WB-PBPK model simulation results showed that most of the observed plasma drug concentrations fell within the 5th-95th percentiles of the simulations, and the estimated peak concentrations (Cmax) and area under the curve (AUC) of drugs were also within 0.5-2.0 folds of observations. Sensitivity analysis showed that exercise intensity, exercise duration, medication time, and alterations in physiological parameters significantly affected drug pharmacokinetics and the net effect depending on drug characteristics and exercise conditions. In conclusion, the pharmacokinetics of drugs during exercise could be quantitatively predicted using the developed WB-PBPK model and database of physiological parameters. SIGNIFICANCE STATEMENT: This study simulated real-time changes of human physiological parameters during exercise in the WB-PBPK model and comprehensively investigated pharmacokinetic changes during exercise following oral and intravenous administration. Furthermore, the factors affecting pharmacokinetics during exercise were also revealed.
Collapse
Affiliation(s)
- Zeyu Guo
- Department of Pharmacology, China Pharmaceutical University, Nanjing, China
| | - Jingjing Gao
- Department of Pharmacology, China Pharmaceutical University, Nanjing, China
| | - Li Liu
- Department of Pharmacology, China Pharmaceutical University, Nanjing, China
| | - Xiaodong Liu
- Department of Pharmacology, China Pharmaceutical University, Nanjing, China
| |
Collapse
|
|
8
|
Newsom SA, Robinson MM. Recent advances in understanding the mechanisms in skeletal muscle of interaction between exercise and frontline antihyperglycemic drugs. Physiol Rep 2024; 12:e16093. [PMID: 38845596 PMCID: PMC11157199 DOI: 10.14814/phy2.16093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 04/30/2024] [Accepted: 05/17/2024] [Indexed: 06/10/2024] Open
Abstract
Regular exercise and antihyperglycemic drugs are front-line treatments for type-2 diabetes and related metabolic disorders. Leading drugs are metformin, sodium-glucose cotransporter-2 inhibitors, and glucagon-like peptide 1 receptor agonists. Each class has strong individual efficacy to treat hyperglycemia, yet the combination with exercise can yield varied results, some of which include blunting of expected metabolic benefits. Skeletal muscle insulin resistance contributes to the development of type-2 diabetes while improvements in skeletal muscle insulin signaling are among key adaptations to exercise training. The current review identifies recent advances into the mechanisms, with an emphasis on skeletal muscle, of the interaction between exercise and these common antihyperglycemic drugs. The review is written toward researchers and thus highlights specific gaps in knowledge and considerations for future study directions.
Collapse
Affiliation(s)
- Sean A. Newsom
- School of Exercise, Sport, and Health Sciences, College of HealthOregon State UniversityCorvallisOregonUSA
| | - Matthew M. Robinson
- School of Exercise, Sport, and Health Sciences, College of HealthOregon State UniversityCorvallisOregonUSA
| |
Collapse
|
|
9
|
Kim Y, Campbell JP, Johannsen NM, Church TS, Cho E, Heaney J, Spielmann G. Effects of aerobic and resistance exercise for 9 months on serum free light chains in type 2 diabetes. Front Physiol 2024; 15:1328470. [PMID: 38725572 PMCID: PMC11079445 DOI: 10.3389/fphys.2024.1328470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Accepted: 03/26/2024] [Indexed: 05/12/2024] Open
Abstract
Background and aims: Serum polyclonal free light chains (FLCs) levels are associated with overall survival in the general population, reflecting their utility as a biomarker of underlying immune activation and inflammation. Regular exercise is known to ameliorate low-grade inflammation in chronic diseases such as type 2 diabetes; however, the effects of different exercise training modalities on FLCs in adults with type 2 diabetes is unknown. This study investigated the effects of 9-month of aerobic, resistance or combined supervised exercise on serum FLCs in 164 patients with type 2 diabetes (age 58 ± 8 years; 63% female). Methods: 164 participants from the Health Benefits of Aerobic and Resistance Training in individuals with type 2 diabetes trial (HART-D) were randomly assigned to no exercise (n = 27), aerobic exercise alone (n = 41), resistance exercise alone (n = 49), or a combination of aerobic and resistance exercise (n = 47). Fasting serum samples were collected before and after completion of the intervention to quantify changes in kappa and lambda FLCs, and serum creatinine, using commercially-available ELISAs. Results: At baseline, combined kappa and lambda FLCs (FLC sum; calculated as kappa + lambda FLCs) were positively correlated with high-sensitive C-reactive protein (hs-CRP) (r = 0.237, p < 0.05) and fat mass (r = 0.162, p < 0.05), and negatively associated with aerobic fitness (r = -0.238, p < 0.05). While non-exercise controls exhibited an increase in FLCs over the 9-month study, exercise training blunted this increase (Δ FLC sum control arm: 3.25 ± 5.07 mg∙L-1 vs. all exercise arms: -0.252 ± 6.60 mg∙L-1, p < 0.05), regardless of exercise modality. Conclusion: Serum FLCs were associated with physical fitness and body composition in patients with type 2 diabetes. 9-month of exercise training prevented the accumulation of FLCs, regardless of exercise modality. Unlike hs-CRP-which did not change during the trial-serum FLCs may serve as a more sensitive biomarker of chronic low-grade inflammation in this population.
Collapse
Affiliation(s)
- Youyoung Kim
- School of Kinesiology, Louisiana State University, Baton Rouge, LA, United States
| | - John P. Campbell
- Department for Health, University of Bath, Bath, United Kingdom
- School of Medical and Health Sciences, Edith Cowan University, Perth, WA, Australia
| | - Neil M. Johannsen
- School of Kinesiology, Louisiana State University, Baton Rouge, LA, United States
- Pennington Biomedical Research Center, Baton Rouge, LA, United States
| | - Timothy S. Church
- Pennington Biomedical Research Center, Baton Rouge, LA, United States
| | - Eunhan Cho
- School of Kinesiology, Louisiana State University, Baton Rouge, LA, United States
| | - Jennifer Heaney
- Institute of Immunology and Immunotherapy, Birmingham, United Kingdom
| | - Guillaume Spielmann
- School of Kinesiology, Louisiana State University, Baton Rouge, LA, United States
- Pennington Biomedical Research Center, Baton Rouge, LA, United States
| |
Collapse
|
|
10
|
Bellini A, Scotto di Palumbo A, Nicolò A, Bazzucchi I, Sacchetti M. Exercise Prescription for Postprandial Glycemic Management. Nutrients 2024; 16:1170. [PMID: 38674861 PMCID: PMC11053955 DOI: 10.3390/nu16081170] [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: 02/21/2024] [Revised: 03/22/2024] [Accepted: 04/12/2024] [Indexed: 04/28/2024] Open
Abstract
The detrimental impacts of postprandial hyperglycemia on health are a critical concern, and exercise is recognized a pivotal tool in enhancing glycemic control after a meal. However, current exercise recommendations for managing postprandial glucose levels remain fairly broad and require deeper clarification. This review examines the existing literature aiming to offer a comprehensive guide for exercise prescription to optimize postprandial glycemic management. Specifically, it considers various exercise parameters (i.e., exercise timing, type, intensity, volume, pattern) for crafting exercise prescriptions. Findings predominantly indicate that moderate-intensity exercise initiated shortly after meals may substantially improve glucose response to a meal in healthy individuals and those with type 2 diabetes. Moreover, incorporating short activity breaks throughout the exercise session may provide additional benefits for reducing glucose response.
Collapse
Affiliation(s)
| | | | | | - Ilenia Bazzucchi
- Department of Movement, Human and Health Sciences, University of Rome “Foro Italico”, Piazza Lauro De Bosis 6, 00135 Rome, Italy; (A.B.); (A.S.d.P.); (A.N.); (M.S.)
| | | |
Collapse
|
|
11
|
Henson J, Davies MJ, Brady EM, Edwardson CL, Hall AP, Khunti K, Redman E, Rowlands AV, Sargeant J, Yates T. The potential blunting effect of metformin and/or statin therapy on physical activity-induced associations with HbA1c in type 2 diabetes. J Diabetes 2024; 16:e13495. [PMID: 37964490 PMCID: PMC10859307 DOI: 10.1111/1753-0407.13495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 09/22/2023] [Accepted: 10/21/2023] [Indexed: 11/16/2023] Open
Abstract
Highlights Our analysis indicates a potential blunting effect of metformin and/or statin therapy on physical activity-induced associations with HbA1c. The benefit of daily physical activity on glycemic control in people with type 2 diabetes is potentially more apparent in those prescribed neither metformin nor statin therapy. As physical activity is rarely prescribed in isolation of other background medications used to manage type 2 diabetes, the results of this analysis may help to maximize interventions delivered through routine clinical care, while allowing for personalization in prescribed physical activity and pharmacotherapy.
Collapse
Affiliation(s)
- Joseph Henson
- NIHRLeicester Biomedical Research CentreLeicesterUK
- Diabetes Research CentreCollege of Life Sciences, University of LeicesterLeicesterUK
| | - Melanie J. Davies
- NIHRLeicester Biomedical Research CentreLeicesterUK
- Diabetes Research CentreCollege of Life Sciences, University of LeicesterLeicesterUK
| | - Emer M. Brady
- Department of Cardiovascular SciencesUniversity of LeicesterLeicesterUK
| | - Charlotte L. Edwardson
- NIHRLeicester Biomedical Research CentreLeicesterUK
- Diabetes Research CentreCollege of Life Sciences, University of LeicesterLeicesterUK
| | - Andrew P. Hall
- Hanning Sleep LaboratoryLeicester General HospitalLeicesterUK
| | - Kamlesh Khunti
- Diabetes Research CentreCollege of Life Sciences, University of LeicesterLeicesterUK
- NIHRApplied Health Research Collaboration – East Midlands (NIHR ARC‐EM), Leicester Diabetes CentreLeicesterUK
| | - Emma Redman
- Leicester Diabetes CentreUniversity Hospitals of Leicester NHS TrustLeicesterUK
| | - Alex V. Rowlands
- NIHRLeicester Biomedical Research CentreLeicesterUK
- Diabetes Research CentreCollege of Life Sciences, University of LeicesterLeicesterUK
- Alliance for Research in Exercise, Nutrition and Activity (ARENA), UniSA Allied Health and Human PerformanceUniversity of South Australia, Adelaide, AustraliaAdelaideSouth AustraliaAustralia
| | - Jack Sargeant
- NIHRLeicester Biomedical Research CentreLeicesterUK
- Diabetes Research CentreCollege of Life Sciences, University of LeicesterLeicesterUK
- Leicester Diabetes CentreUniversity Hospitals of Leicester NHS TrustLeicesterUK
| | - Thomas Yates
- NIHRLeicester Biomedical Research CentreLeicesterUK
- Diabetes Research CentreCollege of Life Sciences, University of LeicesterLeicesterUK
| |
Collapse
|
|
12
|
Scontri CMCB, de Castro Magalhães F, Damiani APM, Hamblin MR, Zamunér AR, Ferraresi C. Dose and time-response effect of photobiomodulation therapy on glycemic control in type 2 diabetic patients combined or not with hypoglycemic medicine: A randomized, crossover, double-blind, sham-controlled trial. JOURNAL OF BIOPHOTONICS 2023; 16:e202300083. [PMID: 37171054 PMCID: PMC10662441 DOI: 10.1002/jbio.202300083] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Revised: 04/21/2023] [Accepted: 05/09/2023] [Indexed: 05/13/2023]
Abstract
Photobiomodulation therapy (PBMt) combined or not with oral hypoglycemic medication has not been investigated in type 2 diabetes (T2DM) patients. All 10 T2DM patients were assessed randomly at 6 different occasions (3 with and 3 without regular oral hypoglycemic medication). Capillary glycemia was assessed after overnight fast (pre-prandial), 1 h postprandially (standardized meal, 338 kcal), and 30 min, 3 h, 6 h, 12 h post-PBMt (830 nm; 25 arrays of LEDs, 80 mW/array). Three doses (0 J-sham, 100 J, 240 J per site) were applied bilaterally on quadriceps femoris muscles, hamstrings, triceps surae, ventral upper arm and forearm; and randomly combined or not with oral hypoglicemic medication, totaling six different therapies applied for all 10 TDM2 patients (PBMt sham, PBMt 100 J, PBMt 240 J, PBMt sham + medication, PBMt 100 J + medication, PBMt 240 J + medication). Cardiac autonomic control was assessed by heart rate variability (HRV) indices. Without medication, there was reduction in glycemia after all PBMt doses, with 100 J as the best dose that persisted until 12 h and presented lower area under the curve (AUC). With medication, glycemia decreased similarly among doses. No differences between 100 J and sham + medication, but AUC was significantly lower after 100 J, suggesting better glycemic control. Low frequency component of HRV increased after sham + medication and 100 J, suggesting higher sympathetic activation. PBMt showed time- and dose-response effect to reduce glycemia in T2DM patients. Effects on HRV were consistent with glycemic control.
Collapse
Affiliation(s)
| | - Flávio de Castro Magalhães
- Department of Physical Education, Federal University of the Jequitinhonha and Mucuri Valleys, Campus JK - Diamantina, MG – Brazil
| | | | - Michael R. Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028 – South Africa
| | - Antonio Roberto Zamunér
- Laboratory of Clinical Research in Kinesiology, Department of Kinesiology, Universidad Católica del Maule, Talca 34809112 – Chile
| | - Cleber Ferraresi
- Department of Physical Therapy, Federal University of Sao Carlos, Sao Carlos, SP – Brazil
| |
Collapse
|
|
13
|
Moreno-Cabañas A, Morales-Palomo F, Alvarez-Jimenez L, Mora-Gonzalez D, Ortega JF, Mora-Rodriguez R. Metformin and exercise effects on postprandial insulin sensitivity and glucose kinetics in pre-diabetic and diabetic adults. Am J Physiol Endocrinol Metab 2023; 325:E310-E324. [PMID: 37584610 DOI: 10.1152/ajpendo.00118.2023] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 08/09/2023] [Accepted: 08/09/2023] [Indexed: 08/17/2023]
Abstract
The potential interaction between metformin and exercise on glucose-lowering effects remains controversial. We studied the separated and combined effects of metformin and/or exercise on fasting and postprandial insulin sensitivity in individuals with pre-diabetes and type 2 diabetes (T2D). Eight T2D adults (60 ± 4 yr) with overweight/obesity (32 ± 4 kg·m-2) under chronic metformin treatment (9 ± 6 yr; 1281 ± 524 mg·day-1) underwent four trials; 1) taking their habitual metformin treatment (MET), 2) substituting during 96 h their metformin medication by placebo (PLAC), 3) placebo combined with 50 min bout of high-intensity interval exercise (PLAC + EX), and 4) metformin combined with exercise (MET + EX). Plasma glucose kinetics using stable isotopes (6,6-2H2 and [U-13C] glucose), and glucose oxidation by indirect calorimetry, were assessed at rest, during exercise, and in a subsequent oral glucose tolerance test (OGTT). Postprandial glucose and insulin concentrations were analyzed as mean and incremental area under the curve (iAUC), and insulin sensitivity was calculated (i.e., MATSUDAindex and OGISindex). During OGTT, metformin reduced glucose iAUC (i.e., MET and MET + EX lower than PLAC and PLAC + EX, respectively; P = 0.023). MET + EX increased MATSUDAindex above PLAC (4.8 ± 1.4 vs. 3.3 ± 1.0, respectively; P = 0.018) and OGISindex above PLAC (358 ± 52 vs. 306 ± 46 mL·min-1·m-2, respectively; P = 0.006). Metformin decreased the plasma appearance of the ingested glucose (Ra OGTT; MET vs. PLAC, -3.5; 95% CI -0.1 to -6.8 µmol·kg-1·min-1; P = 0.043). Metformin combined with exercise potentiates insulin sensitivity during an OGTT in individuals with pre-diabetes and type 2 diabetes. Metformin's blood glucose-lowering effect seems mediated by decreased oral glucose entering the circulation (gut-liver effect) an effect partially blunted after exercise.NEW & NOTEWORTHY Metformin is the most prescribed oral antidiabetic medicine in the world but its mechanism of action and its interactions with exercise are not fully understood. Our stable isotope tracer data suggested that metformin reduces the rates of oral glucose entering the circulation (gut-liver effect). Exercise, in turn, tended to reduce postprandial insulin blood levels potentiating metformin improvements in insulin sensitivity. Thus, exercise potentiates metformin improvements in glycemic control and should be advised to metformin users.
