Exercise Dose and Metformin for Vascular Health in Metabolic Syndrome

Summary

Health organizations recommend exercise in an intensity based manner to promote cardiovascular adaptation and prevent disease. Metformin is a common anti-diabetes medication that reduces future type 2 diabetes and cardiovascular disease (CVD) risk. However, the optimal dose of exercise to be combined with metformin for vascular health remains unknown. The purpose of this study is to evaluate whether combining high or low intensity exercise with metformin has the potential to outperform either exercise intensity alone on blood flow across the arterial tree as well as impact insulin action in individuals with metabolic syndrome. Identification of such outcomes will indicate 1) whether and how metformin should be combined with physical activity for CVD prevention, 2) provide the first indication of whether exercise intensity reduces CVD risk via multi-level vasculature function vs. metabolic insulin action, and 3) provide a rational early treatment for people with metabolic syndrome to prevent/treat type 2 diabetes and CVD.

Timeline

Start

2017-08-07

Primary completion

2024-03-11

Completion

2024-05-23

Publications

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• Background Malin SK, Nightingale J, Choi SE, Chipkin SR, Braun B. Metformin modifies the exercise training effects on risk factors for cardiovascular disease in impaired glucose tolerant adults. Obesity (Silver Spring). 2013 Jan;21(1):93-100. doi: 10.1002/oby.20235.
• Background Malin SK, Niemi N, Solomon TP, Haus JM, Kelly KR, Filion J, Rocco M, Kashyap SR, Barkoukis H, Kirwan JP. Exercise training with weight loss and either a high- or low-glycemic index diet reduces metabolic syndrome severity in older adults. Ann Nutr Metab. 2012;61(2):135-41. doi: 10.1159/000342084.
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• Background Mestek ML, Westby CM, Van Guilder GP, Greiner JJ, Stauffer BL, DeSouza CA. Regular aerobic exercise, without weight loss, improves endothelium-dependent vasodilation in overweight and obese adults. Obesity (Silver Spring). 2010 Aug;18(8):1667-9. doi: 10.1038/oby.2009.467. Epub 2010 Jan 7.
• Background Phillips SA, Mahmoud AM, Brown MD, Haus JM. Exercise interventions and peripheral arterial function: implications for cardio-metabolic disease. Prog Cardiovasc Dis. 2015 Mar-Apr;57(5):521-34. doi: 10.1016/j.pcad.2014.12.005. Epub 2014 Dec 18.
• Background Tjonna AE, Lee SJ, Rognmo O, Stolen TO, Bye A, Haram PM, Loennechen JP, Al-Share QY, Skogvoll E, Slordahl SA, Kemi OJ, Najjar SM, Wisloff U. Aerobic interval training versus continuous moderate exercise as a treatment for the metabolic syndrome: a pilot study. Circulation. 2008 Jul 22;118(4):346-54. doi: 10.1161/CIRCULATIONAHA.108.772822. Epub 2008 Jul 7.
• Background Malin SK, Gerber R, Chipkin SR, Braun B. Independent and combined effects of exercise training and metformin on insulin sensitivity in individuals with prediabetes. Diabetes Care. 2012 Jan;35(1):131-6. doi: 10.2337/dc11-0925. Epub 2011 Oct 31.
• Background Gokce N, Keaney JF Jr, Hunter LM, Watkins MT, Nedeljkovic ZS, Menzoian JO, Vita JA. Predictive value of noninvasively determined endothelial dysfunction for long-term cardiovascular events in patients with peripheral vascular disease. J Am Coll Cardiol. 2003 May 21;41(10):1769-75. doi: 10.1016/s0735-1097(03)00333-4.
• Background Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis. J Am Coll Cardiol. 2010 Mar 30;55(13):1318-27. doi: 10.1016/j.jacc.2009.10.061.
• Background Eggleston EM, Jahn LA, Barrett EJ. Early microvascular recruitment modulates subsequent insulin-mediated skeletal muscle glucose metabolism during lipid infusion. Diabetes Care. 2013 Jan;36(1):104-10. doi: 10.2337/dc11-2399. Epub 2012 Sep 6.
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• Background Vincent MA, Clerk LH, Lindner JR, Price WJ, Jahn LA, Leong-Poi H, Barrett EJ. Mixed meal and light exercise each recruit muscle capillaries in healthy humans. Am J Physiol Endocrinol Metab. 2006 Jun;290(6):E1191-7. doi: 10.1152/ajpendo.00497.2005.
• Background Barrett EJ, Wang H, Upchurch CT, Liu Z. Insulin regulates its own delivery to skeletal muscle by feed-forward actions on the vasculature. Am J Physiol Endocrinol Metab. 2011 Aug;301(2):E252-63. doi: 10.1152/ajpendo.00186.2011. Epub 2011 May 24.
• Background Clerk LH, Vincent MA, Jahn LA, Liu Z, Lindner JR, Barrett EJ. Obesity blunts insulin-mediated microvascular recruitment in human forearm muscle. Diabetes. 2006 May;55(5):1436-42. doi: 10.2337/db05-1373.