Collapse
Affiliation(s)
- Alfonso Moreno-Cabañas
- Exercise Physiology Lab at Toledo, University of Castilla-La Mancha, Toledo, Spain
- Center for Nutrition, Exercise and Metabolism, University of Bath, Bath, United Kingdom
- Department for Health, University of Bath, Bath, United Kingdom
| | - Felix Morales-Palomo
- Exercise Physiology Lab at Toledo, University of Castilla-La Mancha, Toledo, Spain
| | | | - Diego Mora-Gonzalez
- Department of Nursing, Physiotherapy, and Occupational Therapy, University of Castilla-La Mancha, Toledo, Spain
| | - Juan Fernando Ortega
- Exercise Physiology Lab at Toledo, University of Castilla-La Mancha, Toledo, Spain
| | | |
Collapse
|
|
14
|
Scott SN, Hayes C, Zeuger T, Davies AP, Andrews RC, Cocks M. Clinical Considerations and Practical Advice for People Living With Type 2 Diabetes Who Undertake Regular Exercise or Aim to Exercise Competitively. Diabetes Spectr 2023; 36:114-126. [PMID: 37193206 PMCID: PMC10182970 DOI: 10.2337/dsi22-0015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/18/2023]
Abstract
This article provides practical tips for advising people with type 2 diabetes on how to engage in regular exercise safely and effectively. Its focus is on individuals who wish to exceed the minimum physical activity recommendation of 150 minutes/week of moderate-intensity exercise or even compete in their chosen sport. Health care professionals who work with such individuals must have a basic understanding of glucose metabolism during exercise, nutritional requirements, blood glucose management, medications, and sport-related considerations. This article reviews three key aspects of individualized care for physically active people with type 2 diabetes: 1) initial medical assessment and pre-exercise screenings, 2) glucose monitoring and nutritional considerations, and 3) the combined glycemic effects of exercise and medications.
Collapse
Affiliation(s)
- Sam N. Scott
- Team Novo Nordisk Professional Cycling Team, Atlanta, GA
| | | | - Thomas Zeuger
- Department of Endocrinology and Metabolic Diseases, Kantonsspital Olten, Olten, Switzerland
- Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Inselspital, Bern, University Hospital, University of Bern, Bern, Switzerland
| | - Andrew P. Davies
- Research Institute for Sport and Exercise Science, Liverpool John Moores University, Liverpool, U.K
| | - Rob C. Andrews
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K
| | - Matthew Cocks
- Research Institute for Sport and Exercise Science, Liverpool John Moores University, Liverpool, U.K
| |
Collapse
|
|
15
|
Peng Y, Qin D, Wang Y, Xue L, Qin Y, Xu X. The effect of SGLT-2 inhibitors on cardiorespiratory fitness capacity: A systematic review and meta-analysis. Front Physiol 2023; 13:1081920. [PMID: 36703925 PMCID: PMC9871354 DOI: 10.3389/fphys.2022.1081920] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 12/12/2022] [Indexed: 01/12/2023] Open
Abstract
Objective: The study aimed to evaluate the effect of sodium-glucose transporter 2 (SGLT-2) inhibitors on various parameters of exercise capacity and provide an evidence-based basis for type 2 diabetes mellitus (T2DM) combined with heart failure (HF) patients or HF patients without T2DM who use SGLT-2 inhibitors to improve cardiorespiratory fitness (CRF). Methods: According to the participant, intervention, comparison, and outcome (PICO) elements, the effects of SGLT-2 inhibitor administration on VO2 or VO2peak were researched in this study. Weighted mean difference (WMD) and 95% confidence intervals (CIs) were calculated (random-effects model). Heterogeneity was assessed by the I2 test. Results: Six studies were included according to the eligibility criteria: four were RCTs, and two were non-RCTs. Compared with the control group, the merge results of RCTs showed that SGLT-2 inhibitors could significantly increase the VO2peak (WMD, 2.02 ml kg-1 min-1, 95% CI: 0.68-3.37, and p = 0.03; I2 = 0% and p = 0.40) and VAT (WMD, 1.57 ml kg-1 min-1, 95% CI: 0.06-3.07, and p = 0.04; I2 = 0% and p = 0.52) of the obese population, patients with T2DM, and chronic HF patients with or without T2DM. Subgroup analysis showed that SGLT-2 inhibitors improved the VO2peak in non-HF patients (WMD, 3.57 ml kg-1 min-1, 95% CI: 0.87-6.26, and p = 0.009; I2 = 4% and p = 0.31) more than in HF patients (WMD, 1.46 ml kg-1 min-1, 95% CI: -0.13-3.04, and p = 0.07; I2 = 0% and p = 0.81). Moreover, the merge of single-arm studies also indicated that empagliflozin could improve VO2peak (MD, 1.11 ml kg-1 min-1, 95% CI: 0.93-1.30, and p = 0.827, Δ p = 0.000 and I2 = 0%) of T2DM patients with chronic HF. Conclusion: Despite the limited number of studies and samples involved, the meta-analysis preliminarily demonstrated that SGLT-2 inhibitors could improve some parameters of exercise capacity (VO2peak, VAT) in chronic HF patients with or without T2DM and obese individuals, which had a positive effect on promoting cardiopulmonary fitness to help these populations improve their prognosis. Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/#recordDetails], identifier [CRD42020202788].
Collapse
Affiliation(s)
- Yong Peng
- School of Kinesiology, Shanghai University of Sport, Shanghai, China,Jiangsu Collaborative Innovation Center for Sports and Health Project, Nanjing Sport Institute, Nanjing, Jiangsu, China,Key Laboratory of Human Sports Science for Jiangsu Province, Nanjing Sport Institute, Nanjing, Jiangsu, China
| | - Di Qin
- School of Sport Health, Nanjing Sport Institute, Nanjing, Jiangsu, China
| | - Yudi Wang
- School of Physical Education and Nursing, Chengdu College of Arts and Sciences, Chengdu, China
| | - Lian Xue
- Key Laboratory of Human Sports Science for Jiangsu Province, Nanjing Sport Institute, Nanjing, Jiangsu, China
| | - YaXuan Qin
- School of Sport Health, Nanjing Sport Institute, Nanjing, Jiangsu, China
| | - Xin Xu
- School of Kinesiology, Shanghai University of Sport, Shanghai, China,*Correspondence: Xin Xu,
| |
Collapse
|
|
16
|
Methnani J, Hajbelgacem M, Ach T, Chaieb F, Sellami S, Bouslama A, Zaouali M, Omezzine A, Bouhlel E. Effect of Pre-Meal Metformin With or Without an Acute Exercise Bout on Postprandial Lipemic and Glycemic Responses in Metabolic Syndrome Patients: A Randomized, Open Label, Crossover Study. J Cardiovasc Pharmacol Ther 2023; 28:10742484231156318. [PMID: 36802839 DOI: 10.1177/10742484231156318] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/23/2023]
Abstract
INTRODUCTION Both exercise and pre-meal metformin could lower postprandial glucose and lipid profiles. AIMS To explore whether pre-meal metformin administration is superior to metformin administration with the meal in reducing postprandial lipid and glucose metabolism, and whether its combination with exercise confer superior benefits in metabolic syndrome patients. MATERIALS AND METHODS In a randomized crossover design, 15 metabolic syndrome patients were assigned to 6 sequences including 3 experimental conditions: metformin administration with a test meal (met-meal), metformin administration 30 min prior to a test meal (pre-meal-met) with or without an exercise bout designed to expend 700 Kcal at 60% VO2 peak performed the evening just before pre-meal-met condition. Only 13 participants (3 males, 10 females; age: 46 ± 9.86, HbA1c: 6.23 ± 0.36) were included in the final analysis. RESULTS Postprandial triglyceridemia was unaffected by any condition (all P > .05). However, both pre-meal-met (-7.1%, P = .009) and pre-meal-metx (-8.2%, P = .013) significantly reduced total cholesterol AUC with no significant differences between the two latter condition (P = .616). Similarly, LDL-cholesterol levels were significantly lower during both pre-meal-met (-10.1%, P = .013) and pre-meal-metx (-10.7%, P = .021) compared to met-meal with no difference between latter conditions (P = .822). Plasma glucose AUC was significantly reduced by pre-meal-metx compared to both pre-meal-met (-7.5%, P = .045) and met-meal (-8%, P = .03). Insulin AUC was significantly lower during pre-meal-metx compared to met-meal (-36.4%, P = .044). CONCLUSIONS Metformin administration 30 minutes prior to meal seems to exert favorable effects on postprandial TC and LDL-Cholesterol levels compared to its administration with meal. Addition of one exercise bout only improved postprandial glycemia and insulinemia. TRIAL REGISTRY Pan African clinical trial registry, Identifier PACTR202203690920424.
Collapse
Affiliation(s)
- Jabeur Methnani
- University of Manouba, High Institute of Sport and Physical Education, Ksar Said, Tunis, Tunisia.,LR12SP11, Biochemistry Department, Sahloul University Hospital, Sousse, Tunisia.,LR19ES09, Laboratoire de Physiologie de l'Exercice et Physiopathologie: de l'Intégré au Moléculaire Biologie, Médecine et Santé, Faculty of Medicine of Sousse, Sousse, Tunisia
| | - Marwa Hajbelgacem
- LR12SP11, Biochemistry Department, Sahloul University Hospital, Sousse, Tunisia.,Faculty of Pharmacy of Monastir, University of Monastir, Monastir, Tunisia
| | - Taieb Ach
- LR19ES09, Laboratoire de Physiologie de l'Exercice et Physiopathologie: de l'Intégré au Moléculaire Biologie, Médecine et Santé, Faculty of Medicine of Sousse, Sousse, Tunisia.,Department of Endocrinology, University Hospital of Farhat Hached, Sousse, Tunisia.,Faculty of Medicine of Sousse, University of Sousse, Sousse, Tunisia
| | - Faten Chaieb
- LR19ES09, Laboratoire de Physiologie de l'Exercice et Physiopathologie: de l'Intégré au Moléculaire Biologie, Médecine et Santé, Faculty of Medicine of Sousse, Sousse, Tunisia.,Faculty of Medicine of Sousse, University of Sousse, Sousse, Tunisia.,Department of Physiology and Functional Exploration, Farhat Hached University Hospital of Sousse, Tunisia
| | - Sana Sellami
- Department of Physiology and Functional Exploration, Farhat Hached University Hospital of Sousse, Tunisia
| | - Ali Bouslama
- LR12SP11, Biochemistry Department, Sahloul University Hospital, Sousse, Tunisia.,Faculty of Pharmacy of Monastir, University of Monastir, Monastir, Tunisia
| | - Monia Zaouali
- LR12SP11, Biochemistry Department, Sahloul University Hospital, Sousse, Tunisia.,Faculty of Medicine of Sousse, University of Sousse, Sousse, Tunisia
| | - Asma Omezzine
- LR12SP11, Biochemistry Department, Sahloul University Hospital, Sousse, Tunisia.,Faculty of Pharmacy of Monastir, University of Monastir, Monastir, Tunisia
| | - Ezdine Bouhlel
- University of Manouba, High Institute of Sport and Physical Education, Ksar Said, Tunis, Tunisia.,LR12SP11, Biochemistry Department, Sahloul University Hospital, Sousse, Tunisia
| |
Collapse
|
|
17
|
Azócar-Gallardo J, Ramirez-Campillo R, Afonso J, Sá M, Granacher U, González-Rojas L, Ojeda-Aravena A, García-García JM. Overweight and Obese Adult Patients Show Larger Benefits from Concurrent Training Compared with Pharmacological Metformin Treatment on Insulin Resistance and Fat Oxidation. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:14331. [PMID: 36361210 PMCID: PMC9655487 DOI: 10.3390/ijerph192114331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 10/21/2022] [Accepted: 10/27/2022] [Indexed: 06/16/2023]
Abstract
Metformin, a drug widely used to treat insulin resistance, and training that combines aerobic and strength exercise modalities (i.e., concurrent training) may improve insulin sensitivity. However, there is a paucity of clinical trials investigating the effects of concurrent training, particularly on insulin resistance and fat oxidation in overweight and obese patients. Furthermore, only a few studies have compared the effects of concurrent training with metformin treatment. Therefore, the aim of this study was to examine the effects of a 12-week concurrent training program versus pharmaceutical treatment with metformin on maximum fat oxidation, glucose metabolism, and insulin resistance in overweight or obese adult patients. Male and female patients with insulin resistance were allocated by convenience to a concurrent training group (n = 7 (2 males); age = 32.9 ± 8.3 years; body mass index = 30 ± 4.0 kg·m-2) or a metformin group (n = 7 (2 males); age = 34.4 ± 14.0 years; body mass index = 34.4 ± 6.0 kg·m-2). Before and after the interventions, all participants were assessed for total body mass, body mass index, fat mass, fat-free mass, maximum oxygen consumption, maximal fat oxidization during exercise, fasting glucose, and insulin resistance through the homeostatic model assessment (HOMA-IR). Due to non-normal distribution of the variable maximal fat oxidation, the Mann-Whitney U test was applied and revealed better maximal fat oxidization (Δ = 308%) in the exercise compared with the metformin group (Δ = -30.3%; p = 0.035). All other outcome variables were normally distributed, and significant group-by-time interactions were found for HOMA-IR (p < 0.001, Δ = -84.5%), fasting insulin (p < 0.001, Δ = -84.6%), and increased maximum oxygen consumption (p = 0.046, Δ = 12.3%) in favor of the exercise group. Similar changes were found in both groups for the remaining dependent variables. Concurrent training seems to be more effective compared with pharmaceutical metformin treatment to improve insulin resistance and fat oxidation in overweight and obese adult patients with insulin resistance. The rather small sample size calls for more research in this area.
Collapse
Affiliation(s)
- Jairo Azócar-Gallardo
- Programa de Investigación en Deporte, Sociedad y Buen Vivir (DSBv), Universidad de Los Lagos, Osorno 5290000, Chile
- Departamento de Ciencias de la Actividad Física, Universidad de Los Lagos, Puerto Montt 5480000, Chile
- Facultad de Ciencias del Deporte, Universidad de Castilla-La Mancha (UCLM), 45071 Toledo, Spain
| | - Rodrigo Ramirez-Campillo
- Exercise and Rehabilitation Sciences Institute, School of Physical Therapy, Faculty of Rehabilitation Sciences, Universidad Andres Bello, Santiago 7591538, Chile
| | - José Afonso
- Centre for Research, Education, Innovation and Intervention in Sport (CIFI2D), Faculty of Sport, University of Porto, 4200-450 Porto, Portugal
| | - Mário Sá
- Faculdade de Motricidade Humana, Universidade de Lisboa, 1495-751 Lisboa, Portugal
| | - Urs Granacher
- Department of Sport and Sport Science, Exercise and Human Movement Science, University of Freiburg, 79102 Freiburg, Germany
| | - Luis González-Rojas
- Centro Tratamiento de la Obesidad, Pontificia Universidad Católica de Chile, Santiago 7550000, Chile
| | - Alex Ojeda-Aravena
- IRyS Group, Physical Education School, Pontificia Universidad Católica de Valparaíso, Valparaíso 2581967, Chile
| | | |
Collapse
|
|
18
|
Nylén E. Newer Diabetes Management Options and Physical Fitness to Promote Cardiovascular Benefits. Rev Cardiovasc Med 2022; 23:282. [PMID: 39076636 PMCID: PMC11266947 DOI: 10.31083/j.rcm2308282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 07/08/2022] [Accepted: 07/14/2022] [Indexed: 07/31/2024] Open
Abstract
A plethora of diabetes studies and established clinical guidelines show the strong salutary benefit of aerobic, resistance, and/or combination exercise for improved glycemic and cardiovascular outcomes. Promotion of physical fitness is a cornerstone approach to improved diabetes management especially since subjects with diabetes have reduced baseline aerobic exercise capacity (i.e., reduced cardiorespiratory fitness) with associated increased risk for premature all-cause and cardiovascular mortality. Since medications are often used in conjunction with fitness promotion this can result in complex interaction between management modalities. More recently, newer options such as glucose transporter-2 inhibitors and incretin agonists have shown to improve cardiovascular disease (CVD) outcomes in cardiovascular outcomes trials. Indeed, both classes of agents have experimentally the potential to synergize with exercise training but clinical data vis-à-vis cardiorespiratory fitness is still preliminary. Review of the interaction of exercise and metformin shows no improvement in cardiorespiratory fitness. The use of glucose transporter-2 inhibitors may improve fitness performance in those with diabetes and heart failure. Although incretin agonists have physiological effects on the vasculature and heart, they lack similar clinical supportive data.
Collapse
Affiliation(s)
- Eric Nylén
- Veterans Affairs Medical Center, George Washington University School of Medicine, Washington, DC 20422, USA
| |
Collapse
|
|
19
|
Ogando PHM, Silveira-Rodrigues JG, Melo BP, Campos BT, Silva ADC, Barbosa EG, Aleixo IMS, Soares DD. Effects of high- and moderate-intensity resistance training sessions on glycemia of insulin-treated and non-insulin-treated type 2 diabetes mellitus individuals. SPORT SCIENCES FOR HEALTH 2022. [DOI: 10.1007/s11332-022-00931-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
|
|
20
|
Kanaley JA, Colberg SR, Corcoran MH, Malin SK, Rodriguez NR, Crespo CJ, Kirwan JP, Zierath JR. Exercise/Physical Activity in Individuals with Type 2 Diabetes: A Consensus Statement from the American College of Sports Medicine. Med Sci Sports Exerc 2022; 54:353-368. [PMID: 35029593 PMCID: PMC8802999 DOI: 10.1249/mss.0000000000002800] [Citation(s) in RCA: 346] [Impact Index Per Article: 115.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
ABSTRACT This consensus statement is an update of the 2010 American College of Sports Medicine position stand on exercise and type 2 diabetes. Since then, a substantial amount of research on select topics in exercise in individuals of various ages with type 2 diabetes has been published while diabetes prevalence has continued to expand worldwide. This consensus statement provides a brief summary of the current evidence and extends and updates the prior recommendations. The document has been expanded to include physical activity, a broader, more comprehensive definition of human movement than planned exercise, and reducing sedentary time. Various types of physical activity enhance health and glycemic management in people with type 2 diabetes, including flexibility and balance exercise, and the importance of each recommended type or mode are discussed. In general, the 2018 Physical Activity Guidelines for Americans apply to all individuals with type 2 diabetes, with a few exceptions and modifications. People with type 2 diabetes should engage in physical activity regularly and be encouraged to reduce sedentary time and break up sitting time with frequent activity breaks. Any activities undertaken with acute and chronic health complications related to diabetes may require accommodations to ensure safe and effective participation. Other topics addressed are exercise timing to maximize its glucose-lowering effects and barriers to and inequities in physical activity adoption and maintenance.
Collapse
Affiliation(s)
- Jill A Kanaley
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO
| | - Sheri R Colberg
- Human Movement Sciences Department, Old Dominion University, Norfolk, VA
| | | | - Steven K Malin
- Department of Kinesiology and Health, Rutgers University, New Brunswick, NJ
| | - Nancy R Rodriguez
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT
| | - Carlos J Crespo
- Oregon Health and Science University-Portland State University School of Public Health, Portland, OR
| | - John P Kirwan
- Pennington Biomedical Research Center, Baton Rouge, LA
| | - Juleen R Zierath
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, SWEDEN
| |
Collapse
|
|
21
|
Rizvi AA, Abbas M, Verma S, Verma S, Khan A, Raza ST, Mahdi F. Determinants in Tailoring Antidiabetic Therapies: A Personalized Approach. Glob Med Genet 2022; 9:63-71. [PMID: 35707783 PMCID: PMC9192178 DOI: 10.1055/s-0041-1741109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 11/20/2021] [Indexed: 11/02/2022] Open
Abstract
AbstractDiabetes has become a pandemic as the number of diabetic people continues to rise globally. Being a heterogeneous disease, it has different manifestations and associated complications in different individuals like diabetic nephropathy, neuropathy, retinopathy, and others. With the advent of science and technology, this era desperately requires increasing the pace of embracing precision medicine and tailoring of drug treatment based on the genetic composition of individuals. It has been previously established that response to antidiabetic drugs, like biguanides, sulfonylureas, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide 1 (GLP-1) agonists, and others, depending on variations in their transporter genes, metabolizing genes, genes involved in their action, etc. Responsiveness of these drugs also relies on epigenetic factors, including histone modifications, miRNAs, and DNA methylation, as well as environmental factors and the lifestyle of an individual. For precision medicine to make its way into clinical procedures and come into execution, all these factors must be reckoned with. This review provides an insight into several factors oscillating around the idea of precision medicine in type-2 diabetes mellitus.
Collapse
Affiliation(s)
- Aliya A. Rizvi
- Department of Personalized and Molecular Medicine, Era University, Lucknow, Uttar Pradesh, India
| | - Mohammad Abbas
- Department of Personalized and Molecular Medicine, Era University, Lucknow, Uttar Pradesh, India
| | - Sushma Verma
- Department of Personalized and Molecular Medicine, Era University, Lucknow, Uttar Pradesh, India
| | - Shrikant Verma
- Department of Personalized and Molecular Medicine, Era University, Lucknow, Uttar Pradesh, India
| | - Almas Khan
- Department of Personalized and Molecular Medicine, Era University, Lucknow, Uttar Pradesh, India
| | - Syed T. Raza
- Department of Biochemistry, Era University, Lucknow Medical College and Hospital, Lucknow, Uttar Pradesh, India
| | - Farzana Mahdi
- Department of Personalized and Molecular Medicine, Era University, Lucknow, Uttar Pradesh, India
| |
Collapse
|
|
22
|
Kudiarasu C, Rohadhia W, Katsura Y, Koeda T, Singh F, Nosaka K. Eccentric-only versus concentric-only resistance training effects on biochemical and physiological parameters in patients with type 2 diabetes. BMC Sports Sci Med Rehabil 2021; 13:162. [PMID: 34930480 PMCID: PMC8686274 DOI: 10.1186/s13102-021-00384-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 12/06/2021] [Indexed: 11/16/2022]
Abstract
Background The benefits of resistance training for patients with type 2 diabetes (T2D) are well documented; however, the effects of exercise with different muscle contraction types such as eccentric versus concentric contractions on physiological outcomes for this population are not clear. This study compared eccentric-only (ECC) and concentric-only resistance training (CON) to test the hypothesis that ECC would be superior to CON to improve insulin sensitivity, lipid profile, body composition, muscle strength and physical function of patients with T2D. Methods Adults with T2D (50–79 years) were allocated to the ECC (n = 9) or CON group (n = 9). Resistance exercises (chest press, lateral pulldown, bicep curl, triceps extension, leg extension, leg curl, calf raise, abdominal crunch) consisting of 2–3 sets of 10 eccentric-only (5 s) or concentric-only contractions (1–2 s) was performed twice a week for 12 weeks. Changes in blood biomarkers, body composition, muscle strength and physical function from pre- to post-intervention were compared between groups. Results Overall rating of perceived exertion (RPE, 1–10 Borg scale) was lower (p < 0.05) for ECC (2.9 ± 1.2) than CON (5.4 ± 1.1). No significant changes in blood biomarkers were found for both groups. Lean mass increased [effect size (ES) = 0.148, ECC 3.2 ± 6.9%; CON 3.6 ± 2.3%], and fat mass decreased (ES = 0.545, ECC − 6.1 ± 12.4%; CON − 7.1 ± 16.4%) (p < 0.05) similarly. One-repetition maximal strength of each exercise increased (p < 0.05) for both ECC (12–37%) and CON (27–68%). Both groups improved (p < 0.05) 6-min walk distance (ES = 0.083, ECC 12.2 ± 2.3%; CON 12.5 ± 15.3%) and chair rise time (ES = 0.463, ECC − 13.4 ± 25.4%; CON − 20.0 ± 53.3%) but only ECC improved (p < 0.05) the timed up-and-go test (− 11.3 ± 13.6%, ES 0.014). No significant changes in balance tests were found for both groups. Conclusion These results did not fully support the hypothesis but showed that ECC was as effective as CON to improve body composition, muscle strength, and physical function with lesser RPE. Future studies should investigate whether larger differences between ECC and CON are evident when increasing the exercise frequency and matching the intensities of the two-exercise protocols. Trial registration ACTRN12621001026819 (retrospectively registered on 5th Aug 2021).
Collapse
Affiliation(s)
- Christine Kudiarasu
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia. .,Exercise Medicine Research Institute, Edith Cowan University, Joondalup, WA, Australia.
| | - Wafina Rohadhia
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia
| | - Yoshihiro Katsura
- Centre for Promotion of Higher Education, Kogakuin University, Tokyo, Japan
| | - Tomoko Koeda
- Faculty of Rehabilitation Sciences, Nagoya Gakuin University, Aichi, Japan
| | - Favil Singh
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia.,Exercise Medicine Research Institute, Edith Cowan University, Joondalup, WA, Australia
| | - Kazunori Nosaka
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia.,Exercise Medicine Research Institute, Edith Cowan University, Joondalup, WA, Australia
| |
Collapse
|
|
23
|
Miller BF, Thyfault JP. Exercise-Pharmacology Interactions: Metformin, Statins, and Healthspan. Physiology (Bethesda) 2021; 35:338-347. [PMID: 32783612 DOI: 10.1152/physiol.00013.2020] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
There is an increased focus on treatments to extend the healthspan. There is solid evidence that exercise extends the healthspan, but other treatments, such as metformin and statins, are also gaining traction. If metformin and statins will be used to prolong healthspan, we must understand their effects in those free of disease and in combination with exercise.
Collapse
Affiliation(s)
- Benjamin F Miller
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma.,Oklahoma Nathan Shock Center for Aging, Oklahoma City, Oklahoma.,Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - John P Thyfault
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas.,Research Service, Kansas City VA Medical Center, Kansas City, Missouri.,Center for Children's Healthy Lifestyle and Nutrition, Children's Mercy Hospital, Kansas City, Missouri
| |
Collapse
|
|
24
|
Chen C, Gallagher JR, Tarlton J, van Aalten L, Bray SE, Ashford MLJ, McCrimmon RJ, Pearson ER, McNeilly AD, Sutherland C. The genetic association of the transcription factor NPAT with glycemic response to metformin involves regulation of fuel selection. PLoS One 2021; 16:e0253533. [PMID: 34197485 PMCID: PMC8248654 DOI: 10.1371/journal.pone.0253533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 06/07/2021] [Indexed: 11/19/2022] Open
Abstract
The biguanide, metformin, is the first-choice therapeutic agent for type-2 diabetes, although the mechanisms that underpin metformin clinical efficacy remain the subject of much debate, partly due to the considerable variation in patient response to metformin. Identification of poor responders by genotype could avoid unnecessary treatment and provide clues to the underlying mechanism of action. GWAS identified SNPs associated with metformin treatment success at a locus containing the NPAT (nuclear protein, ataxia-telangiectasia locus) and ATM (ataxia-telangiectasia mutated) genes. This implies that gene sequence dictates a subsequent biological function to influence metformin action. Hence, we modified expression of NPAT in immortalized cell lines, primary mouse hepatocytes and mouse tissues, and analysed the outcomes on metformin action using confocal microscopy, immunoblotting and immunocytochemistry. In addition, we characterised the metabolic phenotype of npat heterozygous knockout mice and established the metformin response following development of insulin resistance. NPAT protein was localised in the nucleus at discrete loci in several cell types, but over-expression or depletion of NPAT in immortalised cell models did not change cellular responses to biguanides. In contrast, metformin regulation of respiratory exchange ratio (RER) was completely lost in animals lacking one allele of npat. There was also a reduction in metformin correction of impaired glucose tolerance, however no other metabolic abnormalities, or response to metformin, were found in the npat heterozygous mice. In summary, we provide methodological advancements for the detection of NPAT, demonstrate that minor reductions in NPAT mRNA levels (20–40%) influence metformin regulation of RER, and propose that the association between NPAT SNPs and metformin response observed in GWAS, could be due to loss of metformin modification of cellular fuel usage.