• Background Keske MA, Clerk LH, Price WJ, Jahn LA, Barrett EJ. Obesity blunts microvascular recruitment in human forearm muscle after a mixed meal. Diabetes Care. 2009 Sep;32(9):1672-7. doi: 10.2337/dc09-0206. Epub 2009 Jun 1.
• Background Liu J, Jahn LA, Fowler DE, Barrett EJ, Cao W, Liu Z. Free fatty acids induce insulin resistance in both cardiac and skeletal muscle microvasculature in humans. J Clin Endocrinol Metab. 2011 Feb;96(2):438-46. doi: 10.1210/jc.2010-1174. Epub 2010 Nov 3.
• Background Anderson TJ, Charbonneau F, Title LM, Buithieu J, Rose MS, Conradson H, Hildebrand K, Fung M, Verma S, Lonn EM. Microvascular function predicts cardiovascular events in primary prevention: long-term results from the Firefighters and Their Endothelium (FATE) study. Circulation. 2011 Jan 18;123(2):163-9. doi: 10.1161/CIRCULATIONAHA.110.953653. Epub 2011 Jan 3.
• Background Cruickshank K, Riste L, Anderson SG, Wright JS, Dunn G, Gosling RG. Aortic pulse-wave velocity and its relationship to mortality in diabetes and glucose intolerance: an integrated index of vascular function? Circulation. 2002 Oct 15;106(16):2085-90. doi: 10.1161/01.cir.0000033824.02722.f7.
• Background Donley DA, Fournier SB, Reger BL, DeVallance E, Bonner DE, Olfert IM, Frisbee JC, Chantler PD. Aerobic exercise training reduces arterial stiffness in metabolic syndrome. J Appl Physiol (1985). 2014 Jun 1;116(11):1396-404. doi: 10.1152/japplphysiol.00151.2014. Epub 2014 Apr 17.
• Background Green DJ, Eijsvogels T, Bouts YM, Maiorana AJ, Naylor LH, Scholten RR, Spaanderman ME, Pugh CJ, Sprung VS, Schreuder T, Jones H, Cable T, Hopman MT, Thijssen DH. Exercise training and artery function in humans: nonresponse and its relationship to cardiovascular risk factors. J Appl Physiol (1985). 2014 Aug 15;117(4):345-52. doi: 10.1152/japplphysiol.00354.2014. Epub 2014 Jun 19.
• Background Swift DL, Weltman JY, Patrie JT, Saliba SA, Gaesser GA, Barrett EJ, Weltman A. Predictors of improvement in endothelial function after exercise training in a diverse sample of postmenopausal women. J Womens Health (Larchmt). 2014 Mar;23(3):260-6. doi: 10.1089/jwh.2013.4420. Epub 2013 Dec 3.
• Background Mather KJ, Verma S, Anderson TJ. Improved endothelial function with metformin in type 2 diabetes mellitus. J Am Coll Cardiol. 2001 Apr;37(5):1344-50. doi: 10.1016/s0735-1097(01)01129-9.
• Background Vitale C, Mercuro G, Cornoldi A, Fini M, Volterrani M, Rosano GM. Metformin improves endothelial function in patients with metabolic syndrome. J Intern Med. 2005 Sep;258(3):250-6. doi: 10.1111/j.1365-2796.2005.01531.x.
• Background Patel C, Ghanim H, Ravishankar S, Sia CL, Viswanathan P, Mohanty P, Dandona P. Prolonged reactive oxygen species generation and nuclear factor-kappaB activation after a high-fat, high-carbohydrate meal in the obese. J Clin Endocrinol Metab. 2007 Nov;92(11):4476-9. doi: 10.1210/jc.2007-0778. Epub 2007 Sep 4.
• Background Malin SK, Braun B. Impact of Metformin on Exercise-Induced Metabolic Adaptations to Lower Type 2 Diabetes Risk. Exerc Sport Sci Rev. 2016 Jan;44(1):4-11. doi: 10.1249/JES.0000000000000070.
• Background Selvin E, Bolen S, Yeh HC, Wiley C, Wilson LM, Marinopoulos SS, Feldman L, Vassy J, Wilson R, Bass EB, Brancati FL. Cardiovascular outcomes in trials of oral diabetes medications: a systematic review. Arch Intern Med. 2008 Oct 27;168(19):2070-80. doi: 10.1001/archinte.168.19.2070.
• Malin SK, Heiston EM, Battillo DJ, Ragland TJ, Shah AM, Patrie JT. Metformin Alters Exercise Training Induced Blood Pressure and Aortic Waveform Adaptations in Adults at Risk for Metabolic Syndrome. J Clin Hypertens (Greenwich). 2026 Mar;28(3):e70215. doi: 10.1111/jch.70215.
• Malin SK, Remchak ME, Heiston EM, Fabris C, Shah AM. Pancreatic beta-cell Function is Higher in Morning Versus Intermediate Chronotypes With Obesity. Obes Sci Pract. 2025 Feb 26;11(2):e70064. doi: 10.1002/osp4.70064. eCollection 2025 Apr.
• Ragland TJ, Heiston EM, Ballantyne A, Stewart NR, La Salvia S, Musante L, Luse MA, Isakson BE, Erdbrugger U, Malin SK. Extracellular vesicles and insulin-mediated vascular function in metabolic syndrome. Physiol Rep. 2023 Jan;11(1):e15530. doi: 10.14814/phy2.15530.
• Remchak ME, Heiston EM, Ballantyne A, Dotson BL, Stewart NR, Spaeth AM, Malin SK. Insulin Sensitivity and Metabolic Flexibility Parallel Plasma TCA Levels in Early Chronotype With Metabolic Syndrome. J Clin Endocrinol Metab. 2022 Jul 14;107(8):e3487-e3496. doi: 10.1210/clinem/dgac233.

Drugs

Indications