Collapse
Affiliation(s)
- Changwei Chen
- Division of Cellular Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, James Arnott Drive, Dundee, United Kingdom
| | - Jennifer R. Gallagher
- Division of Systems Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, James Arnott Drive, Dundee, United Kingdom
| | - Jamie Tarlton
- Division of Systems Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, James Arnott Drive, Dundee, United Kingdom
| | - Lidy van Aalten
- Division of Cellular Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, James Arnott Drive, Dundee, United Kingdom
| | - Susan E. Bray
- Tayside Tissue Bank, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, James Arnott Drive, Dundee, United Kingdom
| | - Michael L. J. Ashford
- Division of Systems Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, James Arnott Drive, Dundee, United Kingdom
| | - Rory J. McCrimmon
- Division of Systems Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, James Arnott Drive, Dundee, United Kingdom
| | - Ewan R. Pearson
- Division of Population Health and Genomics, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, James Arnott Drive, Dundee, United Kingdom
| | - Alison D. McNeilly
- Division of Systems Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, James Arnott Drive, Dundee, United Kingdom
| | - Calum Sutherland
- Division of Cellular Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, James Arnott Drive, Dundee, United Kingdom
- * E-mail:
| |
Collapse
|
|
25
|
Bent B, Cho PJ, Henriquez M, Wittmann A, Thacker C, Feinglos M, Crowley MJ, Dunn JP. Engineering digital biomarkers of interstitial glucose from noninvasive smartwatches. NPJ Digit Med 2021; 4:89. [PMID: 34079049 PMCID: PMC8172541 DOI: 10.1038/s41746-021-00465-w] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 05/11/2021] [Indexed: 12/14/2022] Open
Abstract
Prediabetes affects one in three people and has a 10% annual conversion rate to type 2 diabetes without lifestyle or medical interventions. Management of glycemic health is essential to prevent progression to type 2 diabetes. However, there is currently no commercially-available and noninvasive method for monitoring glycemic health to aid in self-management of prediabetes. There is a critical need for innovative, practical strategies to improve monitoring and management of glycemic health. In this study, using a dataset of 25,000 simultaneous interstitial glucose and noninvasive wearable smartwatch measurements, we demonstrated the feasibility of using noninvasive and widely accessible methods, including smartwatches and food logs recorded over 10 days, to continuously detect personalized glucose deviations and to predict the exact interstitial glucose value in real time with up to 84% and 87% accuracy, respectively. We also establish methods for designing variables using data-driven and domain-driven methods from noninvasive wearables toward interstitial glucose prediction.
Collapse
Affiliation(s)
- Brinnae Bent
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
| | - Peter J Cho
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
| | - Maria Henriquez
- Department of Statistical Science, Duke University, Durham, NC, USA
| | - April Wittmann
- Division of Endocrinology, Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Connie Thacker
- Division of Endocrinology, Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Mark Feinglos
- Division of Endocrinology, Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Matthew J Crowley
- Division of Endocrinology, Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Jessilyn P Dunn
- Department of Biomedical Engineering, Duke University, Durham, NC, USA. .,Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, USA.
| |
Collapse
|
|
26
|
Homer AR, Taylor FC, Dempsey PC, Wheeler MJ, Sethi P, Townsend MK, Grace MS, Green DJ, Cohen ND, Larsen RN, Kingwell BA, Owen N, Dunstan DW. Frequency of Interruptions to Sitting Time: Benefits for Postprandial Metabolism in Type 2 Diabetes. Diabetes Care 2021; 44:1254-1263. [PMID: 33905343 PMCID: PMC8247505 DOI: 10.2337/dc20-1410] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To determine whether interrupting sitting with brief bouts of simple resistance activities (SRAs) at different frequencies improves postprandial glucose, insulin, and triglycerides in adults with medication-controlled type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS Participants (n = 23, 10 of whom were female, with mean ± SD age 62 ± 8 years and BMI 32.7 ± 3.5 kg · m-2) completed a three-armed randomized crossover trial (6- to 14-day washout): sitting uninterrupted for 7 h (SIT), sitting with 3-min SRAs (half squats, calf raises, gluteal contractions, and knee raises) every 30 min (SRA3), and sitting with 6-min SRAs every 60 min (SRA6). Net incremental areas under the curve (iAUCnet) for glucose, insulin, and triglycerides were compared between conditions. RESULTS Glucose and insulin 7-h iAUCnet were attenuated significantly during SRA6 (glucose 17.0 mmol · h · L-1, 95% CI 12.5, 21.4; insulin 1,229 pmol · h · L-1, 95% CI 982, 1,538) in comparison with SIT (glucose 21.4 mmol · h · L-1, 95% CI 16.9, 25.8; insulin 1,411 pmol · h · L-1, 95% CI 1,128, 1,767; P < 0.05) and in comparison with SRA3 (for glucose only) (22.1 mmol · h · L-1, 95% CI 17.7, 26.6; P = 0.01) No significant differences in glucose or insulin iAUCnet were observed in comparison of SRA3 and SIT. There was no statistically significant effect of condition on triglyceride iAUCnet. CONCLUSIONS In adults with medication-controlled T2D, interrupting prolonged sitting with 6-min SRAs every 60 min reduced postprandial glucose and insulin responses. Other frequencies of interruptions and potential longer-term benefits require examination to clarify clinical relevance.
Collapse
Affiliation(s)
- Ashleigh R Homer
- Baker Heart and Diabetes Institute, Melbourne, Australia .,Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Australia
| | - Frances C Taylor
- Baker Heart and Diabetes Institute, Melbourne, Australia.,Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Australia
| | - Paddy C Dempsey
- Baker Heart and Diabetes Institute, Melbourne, Australia.,Institute of Metabolic Science, University of Cambridge, Cambridge, U.K
| | - Michael J Wheeler
- Baker Heart and Diabetes Institute, Melbourne, Australia.,Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Australia.,School of Sport Science, Exercise and Health, University of Western Australia, Perth, Australia
| | - Parneet Sethi
- Baker Heart and Diabetes Institute, Melbourne, Australia
| | | | - Megan S Grace
- Baker Heart and Diabetes Institute, Melbourne, Australia.,School of Clinical Medicine, University of Queensland, Brisbane, Australia
| | - Daniel J Green
- School of Sport Science, Exercise and Health, University of Western Australia, Perth, Australia
| | - Neale D Cohen
- Baker Heart and Diabetes Institute, Melbourne, Australia
| | - Robyn N Larsen
- Baker Heart and Diabetes Institute, Melbourne, Australia.,School of Agriculture and Food, University of Melbourne, Melbourne, Australia
| | - Bronwyn A Kingwell
- Baker Heart and Diabetes Institute, Melbourne, Australia.,CSL Limited, Bio21 Molecular Science & Biotechnology Institute, Parkville, Australia
| | - Neville Owen
- Baker Heart and Diabetes Institute, Melbourne, Australia.,Centre for Urban Transitions, Swinburne University of Technology, Melbourne, Australia
| | - David W Dunstan
- Baker Heart and Diabetes Institute, Melbourne, Australia.,Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Australia
| |
Collapse
|
|
27
|
Allerton TD, Kowalski GM, Stampley J, Irving BA, Lighton JRB, Floyd ZE, Stephens JM. An Ethanolic Extract of Artemisia dracunculus L. Enhances the Metabolic Benefits of Exercise in Diet-induced Obese Mice. Med Sci Sports Exerc 2021; 53:712-723. [PMID: 33105388 PMCID: PMC9045727 DOI: 10.1249/mss.0000000000002516] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE The purpose of this study was to determine the effect of an ethanolic extract of Artemisia dracunculus L. (5011) combined with exercise on in vivo glucose and fat metabolism in diet-induced obese male mice. METHODS After 8 wk of high-fat diet (HFD) feeding, 52 mice were randomly allocated to a voluntary wheel running group (HFD Ex), a 5011 + HFD sedentary group (5011 Sed), a 5011 + HFD Ex (5011 Ex), or an HFD sedentary group (HFD Sed) for 4 wk. Real-time energy expenditure and substrate utilization were measured by indirect calorimetry. A stable isotope glucose tolerance test was performed before and after the 4-wk wheel running period to determine changes in endogenous glucose production and glucose disposal. We also performed an analysis of genes and proteins associated with the early response to exercise and exercise adaptations in skeletal muscle and liver. RESULTS When compared with HFD Ex mice, 5011 Ex mice had increased fat oxidation during speed- and distance-matched wheel running bouts. Both HFD Ex and 5011 Ex mice had reduced endogenous glucose during the glucose tolerance test, whereas only the 5011 Sed and the 5011 Ex mice had improved glucose disposal after the 4-wk experimental period when compared with HFD Sed and HFD Ex mice. 5011 Ex mice had increased Pgc1-α and Tfam expression in skeletal muscle when compared with HFD Ex mice, whereas Pdk4 expression was reduced in the liver of HFD Ex and 5011 Ex mice. CONCLUSIONS Our study demonstrates that 5011, an ethanolic extract of A. dracunculus L., with a history of medicinal use, enhances the metabolic benefits of exercise to improve in vivo fat and glucose metabolism.
Collapse
Affiliation(s)
| | - Greg M Kowalski
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, AUSTRALIA
| | - James Stampley
- Department of Kinesiology, Louisiana State University, Baton Rouge, LA
| | - Brian A Irving
- Department of Kinesiology, Louisiana State University, Baton Rouge, LA
| | | | | | | |
Collapse
|
|
28
|
Abdalhk D, Riddell MC, Swayze S, Kuk JL. Association between metformin and physical activity with glucose control in adults with type 2 diabetes. Endocrinol Diabetes Metab 2021; 4:e00206. [PMID: 33855209 PMCID: PMC8029551 DOI: 10.1002/edm2.206] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 10/30/2020] [Accepted: 10/31/2020] [Indexed: 12/26/2022] Open
Abstract
Objective To examine the combined association between metformin use and physical activity on HbA1c in adults with type 2 diabetes. Research Design and Methods Adults with type 2 diabetes from NHANES continuous survey (1999-2018, n = 6447) were classified as active and inactive based on self-reported engagement in moderate-to-vigorous or vigorous physical activity (MVPA or VigPA) and metformin use over the last month. Results There was a significant negative main effect of metformin usage on HbA1c levels, independent of whether individuals engaged in modest levels of MVPA or VigPA. Moreover, there was a higher prevalence of metformin users with a HbA1c < 6.5% than non-metformin users with no differences by activity status (36.1%-39.5% versus 24.9%-29.7%, respectively). There was a significantly lower HbA1c level (P = .007) and trend for a higher odds of having a HbA1c that achieved the clinical target of <7% (OR, 95% CI = 1.2, 1.0-1.4, P = .06) in the MVPA than non-MVPA group for only those not using metformin. For those using metformin, there was no difference in HbA1c levels by either MVPA or VigPA (both P > .05). Conclusions There appears to be independent benefits of metformin and regular physical activity on glucose control, but the impact of these two treatments are not necessarily additive. Based on this analyses, the benefit of physical activity on HbA1c levels in type 2 diabetes is likely more apparent in those not taking metformin, as compared to those who are.
Collapse
Affiliation(s)
- Diana Abdalhk
- School of Kinesiology and Health ScienceYork UniversityTorontoOntarioCanada
| | - Michael C. Riddell
- School of Kinesiology and Health ScienceYork UniversityTorontoOntarioCanada
| | - Sarah Swayze
- School of Kinesiology and Health ScienceYork UniversityTorontoOntarioCanada
| | - Jennifer L. Kuk
- School of Kinesiology and Health ScienceYork UniversityTorontoOntarioCanada
| |
Collapse
|
|
29
|
Pilmark NS, Lyngbæk M, Oberholzer L, Elkjær I, Petersen-Bønding C, Kofoed K, Siebenmann C, Kellenberger K, van Hall G, Abildgaard J, Ellingsgaard H, Lauridsen C, Ried-Larsen M, Pedersen BK, Hansen KB, Karstoft K. The interaction between metformin and physical activity on postprandial glucose and glucose kinetics: a randomised, clinical trial. Diabetologia 2021; 64:397-409. [PMID: 32979074 DOI: 10.1007/s00125-020-05282-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 08/10/2020] [Indexed: 01/04/2023]
Abstract
AIMS/HYPOTHESIS The aim of this parallel-group, double-blinded (study personnel and participants), randomised clinical trial was to assess the interaction between metformin and exercise training on postprandial glucose in glucose-intolerant individuals. METHODS Glucose-intolerant (2 h OGTT glucose of 7.8-11.0 mmol/l and/or HbA1c of 39-47 mmol/mol [5.7-6.5%] or glucose-lowering-medication naive type 2 diabetes), overweight/obese (BMI 25-42 kg/m2) individuals were randomly allocated to a placebo study group (PLA, n = 15) or a metformin study group (MET, n = 14), and underwent 3 experimental days: BASELINE (before randomisation), MEDICATION (after 3 weeks of metformin [2 g/day] or placebo treatment) and TRAINING (after 12 weeks of exercise training in combination with metformin/placebo treatment). Training consisted of supervised bicycle interval sessions with a mean intensity of 64% of Wattmax for 45 min, 4 times/week. The primary outcome was postprandial glucose (mean glucose concentration) during a mixed meal tolerance test (MMTT), which was assessed on each experimental day. For within-group differences, a group × time interaction was assessed using two-way repeated measures ANOVA. Between-group changes of the outcomes at different timepoints were compared using unpaired two-tailed Student's t tests. RESULTS Postprandial glucose improved from BASELINE to TRAINING in both the PLA group and the MET group (∆PLA: -0.7 [95% CI -1.4, 0.0] mmol/l, p = 0.05 and ∆MET: -0.7 [-1.5, -0.0] mmol/l, p = 0.03), with no between-group difference (p = 0.92). In PLA, the entire reduction was seen from MEDICATION to TRAINING (-0.8 [-1.3, -0.1] mmol/l, p = 0.01). Conversely, in MET, the entire reduction was observed from BASELINE to MEDICATION (-0.9 [-1.6, -0.2] mmol/l, p = 0.01). The reductions in mean glucose concentration during the MMTT from BASELINE to TRAINING were dependent on differential time effects: in the PLA group, a decrease was observed at timepoint (t) = 120 min (p = 0.009), whereas in the MET group, a reduction occurred at t = 30 min (p < 0.001). V̇O2peak increased 15% (4.6 [3.3, 5.9] ml kg-1 min-1, p < 0.0001) from MEDICATION to TRAINING and body weight decreased (-4.0 [-5.2, -2.7] kg, p < 0.0001) from BASELINE to TRAINING, with no between-group differences (p = 0.7 and p = 0.5, respectively). CONCLUSIONS/INTERPRETATION Metformin plus exercise training was not superior to exercise training alone in improving postprandial glucose. The differential time effects during the MMTT suggest an interaction between the two modalities. FUNDING The Beckett foundation, A.P Møller Foundation, DDA, the Research Foundation of Rigshospitalet and Trygfonden. TRIAL REGISTRATION ClinicalTrials.gov (NCT03316690). Graphical abstract.
Collapse
Affiliation(s)
- Nanna S Pilmark
- Centre for Physical Activity Research (CFAS), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Mark Lyngbæk
- Centre for Physical Activity Research (CFAS), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Laura Oberholzer
- Centre for Physical Activity Research (CFAS), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Ida Elkjær
- Centre for Physical Activity Research (CFAS), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Christina Petersen-Bønding
- Centre for Physical Activity Research (CFAS), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Katja Kofoed
- Centre for Physical Activity Research (CFAS), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Christoph Siebenmann
- Centre for Physical Activity Research (CFAS), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- Institute of Mountain Emergency Medicine, EURAC Research, Bolzano, Italy
| | - Katja Kellenberger
- Centre for Physical Activity Research (CFAS), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- Section for Elite Sport, Swiss Federal Institute of Sports, Magglingen, Switzerland
| | - Gerrit van Hall
- Biomedical Sciences, Faculty of Health & Medical Science, University of Copenhagen, Copenhagen, Denmark
- Clinical Metabolomics Core Facility, Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark
| | - Julie Abildgaard
- Centre for Physical Activity Research (CFAS), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- Department of Growth and Reproduction, Rigshospitalet, Copenhagen, Denmark
| | - Helga Ellingsgaard
- Centre for Physical Activity Research (CFAS), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Carsten Lauridsen
- Department of Diagnostic Radiology, Copenhagen University Hospital, Copenhagen, Denmark
- Copenhagen University College, Copenhagen N, Denmark
| | - Mathias Ried-Larsen
- Centre for Physical Activity Research (CFAS), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Bente K Pedersen
- Centre for Physical Activity Research (CFAS), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | | | - Kristian Karstoft
- Centre for Physical Activity Research (CFAS), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
- Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark.
| |
Collapse
|
|
30
|
Li T, Providencia R, Mu N, Yin Y, Chen M, Wang Y, Liu M, Yu L, Gu C, Ma H. Association of metformin monotherapy or combined therapy with cardiovascular risks in patients with type 2 diabetes mellitus. Cardiovasc Diabetol 2021; 20:30. [PMID: 33516224 PMCID: PMC7847575 DOI: 10.1186/s12933-020-01202-5] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 12/24/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Metformin is a first-line drug in type 2 diabetes mellitus (T2DM) treatment, yet whether metformin may increase all-cause or cardiovascular mortality of T2DM patients remains inconclusive. METHODS We searched PubMed and Embase for data extracted from inception to July 14, 2020, with a registration in PROSPERO (CRD42020177283). This study included randomized controlled trials (RCT) assessing the cardiovascular effects of metformin for T2DM. This study is followed by PRISMA and Cochrane guideline. Risk ratio (RR) with 95% CI was pooled across trials by a random-effects model. Primary outcomes include all-cause mortality and cardiovascular mortality. RESULTS We identified 29 studies that randomly assigned patients with 371 all-cause and 227 cardiovascular death events. Compared with untreated T2DM patients, metformin-treated patients was not associated with lower risk of all-cause mortality (RR: 0.98; 95%CI: 0.69-1.38; P = 0.90), cardiovascular mortality (RR: 1.13; 95% CI: 0.60, 2.15; P = 0.70), macrovascular events (RR: 0.87; 95%CI: 0.70-1.07; P = 0.19), heart failure (RR: 1.02; 95% CI:0.61-1.71; P = 0.95), and microvascular events (RR: 0.78; 95% CI:0.54-1.13; P = 0.19). Combination of metformin with another hypoglycemic drug was associated with higher risk of all-cause mortality (RR: 1.49; 95% CI: 1.02, 2.16) and cardiovascular mortality (RR: 2.21; 95% CI: 1.22, 4.00) compared with hypoglycemic drug regimens with no metformin. CONCLUSION The combination of metformin treatment may impose higher risk in all-cause and cardiovascular mortality. This finding, at least in part, shows no evidence for benefits of metformin in combination in terms of all-cause/cardiovascular mortality and cardiovascular events for T2DM. However, the conclusion shall be explained cautiously considering the limitations from UK Prospective Diabetes Study (UKPDS).
Collapse
Affiliation(s)
- Tian Li
- Department of Physiology and Pathophysiology, Fourth Military Medical University, No. 169 Changle West Rd, Xi'an, 710032, China
| | | | - Nan Mu
- Department of Physiology and Pathophysiology, Fourth Military Medical University, No. 169 Changle West Rd, Xi'an, 710032, China
| | - Yue Yin
- Department of Physiology and Pathophysiology, Fourth Military Medical University, No. 169 Changle West Rd, Xi'an, 710032, China
| | - Mai Chen
- Department of Cardiovascular Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Yishi Wang
- Department of Physiology and Pathophysiology, Fourth Military Medical University, No. 169 Changle West Rd, Xi'an, 710032, China
| | - Manling Liu
- Department of Physiology and Pathophysiology, Fourth Military Medical University, No. 169 Changle West Rd, Xi'an, 710032, China
| | - Lu Yu
- Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
| | - Chunhu Gu
- Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
| | - Heng Ma
- Department of Physiology and Pathophysiology, Fourth Military Medical University, No. 169 Changle West Rd, Xi'an, 710032, China.
| |
Collapse
|
|
31
|
Luse MA, Heiston EM, Malin SK, Isakson BE. Cellular and Functional Effects of Insulin Based Therapies and Exercise on Endothelium. Curr Pharm Des 2021; 26:3760-3767. [PMID: 32693765 DOI: 10.2174/1381612826666200721002735] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 06/04/2020] [Indexed: 12/24/2022]
Abstract
Endothelial dysfunction is a hallmark of type 2 diabetes that can have severe consequences on vascular function, including hypertension and changes in blood flow, as well as exercise performance. Because endothelium is also the barrier for insulin movement into tissues, it acts as a gatekeeper for transport and glucose uptake. For this reason, endothelial dysfunction is a tempting area for pharmacological and/or exercise intervention with insulin-based therapies. In this review, we describe the current state of drugs that can be used to treat endothelial dysfunction in type 2 diabetes and diabetes-related diseases (e.g., obesity) at the molecular levels, and also discuss their role in exercise.
Collapse
Affiliation(s)
- Melissa A Luse
- Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Virginia, United States
| | - Emily M Heiston
- Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Virginia, United States
| | - Steven K Malin
- Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Virginia, United States
| | - Brant E Isakson
- Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Virginia, United States
| |
Collapse
|
|
32
|
Joshi DM, Patel J, Bhatt H. In silico study to quantify the effect of exercise on surface GLUT4 translocation in diabetes management. ACTA ACUST UNITED AC 2021. [DOI: 10.1007/s13721-020-00274-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
|
|
33
|
Jevtovic F. Combination of Metformin and Exercise in Management of Metabolic Abnormalities Observed in Type 2 Diabetes Mellitus. Diabetes Metab Syndr Obes 2021; 14:4043-4057. [PMID: 34557007 PMCID: PMC8453852 DOI: 10.2147/dmso.s328694] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 09/07/2021] [Indexed: 12/19/2022] Open
Abstract
Excess nutrient intake and lack of exercise characterize the problem of obesity and are common factors in insulin resistance (IR). With an increasing number of prediabetic, and type 2 diabetic populations, metformin is still the most prescribed glucose-lowering drug and is often accompanied by recommendations for regular physical exercise. Metformin, by the inhibition of complex 1 of the electron transport chain, and exercise, by increasing energy expenditure, both elicit a low cellular energy state that leads to improvements in glucose control via activation of adenosine 5' monophosphate-activated protein kinase (AMPK). An augmented stimulation of the energy-sensing enzyme AMPK by either of the two modalities leads to an increase in glycogenolysis, glucose uptake, fat oxidation, a decrease in glycogen and protein synthesis, and gluconeogenesis in muscle and the liver, which are remarked as having positive effects on metabolic pathophysiology observed in IR and type 2 diabetes mellitus (T2DM). While both modalities exploit the energy-sensing enzyme AMPK to attain glucose homeostasis, the synergistic effect of these two treatments is not distinctly supported by the literature. Further, an antagonistic dynamic has been observed in cases where metformin and exercise were combined. Reduction of insulin-sensitizing effects of exercise and an overall hindrance of exercise performance and adaptations have been reported and could suggest the possible incongruity of these two modalities. The aim of this review is to elucidate the effect that metformin and exercise have on the management of the metabolic abnormalities observed in T2DM and to provide an insight into the interaction of these two modalities.
Collapse
Affiliation(s)
- Filip Jevtovic
- Department of Kinesiology, College of Health and Human Performance, East Carolina University, Greenville, NC, USA
- Correspondence: Filip Jevtovic East Carolina University; School of Dental Medicine, Ledyard E. Ross Hall; 1851 MacGregor Downs Road, Mail Stop 701, Greenville, NC, 27834, USATel +1 616 844 8323Fax +1 252 737 7024 Email
| |
Collapse
|
|
34
|
Pilmark NS, Petersen-Bønding C, Holm NFR, Johansen MY, Pedersen BK, Hansen KB, Karstoft K. The Effect of Metformin on Self-Selected Exercise Intensity in Healthy, Lean Males: A Randomized, Crossover, Counterbalanced Trial. Front Endocrinol (Lausanne) 2021; 12:599164. [PMID: 33716963 PMCID: PMC7947847 DOI: 10.3389/fendo.2021.599164] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Accepted: 01/19/2021] [Indexed: 01/30/2023] Open
Abstract
INTRODUCTION In general, patients with type 2 diabetes have lower cardiorespiratory fitness levels and perform exercise at lower intensities compared to healthy controls. Since metformin (MET) has been shown to increase the rate of perceived exertion (RPE) during exercise with a fixed intensity, MET per se may reduce self-selected exercise intensity. The aim of this study was to assess the effect of MET on self-selected exercise intensity. METHODS Healthy males were eligible for this crossover, counterbalanced study with two treatment periods: MET and placebo (PLA), each lasting 17 days. Treatment dose was gradually increased and reached 2 g/day on treatment day 9, and continued at that level for the rest of the treatment period. The two periods were performed in randomized order. Two experimental days (A+B) were conducted on Day 15 (A) and Day 17 (B) of each period, respectively. Day A consisted of an exercise bout with self-selected exercise intensity (equal to RPE = 14-15 on the Borg Scale). Day B consisted of an exercise bout with fixed intensity (70% of VO2peak). Oxygen consumption rate was assessed continuously during both exercise bouts. RESULTS Fifteen males (age 23.7 ± 0.6 years, BMI 22.3 ± 2.0, VO2peak 3.5 ± 0.6 L/min) were included in the study. On Day B, RPE was higher in MET compared to PLA (14.8 ± 0.4 vs. 14.0 ± 0.3, P = 0.045). On Day A, no difference in self-selected exercise intensity measured by oxygen consumption rate (PLA 2.33 ± 0.09 L O2/min, MET 2.42 ± 0.10 L O2/min, P = 0.09) was seen between treatment periods. CONCLUSIONS Self-selected exercise intensity was not reduced by MET in healthy males, despite the fact that MET increased RPE during an exercise bout with fixed intensity.
Collapse
Affiliation(s)
- Nanna Skytt Pilmark
- Centre for Physical Activity Research (CFAS), University of Copenhagen, Rigshospitalet, Copenhagen, Denmark
| | - Christina Petersen-Bønding
- Centre for Physical Activity Research (CFAS), University of Copenhagen, Rigshospitalet, Copenhagen, Denmark
| | - Nielse Frederich Rose Holm
- Centre for Physical Activity Research (CFAS), University of Copenhagen, Rigshospitalet, Copenhagen, Denmark
| | - Mette Yun Johansen
- Centre for Physical Activity Research (CFAS), University of Copenhagen, Rigshospitalet, Copenhagen, Denmark
| | - Bente Klarlund Pedersen
- Centre for Physical Activity Research (CFAS), University of Copenhagen, Rigshospitalet, Copenhagen, Denmark
| | | | - Kristian Karstoft
- Centre for Physical Activity Research (CFAS), University of Copenhagen, Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
- *Correspondence: Kristian Karstoft, ; orcid.org/0000-0002-6596-4199
| |
Collapse
|
|
35
|
Brown JC, Zhang S, Ligibel JA, Irwin ML, Jones LW, Campbell N, Pollak MN, Sorrentino A, Cartmel B, Harrigan M, Tolaney SM, Winer EP, Ng K, Abrams TA, Sanft T, Douglas PS, Hu FB, Fuchs CS, Meyerhardt JA. Effect of Exercise or Metformin on Biomarkers of Inflammation in Breast and Colorectal Cancer: A Randomized Trial. Cancer Prev Res (Phila) 2020; 13:1055-1062. [PMID: 32859615 PMCID: PMC7718298 DOI: 10.1158/1940-6207.capr-20-0188] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 07/14/2020] [Accepted: 08/19/2020] [Indexed: 12/16/2022]
Abstract
Observational studies report that physical activity and metformin are associated with improved clinical outcome in patients with cancer. Inflammation is one biological mechanism hypothesized to mediate these associations. In this phase II, multicenter, 2 × 2 factorial trial, 139 patients with breast and colorectal cancer who completed standard therapy were randomized to one of four treatment groups for 12 weeks: exercise alone, metformin alone, exercise and metformin, or control. Inflammation outcomes included high-sensitivity C-reactive protein (hs-CRP), soluble tumor necrosis factor alpha receptor two (sTNFαR2), and IL6. The primary modeling strategy evaluated the trial product estimand that was quantified using a generalized linear mixed model. Compared with control, exercise alone reduced hs-CRP [-30.2%; 95% confidence interval (CI), -50.3, -1.0] and IL6 (-30.9%; 95% CI, -47.3, -9.5) but did not change sTNFαR2 (1.0%; 95% CI, -10.4, 13.9). Compared with control, metformin alone did not change hs-CRP (-13.9%; 95% CI, -40.0, 23.4), sTNFαR2 (-10.4%; 95% CI, -21.3, 2.0), or IL6 (-22.9%; 95% CI, -42.3, 2.0). Compared with control, exercise and metformin reduced sTNFαR2 (-13.1%; 95% CI, -22.9, -1.0) and IL6 (-38.7%; 95% CI, -52.3, -18.9) but did not change hs-CRP (-20.5%; 95% CI, -44.0, 12.7). The combination of exercise and metformin was not synergistic for hs-CRP, sTNFαR2, or IL6. In survivors of breast and colorectal cancer with low baseline physical activity and without type 2 diabetes, exercise and metformin reduced measures of inflammation that are associated with cancer recurrence and mortality.
Collapse
Affiliation(s)
- Justin C Brown
- Pennington Biomedical Research Center, Baton Rouge, Louisiana.
- Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana
| | - Sui Zhang
- Dana-Farber Cancer Institute, Boston, Massachusetts
| | | | | | - Lee W Jones
- Memorial Sloan Kettering Cancer Center, New York, New York
| | | | - Michael N Pollak
- McGill University, Jewish General Hospital, Montreal, Quebec, Canada
| | | | | | | | | | - Eric P Winer
- Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Kimmie Ng
- Dana-Farber Cancer Institute, Boston, Massachusetts
| | | | | | | | - Frank B Hu
- Harvard School of Public Health, Boston, Massachusetts
| | | | | |
Collapse
|
|
36
|
Metformin alters skeletal muscle transcriptome adaptations to resistance training in older adults. Aging (Albany NY) 2020; 12:19852-19866. [PMID: 33071237 PMCID: PMC7655218 DOI: 10.18632/aging.104096] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Accepted: 09/17/2020] [Indexed: 12/21/2022]
Abstract
Evidence from clinical trials and observational studies suggests that both progressive resistance exercise training (PRT) and metformin delay a variety of age-related morbidities. Previously, we completed a clinical trial testing the effects of 14 weeks of PRT + metformin (metPRT) compared to PRT with placebo (plaPRT) on muscle hypertrophy in older adults. We found that metformin blunted PRT-induced muscle hypertrophic response. To understand potential mechanisms underlying the inhibitory effect of metformin on PRT, we analyzed the muscle transcriptome in 23 metPRT and 24 plaPRT participants. PRT significantly increased expression of genes involved in extracellular matrix remodeling pathways, and downregulated RNA processing pathways in both groups, however, metformin attenuated the number of differentially expressed genes within these pathways compared to plaPRT. Pathway analysis showed that genes unique to metPRT modulated aging-relevant pathways, such as cellular senescence and autophagy. Differentially expressed genes from baseline biopsies in older adults compared to resting muscle from young volunteers were reduced following PRT in plaPRT and were further reduced in metPRT. We suggest that although metformin may blunt pathways induced by PRT to promote muscle hypertrophy, adjunctive metformin during PRT may have beneficial effects on aging-associated pathways in muscle from older adults.
Collapse
|
|
37
|
Malin SK, Stewart NR. Metformin May Contribute to Inter-individual Variability for Glycemic Responses to Exercise. Front Endocrinol (Lausanne) 2020; 11:519. [PMID: 32849302 PMCID: PMC7431621 DOI: 10.3389/fendo.2020.00519] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 06/26/2020] [Indexed: 12/20/2022] Open
Abstract
Metformin and exercise independently improve glycemic control. Metformin traditionally is considered to reduce hepatic glucose production, while exercise training is thought to stimulate skeletal muscle glucose disposal. Collectively, combining treatments would lead to the anticipation for additive glucose regulatory effects. Herein, we discuss recent literature suggesting that metformin may inhibit, enhance or have no effect on exercise mediated benefits toward glucose regulation, with particular emphasis on insulin sensitivity. Importantly, we address issues surrounding the impact of metformin on exercise induced glycemic benefit across multiple insulin sensitive tissues (e.g., skeletal muscle, liver, adipose, vasculature, and the brain) in effort to illuminate potential sources of inter-individual glycemic variation. Therefore, the review identifies gaps in knowledge that require attention in order to optimize medical approaches that improve care of people with elevated blood glucose levels and are at risk of cardiovascular disease.
Collapse
Affiliation(s)
- Steven K. Malin
- Department of Kinesiology, University of Virginia, Charlottesville, VA, United States
- Division of Endocrinology and Metabolism, University of Virginia, Charlottesville, VA, United States
- Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, United States
| | - Nathan R. Stewart
- Department of Kinesiology, University of Virginia, Charlottesville, VA, United States
| |
Collapse
|
|
38
|
Does Exercise Timing Affect 24-Hour Glucose Concentrations in Adults With Type 2 Diabetes? A Follow Up to the Exercise-Physical Activity and Diabetes Glucose Monitoring Study. Can J Diabetes 2020; 44:711-718.e1. [PMID: 32878737 DOI: 10.1016/j.jcjd.2020.05.012] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 05/17/2020] [Accepted: 05/21/2020] [Indexed: 11/20/2022]
Abstract
OBJECTIVES It is well known that exercise can improve the glycemic profile in individuals with type 2 diabetes (T2D). However, the optimal timing of exercise is often debated. Our aim in this study was to compare the effects of exercise performed at different times of the day and different timing in relation to meals on 24-hour glucose profiles in people with T2D. METHODS Fourteen individuals with T2D were recruited and wore continuous glucose monitors for 12 days. During the 12 days, participants completed 4 conditions according to a randomized, crossover design: i) morning (fasting) exercise (MorEx), ii) afternoon exercise (AftEx), iii) evening exercise (EveEx) and iv) seated control. Exercise consisted of 50 minutes of walking at 5.0 km/h. RESULTS Eight men and 6 women (age, 65±9.0 years; T2D duration, 10.5±6.8 years; mean glycated hemoglobin, 6.7±0.6%) were included in the analysis. Mean 24-hour continuously monitored glucose was 7.4±0.7 mmol/L, 7.3±0.7 mmol/L, 7.5±0.8 mmol/L and 7.5±0.7 mmol/L in the MorEx, AftEx, EveEx and control conditions, respectively, with no significant differences among the 4 conditions (p=0.55). MorEx had a lower respiratory exchange ratio compared with AftEx and EveEx (p<0.01). The decrease in glucose during exercise was less pronounced for MorEx compared with AftEx (p<0.05). CONCLUSIONS Fifty minutes of walking at 3 different times of day and at different timing in relation to meals did not lower 24-hour glucose concentrations in people with T2D. The reasons why exercise was not effective at lowering glucose remain unclear.
Collapse
|
|
39
|
Ramos JS, Dalleck LC, Keith CE, Fennell M, Lee Z, Drummond C, Keating SE, Fassett RG, Coombes JS. Optimizing the Interaction of Exercise Volume and Metformin to Induce a Clinically Significant Reduction in Metabolic Syndrome Severity: A Randomised Trial. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:ijerph17103695. [PMID: 32456272 PMCID: PMC7277162 DOI: 10.3390/ijerph17103695] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 05/11/2020] [Accepted: 05/22/2020] [Indexed: 12/20/2022]
Abstract
Insulin resistance is a central mediating factor of the metabolic syndrome (MetS), with exercise training and metformin proven antidotes to insulin resistance. However, when the two therapies are combined there is conflicting data regarding whether metformin blunts or improves exercise training-induced adaptations. The volume of exercise (duration, intensity, and frequency) on the interaction of exercise training and metformin has yet to be investigated. The aim of this study is therefore to explore the impact of a combination of different exercise volumes and metformin on MetS severity. This is a secondary analysis of data from one of the sites of the ‘Exercise in Prevention of Metabolic Syndrome’ (EX-MET) study. Ninety-nine adults with MetS were randomized into a 16-week exercise program completing either: (i) moderate-intensity continuous training (MICT) at 60–70% of peak heart rate (HRpeak) for 30 min/session (n = 34, 150 min/week); (ii) high-volume high-intensity interval training (HIIT) consisting of 4 × 4 min bouts at 85–95% HRpeak, interspersed with 3 min of active recovery at 50–70% HRpeak (n = 34, 38 min/session, 114 min/week); or (iii) low volume HIIT, 1 × 4 min bout of HIIT at 85–95% HRpeak (n = 31, 17 min/session, 51 min/week). Metformin intake was monitored and recorded throughout the trial. MetS severity was calculated as z-scores derived from MetS risk factors assessed at pre- and post-intervention. Sixty-five participants had complete pre- and post-intervention data for MetS z-score, of which 18 participants (28%) were taking metformin. Over the 16-week intervention, a similar proportion of participants clinically improved MetS severity (Δ ≥ −0.87) with metformin (8/18, 44%) or without metformin (23/47, 49%) (p = 0.75). While there were no between-group differences (p = 0.24), in those who did not take metformin low-volume HIIT had more likely responders (10/15, 67%) compared to MICT (6/16, 38%) and high-volume HIIT (7/16, 44%). In those taking metformin, there was a lower proportion of participants who clinically improved MetS severity following high-volume HIIT (1/6, 17%) compared to MICT (2/4, 50%) and low-volume HIIT (5/8, 63%), but with no between-group difference (p = 0.23). Moreover, in those who performed high-volume HIIT, there was a statistically significantly higher proportion (p = 0.03) of likely non-responders with improved MetS severity in participants taking metformin (4/6, 67%) compared to those not taking metformin (3/16, 19%). In individuals with MetS, the effect of high volume HIIT on MetS severity may be blunted in those taking metformin. These findings need to be confirmed in a larger study.
Collapse
Affiliation(s)
- Joyce S. Ramos
- Caring Futures Institute & SHAPE Research Centre, Exercise Science and Clinical Exercise Physiology, College of Nursing and Health Sciences, Flinders University, Room S268, South Wing, Sturt Building, Bedford Park, Adelaide 5042, South Australia, Australia; (L.C.D.); (C.E.K.); (M.F.); (Z.L.); (C.D.)
- Centre for Research on Exercise, Physical Activity and Health, School of Human Movement and Nutrition Sciences, The University of Queensland, Brisbane 4072, Queensland, Australia; (S.E.K.); (R.G.F.); (J.S.C.)
- Correspondence: ; Tel.: +61-435-942-505
| | - Lance C. Dalleck
- Caring Futures Institute & SHAPE Research Centre, Exercise Science and Clinical Exercise Physiology, College of Nursing and Health Sciences, Flinders University, Room S268, South Wing, Sturt Building, Bedford Park, Adelaide 5042, South Australia, Australia; (L.C.D.); (C.E.K.); (M.F.); (Z.L.); (C.D.)
- Recreation, Exercise, and Sport Science Department, Western Colorado University, Gunnison, CO 81231, USA
| | - Caitlin E. Keith
- Caring Futures Institute & SHAPE Research Centre, Exercise Science and Clinical Exercise Physiology, College of Nursing and Health Sciences, Flinders University, Room S268, South Wing, Sturt Building, Bedford Park, Adelaide 5042, South Australia, Australia; (L.C.D.); (C.E.K.); (M.F.); (Z.L.); (C.D.)
| | - Mackenzie Fennell
- Caring Futures Institute & SHAPE Research Centre, Exercise Science and Clinical Exercise Physiology, College of Nursing and Health Sciences, Flinders University, Room S268, South Wing, Sturt Building, Bedford Park, Adelaide 5042, South Australia, Australia; (L.C.D.); (C.E.K.); (M.F.); (Z.L.); (C.D.)
| | - Zoe Lee
- Caring Futures Institute & SHAPE Research Centre, Exercise Science and Clinical Exercise Physiology, College of Nursing and Health Sciences, Flinders University, Room S268, South Wing, Sturt Building, Bedford Park, Adelaide 5042, South Australia, Australia; (L.C.D.); (C.E.K.); (M.F.); (Z.L.); (C.D.)
| | - Claire Drummond
- Caring Futures Institute & SHAPE Research Centre, Exercise Science and Clinical Exercise Physiology, College of Nursing and Health Sciences, Flinders University, Room S268, South Wing, Sturt Building, Bedford Park, Adelaide 5042, South Australia, Australia; (L.C.D.); (C.E.K.); (M.F.); (Z.L.); (C.D.)
| | - Shelley E. Keating
- Centre for Research on Exercise, Physical Activity and Health, School of Human Movement and Nutrition Sciences, The University of Queensland, Brisbane 4072, Queensland, Australia; (S.E.K.); (R.G.F.); (J.S.C.)
| | - Robert G. Fassett
- Centre for Research on Exercise, Physical Activity and Health, School of Human Movement and Nutrition Sciences, The University of Queensland, Brisbane 4072, Queensland, Australia; (S.E.K.); (R.G.F.); (J.S.C.)
| | - Jeff S. Coombes
- Centre for Research on Exercise, Physical Activity and Health, School of Human Movement and Nutrition Sciences, The University of Queensland, Brisbane 4072, Queensland, Australia; (S.E.K.); (R.G.F.); (J.S.C.)
| |
Collapse
|
|
40
|
Tanaka K, Takahashi H, Katagiri S, Sasaki K, Ohsugi Y, Watanabe K, Rasadul IMD, Mine K, Nagafuchi S, Iwata T, Eguchi Y, Anzai K. Combined effect of canagliflozin and exercise training on high-fat diet-fed mice. Am J Physiol Endocrinol Metab 2020; 318:E492-E503. [PMID: 32017594 DOI: 10.1152/ajpendo.00401.2019] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have been reported to improve obesity, diabetes, and nonalcoholic fatty liver disease (NAFLD) in addition to exercise training, whereas the combined effects remain to be elucidated fully. We investigated the effect of the combination of the SGLT2i canagliflozin (CAN) and exercise training in high-fat diet-induced obese mice. High-fat diet-fed mice were housed in normal cages (sedentary; Sed) or wheel cages (WCR) with or without CAN (0.03% of diet) for 4 wk. The effects on obesity, glucose metabolism, and hepatic steatosis were evaluated in four groups (Control/Sed, Control/WCR, CAN/Sed, and CAN/WCR). Numerically additive improvements were found in body weight, body fat mass, blood glucose, glucose intolerance, insulin resistance, and the fatty liver of the CAN/WCR group, whereas CAN increased food intake and reduced running distance. Exercise training alone, CAN alone, or both did not change the weight of skeletal muscle, but microarray analysis showed that each resulted in a characteristic change of gene expression in gastrocnemius muscle. In particular, in the CAN/WCR group, there was acceleration of the angiogenesis pathway and suppression of the adipogenesis pathway compared with the CAN/Sed group. In conclusion, the combination of an SGLT2i and exercise training improves obesity, insulin resistance, and NAFLD in an additive manner. Changes of gene expression in skeletal muscle may contribute, at least in part, to the improvement of obesity and insulin sensitivity.
Collapse
Affiliation(s)
- Kenichi Tanaka
- Division of Metabolism and Endocrinology, Facility of Medicine, Saga University, Saga, Japan
| | - Hirokazu Takahashi
- Division of Metabolism and Endocrinology, Facility of Medicine, Saga University, Saga, Japan
| | - Sayaka Katagiri
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kazuyo Sasaki
- Ikuyaku. Integrated Value Development Division, Mitsubishi Tanabe Pharma Corporation, Osaka, Japan
| | - Yujin Ohsugi
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kazuki Watanabe
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Islam M D Rasadul
- Division of Metabolism and Endocrinology, Facility of Medicine, Saga University, Saga, Japan
| | - Keiichiro Mine
- Division of Metabolism and Endocrinology, Facility of Medicine, Saga University, Saga, Japan
- Division of Host Defense, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Seiho Nagafuchi
- Division of Metabolism and Endocrinology, Facility of Medicine, Saga University, Saga, Japan
| | - Takanori Iwata
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yuichiro Eguchi
- Division of Metabolism and Endocrinology, Facility of Medicine, Saga University, Saga, Japan
- Liver Center, Saga University Hospital, Saga University, Saga, Japan
| | - Keizo Anzai
- Division of Metabolism and Endocrinology, Facility of Medicine, Saga University, Saga, Japan
| |
Collapse
|
|
41
|
England CY, Andrews RC. James Lind Alliance research priorities: should diet and exercise be used as an alternative to drugs for the management of type 2 diabetes or alongside them? Diabet Med 2020; 37:564-572. [PMID: 31849092 DOI: 10.1111/dme.14217] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/13/2019] [Indexed: 12/31/2022]
Abstract
AIM To review evidence on whether diet and exercise should be used as an alternative to drug therapy for the management of type 2 diabetes or alongside. METHOD We present a narrative review that draws on evidence from other systematic reviews and meta-analyses, narrative reviews, trials and cohort studies. We focused mainly on glycaemic control rather than control of blood pressure or cholesterol. RESULTS Good-quality dietary advice that results in weight loss of >5% and physical activity interventions of >150 min/week of moderate to vigorous physical activity, combined with resistance exercise, can produce improvements in HbA1c similar to those produced by the addition of glucose-lowering drugs. These improvements can be seen at all stages of the disease. There are recognized interactions between glucose-lowering drugs and physical activity which may not be synergistic, but these are not well understood, and it is not clear if they are considered in clinical practice. Studies that explicitly compare drugs with diet or physical activity or control for drug use found that lifestyle could delay or reduce medication use, but most people eventually needed to progress to drug treatment. There are few studies, however, that provide strategies for the long-term maintenance of weight loss or physical activity. CONCLUSION Diet and physical activity are of key importance in type 2 diabetes management, and attention to them improves glycaemic control and cardiovascular disease risk, but it is not yet known whether maintained lifestyle changes provide an alternative to drug therapy in the long term.
Collapse
Affiliation(s)
- C Y England
- National Institute for Health Research Bristol Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and University of Bristol, Bristol, UK
- Centre for Exercise Nutrition and Health Sciences, School for Policy Studies, University of Bristol, Bristol, UK
| | - R C Andrews
- Department of Diabetes, Taunton and Somerset NHS Foundation Trust, Taunton, UK
- University of Exeter Medical School, Exeter, UK
| |
Collapse
|
|
42
|
Nikolaidis S, Virgiliou C, Vekiou M, Skari A, Kechagidou A, Gika H, Theodoridis G, Pappas P, Leondaritis G, Mougios V. Effect of exercise on key pharmacokinetic parameters related to metformin absorption in healthy humans: A pilot study. Scand J Med Sci Sports 2020; 30:858-864. [PMID: 31975547 DOI: 10.1111/sms.13628] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Revised: 01/11/2020] [Accepted: 01/16/2020] [Indexed: 12/14/2022]
Abstract
Exercise is widely accepted as having therapeutic effects; thus, it is important to know whether it interacts with medications. The aim of the present pilot study was to examine the effect of high-intensity interval exercise (known to have antidiabetic action) on key pharmacokinetic parameters related to absorption of metformin (the first-line medication against type 2 diabetes). Ten healthy men participated in two sessions, spaced one to two weeks apart in random, counterbalanced order. In both sessions, participants received 1000 mg of metformin orally, 1-1.5 hours after breakfast. Then, they either ran for 60 minutes at alternating intensity, starting at 40 minutes after metformin administration, and rested without food consumption over the next 3 hours or they rested without food consumption during the entire testing period. Venous blood samples were collected before and at 0.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours after metformin administration for metformin determination by liquid chromatography-mass spectrometry. Capillary blood samples were also collected for lactate and glucose measurements. Data from the two sessions were compared through Wilcoxon or Student's t test, as appropriate. Maximum plasma concentration of metformin (Cmax ) was higher at exercise compared to rest (P = .059). Time to reach Cmax (Tmax ) decreased with exercise (P = .009), and the area under the metformin concentration vs time curve was higher at exercise (P = .047). The addition of exercise to metformin administration did not cause hypoglycemia or lactic acidosis. In conclusion, our results provide the first evidence that pharmacokinetic values related to metformin absorption are affected by exercise.
Collapse
Affiliation(s)
- Stefanos Nikolaidis
- Laboratory of Evaluation of Human Biological Performance, School of Physical Education and Sport Science, Aristotle University of Thessaloniki, Thessaloniki, Greece.,Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - Christina Virgiliou
- BIOMIC_AUTh, Center for Interdisciplinary Research and Innovation, Thermi, Greece.,FoodOmicsGR RI, Center for Interdisciplinary Research and Innovation, Thermi, Greece.,School of Chemistry, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Magdalini Vekiou
- Department of Critical Care and Emergency, General Hospital of Grevena, Grevena, Greece
| | - Ariadni Skari
- Laboratory of Evaluation of Human Biological Performance, School of Physical Education and Sport Science, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | | | - Helen Gika
- BIOMIC_AUTh, Center for Interdisciplinary Research and Innovation, Thermi, Greece.,FoodOmicsGR RI, Center for Interdisciplinary Research and Innovation, Thermi, Greece.,School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Georgios Theodoridis
- BIOMIC_AUTh, Center for Interdisciplinary Research and Innovation, Thermi, Greece.,FoodOmicsGR RI, Center for Interdisciplinary Research and Innovation, Thermi, Greece.,School of Chemistry, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Periklis Pappas
- Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - George Leondaritis
- Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - Vassilis Mougios
- Laboratory of Evaluation of Human Biological Performance, School of Physical Education and Sport Science, Aristotle University of Thessaloniki, Thessaloniki, Greece.,BIOMIC_AUTh, Center for Interdisciplinary Research and Innovation, Thermi, Greece.,FoodOmicsGR RI, Center for Interdisciplinary Research and Innovation, Thermi, Greece
| |
Collapse
|
|
43
|
Ali S, Mansour AG, Huang W, Queen NJ, Mo X, Anderson JM, Hassan II QN, Patel RS, Wilkins RK, Caligiuri MA, Cao L. CSF1R inhibitor PLX5622 and environmental enrichment additively improve metabolic outcomes in middle-aged female mice. Aging (Albany NY) 2020; 12:2101-2122. [PMID: 32007953 PMCID: PMC7041757 DOI: 10.18632/aging.102724] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 01/02/2020] [Indexed: 04/12/2023]
Abstract
As the elderly population grows, chronic metabolic dysfunction including obesity and diabetes are becoming increasingly common comorbidities. Hypothalamic inflammation through CNS resident microglia serves as a common pathway between developing obesity and developing systemic aging pathologies. Despite understanding aging as a life-long process involving interactions between individuals and their environment, limited studies address the dynamics of environment interactions with aging or aging therapeutics. We previously demonstrated environmental enrichment (EE) is an effective model for studying improved metabolic health and overall healthspan in mice, which acts through a brain-fat axis. Here we investigated the CSF1R inhibitor PLX5622 (PLX), which depletes microglia, and its effects on metabolic decline in aging in interaction with EE. PLX in combination with EE substantially improved metabolic outcomes in middle-aged female mice over PLX or EE alone. Chronic PLX treatment depleted 75% of microglia from the hypothalamus and reduced markers of inflammation without affecting brain-derived neurotrophic factor levels induced by EE. Adipose tissue remodeling and adipose tissue macrophage modulation were observed in response to CSF1R inhibition, which may contribute to the combined benefits seen in EE with PLX. Our study suggests benefits exist from combined drug and lifestyle interventions in aged animals.
Collapse
Affiliation(s)
- Seemaab Ali
- Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
- The Ohio State University Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, Columbus, OH 43210, USA
- Medical Scientist Training Program, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Anthony G. Mansour
- The Ohio State University Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, Columbus, OH 43210, USA
- Department of Hematological Malignancies and Stem Cell Transplantation, City of Hope National Medical Center and the Beckman Research Institute, Los Angeles, CA 91010, USA
| | - Wei Huang
- Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
- The Ohio State University Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, Columbus, OH 43210, USA
| | - Nicholas J. Queen
- Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
- The Ohio State University Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, Columbus, OH 43210, USA
| | - Xiaokui Mo
- Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Jacqueline M. Anderson
- Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
- The Ohio State University Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, Columbus, OH 43210, USA
| | - Quais N. Hassan II
- Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
- The Ohio State University Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, Columbus, OH 43210, USA
- Medical Scientist Training Program, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Ripal S. Patel
- Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
- The Ohio State University Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, Columbus, OH 43210, USA
| | - Ryan K. Wilkins
- Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
- The Ohio State University Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, Columbus, OH 43210, USA
| | - Michael A. Caligiuri
- Department of Hematological Malignancies and Stem Cell Transplantation, City of Hope National Medical Center and the Beckman Research Institute, Los Angeles, CA 91010, USA
| | - Lei Cao
- Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
- The Ohio State University Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, Columbus, OH 43210, USA
| |
Collapse
|
|
44
|
Santa Mina D, Au D, Papadopoulos E, O'Neill M, Diniz C, Dolan L, Lipton J, Chang E, Jones JM. Aerobic capacity attainment and reasons for cardiopulmonary exercise test termination in people with cancer: a descriptive, retrospective analysis from a single laboratory. Support Care Cancer 2020; 28:4285-4294. [PMID: 31900621 DOI: 10.1007/s00520-019-05094-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Accepted: 09/20/2019] [Indexed: 02/02/2023]
Abstract
PURPOSE Aerobic exercise prescriptions in clinical populations commonly involve target intensities based on cardiopulmonary exercise tests (CPET). CPETs are often discontinued prior to a patient achieving true maximum oxygen consumption (VO2 max) which can adversely affect exercise dose and efficacy monitoring; however, reasons for early discontinuation are poorly reported. Accordingly, we explored the CPET termination reasons in persons with cancer participating in exercise intervention studies. METHODS This study comprised of an exploratory, descriptive analysis of retrospective CPET data (VO2 and anaerobic threshold) and termination reasons in a convenience sample of people with cancer participating in exercise intervention studies in a single laboratory. CPETs were standardized using the modified Bruce treadmill protocol with expired gas collection and analysis using a metabolic cart. VO2 max was considered "met" when participants demonstrated (a) oxygen consumption plateau or (b) two of the following criteria: rating of perceived exertion ≥ 9/10, respiratory exchange ratio ≥ 1.15, and/or heart rate of 95% of age-predicted maximum. The frequency and distribution of reasons for test termination relative to the number of CPET exposures for the participants were reported. RESULTS Forty-four participants engaged in exercise studies between February 2016 and March 2018 provided data for the analysis. Participants completed up to three CPETs during this period (total of 78 CPETs in the current analysis). Eighty-six percent of all CPETs were terminated prior to achieving VO2 max verification criteria and no tests resulted in an oxygen consumption plateau. For those that did not demonstrate achievement of VO2 max verification criteria, reasons for discontinuation were distributed as follows: equipment discomfort-49%, volitional peak-36%, and physical discomfort-14.9%. For those who met VO2 max criteria, volitional peak was the most common reason for test termination (45.5%), followed by physical discomfort (36.4%), and equipment discomfort (18.2%). CONCLUSIONS In our sample of cancer survivors, VO2 max criteria were infrequently met with equipment discomfort being a primary reason for participant-driven test termination. Protocol and equipment considerations are necessary for interpretation and application of CPET findings in clinical practice.
Collapse
Affiliation(s)
- Daniel Santa Mina
- Faculty of Kinesiology and Physical Education, University of Toronto, 55 Harbord St, Toronto, Ontario, M5S 2 W6, Canada.,University Health Network, Toronto, Ontario, Canada.,Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Darren Au
- Faculty of Kinesiology and Physical Education, University of Toronto, 55 Harbord St, Toronto, Ontario, M5S 2 W6, Canada. .,University Health Network, Toronto, Ontario, Canada.
| | - Efthymios Papadopoulos
- Faculty of Kinesiology and Physical Education, University of Toronto, 55 Harbord St, Toronto, Ontario, M5S 2 W6, Canada.,University Health Network, Toronto, Ontario, Canada
| | - Meagan O'Neill
- University Health Network, Toronto, Ontario, Canada.,Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Camilla Diniz
- Faculty of Kinesiology and Physical Education, University of Toronto, 55 Harbord St, Toronto, Ontario, M5S 2 W6, Canada
| | - Lianne Dolan
- University Health Network, Toronto, Ontario, Canada
| | - Jeffrey Lipton
- University Health Network, Toronto, Ontario, Canada.,Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Eugene Chang
- University Health Network, Toronto, Ontario, Canada.,Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Jennifer M Jones
- University Health Network, Toronto, Ontario, Canada.,Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| |
Collapse
|
|
45
|
Kristensen JM, Lillelund C, Kjøbsted R, Birk JB, Andersen NR, Nybo L, Mellberg K, Balendran A, Richter EA, Wojtaszewski JFP. Metformin does not compromise energy status in human skeletal muscle at rest or during acute exercise: A randomised, crossover trial. Physiol Rep 2019; 7:e14307. [PMID: 31833226 PMCID: PMC6908741 DOI: 10.14814/phy2.14307] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2019] [Revised: 11/01/2019] [Accepted: 11/04/2019] [Indexed: 12/25/2022] Open
Abstract
5´AMP-activated protein kinase (AMPK) is a mediator of a healthy metabolic phenotype in skeletal muscle. Metformin may exacerbate the energy disturbances observed during exercise leading to enhanced AMPK activation, and these disturbances may provoke early muscular fatigue. We studied acute (1 day) and short-term (4 days) effects of metformin treatment on AMPK and its downstream signaling network, in healthy human skeletal muscle and adipose tissue at rest and during exercise, by applying a randomized blinded crossover study design in 10 lean men. Muscle and fat biopsies were obtained before and after the treatment period at rest and after a single bout of exercise. Metformin treat ment elicited peak plasma and muscle metformin concentrations of 31 μM and 11 μM, respectively. Neither of the treatments affected AMPK activity in skeletal muscle and adipose at rest or during exercise. In contrast, whole-body stress during exercise was elevated as indicated by increased plasma lactate and adrenaline concentrations as well as increased heart rate and rate of perceived exertion. Also whole-body insulin sensitivity was enhanced by 4 days metformin treatment, that is reduced fasting plasma insulin and HOMA-IR. In conclusion, acute and short-term metformin treatment does not affect energy homeostasis and AMPK activation at rest or during exercise in skeletal muscle and adipose tissue of healthy subjects. However, metformin treatment is accompanied by slightly enhanced perceived exertion and whole-body stress which may provoke a lesser desire for physical activity in the metformin-treated patients.
Collapse
Affiliation(s)
- Jonas M. Kristensen
- Section of Molecular PhysiologyDepartment of Nutrition, Exercise and SportsFaculty of ScienceUniversity of CopenhagenCopenhagenDenmark
| | - Christian Lillelund
- Section of Molecular PhysiologyDepartment of Nutrition, Exercise and SportsFaculty of ScienceUniversity of CopenhagenCopenhagenDenmark
- The University Hospitals Centre for Health ResearchUCSFCopenhagen University HospitalCopenhagenDenmark
| | - Rasmus Kjøbsted
- Section of Molecular PhysiologyDepartment of Nutrition, Exercise and SportsFaculty of ScienceUniversity of CopenhagenCopenhagenDenmark
| | - Jesper B. Birk
- Section of Molecular PhysiologyDepartment of Nutrition, Exercise and SportsFaculty of ScienceUniversity of CopenhagenCopenhagenDenmark
| | - Nicoline R. Andersen
- Section of Molecular PhysiologyDepartment of Nutrition, Exercise and SportsFaculty of ScienceUniversity of CopenhagenCopenhagenDenmark
| | - Lars Nybo
- Section of Integrative PhysiologyDepartment of Nutrition, Exercise and SportsFaculty of ScienceUniversity of CopenhagenCopenhagenDenmark
| | - Karin Mellberg
- Astra Zeneca R&D MölndalGothenburgSweden
- Present address:
Laird Thermal SystemsGothenburgSweden
| | - Anudharan Balendran
- Astra Zeneca R&D MölndalGothenburgSweden
- Present address:
Alligator Bioscience ABLundSweden
| | - Erik A. Richter
- Section of Molecular PhysiologyDepartment of Nutrition, Exercise and SportsFaculty of ScienceUniversity of CopenhagenCopenhagenDenmark
| | - Jørgen F. P. Wojtaszewski
- Section of Molecular PhysiologyDepartment of Nutrition, Exercise and SportsFaculty of ScienceUniversity of CopenhagenCopenhagenDenmark
| |
Collapse
|
|
46
|
Chiang SL, Heitkemper MM, Hung YJ, Tzeng WC, Lee MS, Lin CH. Effects of a 12-week moderate-intensity exercise training on blood glucose response in patients with type 2 diabetes: A prospective longitudinal study. Medicine (Baltimore) 2019; 98:e16860. [PMID: 31490370 PMCID: PMC6739009 DOI: 10.1097/md.0000000000016860] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/26/2022] Open
Abstract
BACKGROUND The blood glucose response to moderate-intensity exercise remains unclear for patients with type 2 diabetes (T2DM). In addition, little is known about determinants of blood glucose response to a 12-week moderate-intensity exercise training. Therefore, this study aimed to explore trends in blood glucose in response to a 12-week moderate-intensity exercise training in patients with T2DM and to explore the predictors of post-exercise blood glucose (PEBG) and exercise-induced glucose response (EIGR). METHODS A prospective longitudinal study was conducted. Of the 66 participants with T2DM recruited from outpatient clinics of a medical center, 20 were eligible to enroll in a 12-week moderate-intensity exercise training. Participants were randomly assigned to 1 of 3 exercise times (morning, afternoon, or evening). Blood glucose were measured pre- and post-exercise. The EIGR was calculated by subtracting the PEBG from the before-exercise blood glucose (BEBG). Generalized estimating equations were used to examine the trends and predictors of PEBG and EIGR. RESULTS The BEBG declined progressively (β = -1.69, P < .001); while the PEBG (β = -0.18, P = .08) remained stable over time during the 12-week exercise training. Higher BEBG predicted higher (β = 0.53, P < .001) PEBG. Higher baseline maximum oxygen uptake (VO2max) contributed to a larger magnitude of EIGR; higher HgbA1c and BEBG predicted higher EIGR (β = 0.27, P = .02; β = 0.45, P < .001); afternoon or evening exercise predicted lower (β = -13.2, P = .04; β = -5.96, P = .005) EIGR than did morning exercise. CONCLUSIONS A 12-week moderate-intensity exercise training appears safe for patients with T2DM. Time of day for exercise, baseline VO2max, and baseline metabolic control may influence the impact of exercise for individuals with T2DM. These findings provide considerations for design of optimal exercise training for T2DM patients.
Collapse
Affiliation(s)
- Shang-Lin Chiang
- School of Medicine, National Defense Medical Center; Department of Physical Medicine and Rehabilitation, Tri-Service General Hospital, Taipei, Taiwan, ROC
| | - Margaret McLean Heitkemper
- Department of Biobehavioral Nursing and Health Systems, Division of Gastroenterology, School of Medicine, University of Washington, USA
| | - Yi-Jen Hung
- Division of Endocrinology & Metabolism, School of Medicine, National Defense Medical Center; Tri-Service General Hospital, Songshan Branch
| | | | - Meei-Shyuan Lee
- School of Public Health & Graduated Institute of Medical Science, National Defense Medical Center
| | - Chia-Huei Lin
- School of Nursing & School of Medicine, National Defense Medical Center; Department of Nursing, Tri-Service General Hospital Songshan Branch, Taipei, Taiwan, ROC
| |
Collapse
|
|
47
|
Linden MA, Ross TT, Beebe DA, Gorgoglione MF, Hamilton KL, Miller BF, Braun B, Esler WP. The combination of exercise training and sodium-glucose cotransporter-2 inhibition improves glucose tolerance and exercise capacity in a rodent model of type 2 diabetes. Metabolism 2019; 97:68-80. [PMID: 31132381 DOI: 10.1016/j.metabol.2019.05.009] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 04/19/2019] [Accepted: 05/21/2019] [Indexed: 01/24/2023]
Abstract
PURPOSE Exercise is recommended in addition to pharmacotherapies for the management of type 2 diabetes, but metformin and exercise training may have non-additive or even inhibitory effects on exercise-induced improvements in glycemic control and exercise capacity. The objectives of this report were to determine if co-treatment with a sodium-glucose cotransporter-2 inhibitor and exercise could (1) further improve glycemic control when compared to either monotherapy and (2) not worsen exercise capacity when compared to exercise alone. METHODS A rodent model of type 2 diabetes (30 mg/kg streptozotocin and high-fat feeding in male Sprague-Dawley rats) was used to assess 12 weeks of co-treatment with a sodium-glucose cotransporter 2 inhibitor (SGLT2i) and exercise (EX; treadmill running) on glycemic control and exercise capacity. Animals were randomized to the following conditions (n = 7-10/group): vehicle (0.5% methyl cellulose) sedentary (VEH SED), VEH EX, canagliflozin (3 mg kg-1 d-1) SED (SGLT2i SED), or SGLT2i EX. RESULTS Both EX and SGLT2i independently improved indices of glycemic control. The combination of SGLT2i and EX further improved glucose tolerance (glucose area under the curve 1109 ± 51 vs 1427 ± 82 mmol/ L 120 min-1 for SGLT2i EX vs. SGLT2i SED, respectively; p < 0.05) and insulin responses (insulin area under the curve 24,524 ± 4126 vs. 41,208 ± 2714 pmol L-1 120 min-1 for SGLT2i EX vs. VEH EX, respectively; p < 0.05) during an oral glucose tolerance test. Only the combination of SGLT2i EX lowered body weight compared to VEH SED (p < 0.01). SGLT2i caused several metabolic adaptations including increased ketone production and a greater reliance on fat as a source of energy during normal cage activity. Interestingly, animals that were given the SGLT2i and underwent exercise training (SGLT2i EX) had better submaximal exercise capacity than EX alone, as indicated by distance run prior to fatigue (882 ± 183 vs.433 ± 33 m for SGLT2i EX and VEH EX, respectively; p < 0.01), and this was accompanied by a greater reliance on fat as an energy source during exercise (p < 0.01). CONCLUSIONS If these findings with the combination of SGLT2i and exercise translate to humans, they will have important clinical health implications.
Collapse
Affiliation(s)
- Melissa A Linden
- Internal Medicine Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA, United States of America; Department of Health and Exercise Science, Colorado State University, Fort Collins, CO, United States of America
| | - Trenton T Ross
- Internal Medicine Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA, United States of America
| | - David A Beebe
- Internal Medicine Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA, United States of America
| | - Matthew F Gorgoglione
- Internal Medicine Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA, United States of America
| | - Karyn L Hamilton
- Department of Health and Exercise Science, Colorado State University, Fort Collins, CO, United States of America
| | - Benjamin F Miller
- Department of Health and Exercise Science, Colorado State University, Fort Collins, CO, United States of America; Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK., United States of America
| | - Barry Braun
- Department of Health and Exercise Science, Colorado State University, Fort Collins, CO, United States of America
| | - William P Esler
- Internal Medicine Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA, United States of America.
| |
Collapse
|
|
48
|
Bastien M, Poirier P, Brassard P, Arsenault BJ, Bertrand OF, Després JP, Costerousse O, Piché ME. Effect of PPARγ agonist on aerobic exercise capacity in relation to body fat distribution in men with type 2 diabetes mellitus and coronary artery disease: a 1-yr randomized study. Am J Physiol Endocrinol Metab 2019; 317:E65-E73. [PMID: 30964707 DOI: 10.1152/ajpendo.00505.2018] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Targeting metabolic determinants of exercise performance with pharmacological agents that would mimic/potentiate the effects of exercise represents an attractive clinical alternative to counterbalance the poor exercise capacity in patients with type 2 diabetes mellitus (T2DM). We examined the effect of 1-yr treatment with the insulin sensitizer peroxisome proliferator-activated receptor (PPAR)γ agonist rosiglitazone on aerobic exercise capacity and body fat composition/distribution in men with T2DM and stable coronary artery disease (CAD). One-hundred four men (age: 64 ± 7 yr; body mass index: 30.0 ± 4.4 kg/m2) with T2DM and CAD were randomized to receive rosiglitazone or placebo for 1 yr. Aerobic exercise capacity (exercise duration) was assessed with a maximal treadmill test, and body composition/distribution were assessed by dual-energy X-ray absorptiometry/computed tomography scans. At 1 yr, patients with T2DM under PPARγ agonist treatment showed a reduction in aerobic exercise capacity compared with the control group (exercise duration change, -31 ± 8 versus 7 ± 11 s, P = 0.009). Significant increases in body fat mass (3.1 ± 0.4 kg, 12%), abdominal and mid-thigh subcutaneous adipose tissue (AT) levels, and mid-thigh skeletal muscle fat were found (all P < 0.01), whereas no effect on visceral AT levels was observed (P > 0.05) under treatment. Subcutaneous fat mass gained under PPARγ agonist was the strongest predictor of the worsening in aerobic exercise capacity (P > 0.0001); no association was found with skeletal muscle fat infiltration nor visceral AT. Treatment with the insulin sensitizer PPARγ agonist rosiglitazone in patients with T2DM and CAD is associated with a worsening in aerobic exercise capacity, which seems to be mainly attributable to weight gain and subcutaneous fat mass expansion.
Collapse
Affiliation(s)
- Marjorie Bastien
- Quebec Heart and Lung Institute, Laval University , Quebec , Canada
| | - Paul Poirier
- Quebec Heart and Lung Institute, Laval University , Quebec , Canada
- Faculty of Pharmacy, Laval University , Quebec , Canada
| | - Patrice Brassard
- Quebec Heart and Lung Institute, Laval University , Quebec , Canada
- Faculty of Medicine, Department of Kinesiology, Laval University , Quebec , Canada
| | - Benoit J Arsenault
- Quebec Heart and Lung Institute, Laval University , Quebec , Canada
- Faculty of Medicine, Department of Medicine, Laval University , Quebec , Canada
| | | | - Jean-Pierre Després
- Quebec Heart and Lung Institute, Laval University , Quebec , Canada
- Faculty of Medicine, Department of Kinesiology, Laval University , Quebec , Canada
| | | | - Marie-Eve Piché
- Quebec Heart and Lung Institute, Laval University , Quebec , Canada
- Faculty of Medicine, Department of Medicine, Laval University , Quebec , Canada
| |
Collapse
|
|
49
|
Newman AA, Grimm NC, Wilburn JR, Schoenberg HM, Trikha SRJ, Luckasen GJ, Biela LM, Melby CL, Bell C. Influence of Sodium Glucose Cotransporter 2 Inhibition on Physiological Adaptation to Endurance Exercise Training. J Clin Endocrinol Metab 2019; 104:1953-1966. [PMID: 30597042 DOI: 10.1210/jc.2018-01741] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Accepted: 12/21/2018] [Indexed: 12/11/2022]
Abstract
CONTEXT The combination of two beneficial antidiabetes interventions, regular exercise and pharmaceuticals, is intuitively appealing. However, metformin, the most commonly prescribed diabetes medication, attenuates the favorable physiological adaptations to exercise; in turn, exercise may impede the action of metformin. OBJECTIVE We sought to determine the influence of an alternative diabetes treatment, sodium glucose cotransporter 2 (SGLT2) inhibition, on the response to endurance exercise training. DESIGN, PARTICIPANTS, AND INTERVENTION In a randomized, double-blind, repeated measures parallel design, 30 sedentary overweight and obese men and women were assigned to 12 weeks of supervised endurance exercise training, with daily ingestion of either a placebo or SGLT2 inhibitor (dapagliflozin: ≤10 mg/day). OUTCOME MEASUREMENTS AND RESULTS Endurance exercise training favorably modified body mass, body composition (dual-energy x-ray absorptiometry), peak oxygen uptake (graded exercise with indirect calorimetry), responses to standardized submaximal exercise (indirect calorimetry, heart rate, and blood lactate), and skeletal muscle (vastus lateralis) citrate synthase activity (main effects of exercise training, all P < 0.05); SGLT2 inhibition did not influence any of these physiological adaptations (exercise training × treatment interaction, all P > 0.05). However, after endurance exercise training, fasting blood glucose was greater with SGLT2 inhibition, and increased insulin sensitivity (oral glucose tolerance test/Matsuda index) was abrogated with SGLT2 inhibition (exercise training × treatment interaction, P < 0.01). CONCLUSION The efficacy of combining two beneficial antidiabetes interventions, regular endurance exercise and SGLT2 inhibition, was not supported. SGLT2 inhibition blunted endurance exercise training-induced improvements in insulin sensitivity, independent of effects on aerobic fitness or body composition.
Collapse
Affiliation(s)
- Alissa A Newman
- Department of Health and Exercise Science, Colorado State University, Fort Collins, Colorado
| | - Nathan C Grimm
- Department of Health and Exercise Science, Colorado State University, Fort Collins, Colorado
| | - Jessie R Wilburn
- Department of Health and Exercise Science, Colorado State University, Fort Collins, Colorado
| | - Hayden M Schoenberg
- Department of Health and Exercise Science, Colorado State University, Fort Collins, Colorado
| | - S Raj J Trikha
- Department of Health and Exercise Science, Colorado State University, Fort Collins, Colorado
| | - Gary J Luckasen
- Medical Center of the Rockies Foundation, University of Colorado Health, Loveland, Colorado
| | - Laurie M Biela
- Department of Health and Exercise Science, Colorado State University, Fort Collins, Colorado
| | - Christopher L Melby
- Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, Colorado
| | - Christopher Bell
- Department of Health and Exercise Science, Colorado State University, Fort Collins, Colorado
| |
Collapse
|
|
50
|
Terada T, Boulé NG. Does metformin therapy influence the effects of intensive lifestyle intervention? Exploring the interaction between first line therapies in the Look AHEAD trial. Metabolism 2019; 94:39-46. [PMID: 30653978 DOI: 10.1016/j.metabol.2019.01.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Revised: 12/24/2018] [Accepted: 01/10/2019] [Indexed: 12/18/2022]
Abstract
AIMS Metformin and lifestyle intervention are frequently prescribed together as first-line treatments for type 2 diabetes. However, little is known about their interplay. We investigated if the effects of a lifestyle intervention on glycemia, body mass and cardiorespiratory fitness (CRF) were influenced by metformin therapy. METHODS Participants randomized to intensive lifestyle intervention (ILI) or diabetes support and education (DSE) from the Look AHEAD trial were categorized into metformin therapy vs. no metformin. A two-by-two ANCOVA (i.e., metformin therapy vs. no metformin by ILI vs. DSE) was used to examine the changes in glycated hemoglobin A1C, fasting plasma glucose (FPG), body mass, and CRF over the first year post-randomization, with a primary interest in the metformin-by-lifestyle interaction effect. RESULTS Data from 1982 participants were analyzed. There was a significant metformin-by-lifestyle interaction effect on A1C (p = 0.031) and FPG (p = 0.043), resulting from larger reductions associated with metformin therapy compared to no metformin following DSE, but slightly smaller reduction associated with metformin therapy compared to no metformin following ILI. Metformin therapy was associated with smaller weight loss (-4.7 ± 6.2 vs. -5.7 ± 6.3 kg; main effect: p = 0.001) but not with differential CRF changes when compared to no metformin. CONCLUSIONS The interaction between metformin therapy and lifestyle intervention on glycemia highlights the complicated nature of combining therapies. While the small influence of background metformin therapy on intensive lifestyle intervention should not discourage the concomitant use of these therapies, our results showed that, for individuals undergoing intensive lifestyle therapy, background metformin therapy conferred little additional benefits.
Collapse
Affiliation(s)
- Tasuku Terada
- Division of Cardiac Prevention and Rehabilitation, Exercise Physiology and Cardiovascular Health Lab, University of Ottawa Heart Institute, Ottawa, ON K1C 4W7, Canada
| | - Normand G Boulé
- Faculty of Kinesiology, Sport, and Recreation, and Alberta Diabetes Institute, University of Alberta, 1-052 Li Ka Shing Centre for Health Research Innovation, Edmonton, AB T6G 2E1, Canada.
| |
Collapse
|