Effect of Metformin on Insulin Sensitivity and Pan-Arterial Vascular Function in Adults With Metabolic Syndrome

Summary

The purpose of this study is to look at how insulin (a hormone that helps the cells get energy from sugar) in our body affects blood vessels (elasticity in the bigger blood vessels and blood flow in the smaller blood vessels in the arm) and how Metformin (a drug that makes you more sensitive to insulin) affects insulin's action on the blood vessels.

Timeline

Start

2014-06

Primary completion

2016-07

Completion

2016-07

Publications

• Background ACCORD Study Group; Cushman WC, Evans GW, Byington RP, Goff DC Jr, Grimm RH Jr, Cutler JA, Simons-Morton DG, Basile JN, Corson MA, Probstfield JL, Katz L, Peterson KA, Friedewald WT, Buse JB, Bigger JT, Gerstein HC, Ismail-Beigi F. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010 Apr 29;362(17):1575-85. doi: 10.1056/NEJMoa1001286. Epub 2010 Mar 14.
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• Background Cooper-DeHoff RM, Gong Y, Handberg EM, Bavry AA, Denardo SJ, Bakris GL, Pepine CJ. Tight blood pressure control and cardiovascular outcomes among hypertensive patients with diabetes and coronary artery disease. JAMA. 2010 Jul 7;304(1):61-8. doi: 10.1001/jama.2010.884.
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• Background Steinberg HO, Tarshoby M, Monestel R, Hook G, Cronin J, Johnson A, Bayazeed B, Baron AD. Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation. J Clin Invest. 1997 Sep 1;100(5):1230-9. doi: 10.1172/JCI119636.
• Background Tripathy D, Mohanty P, Dhindsa S, Syed T, Ghanim H, Aljada A, Dandona P. Elevation of free fatty acids induces inflammation and impairs vascular reactivity in healthy subjects. Diabetes. 2003 Dec;52(12):2882-7. doi: 10.2337/diabetes.52.12.2882.
• Background de Jongh RT, Serne EH, Ijzerman RG, de Vries G, Stehouwer CD. Free fatty acid levels modulate microvascular function: relevance for obesity-associated insulin resistance, hypertension, and microangiopathy. Diabetes. 2004 Nov;53(11):2873-82. doi: 10.2337/diabetes.53.11.2873.
• Background Liu Z, Liu J, Jahn LA, Fowler DE, Barrett EJ. Infusing lipid raises plasma free fatty acids and induces insulin resistance in muscle microvasculature. J Clin Endocrinol Metab. 2009 Sep;94(9):3543-9. doi: 10.1210/jc.2009-0027. Epub 2009 Jun 30.
• Background Westerbacka J, Seppala-Lindroos A, Yki-Jarvinen H. Resistance to acute insulin induced decreases in large artery stiffness accompanies the insulin resistance syndrome. J Clin Endocrinol Metab. 2001 Nov;86(11):5262-8. doi: 10.1210/jcem.86.11.8047.
• Background Westerbacka J, Vehkavaara S, Bergholm R, Wilkinson I, Cockcroft J, Yki-Jarvinen H. Marked resistance of the ability of insulin to decrease arterial stiffness characterizes human obesity. Diabetes. 1999 Apr;48(4):821-7. doi: 10.2337/diabetes.48.4.821.
• Background Baron AD, Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G. Insulin-mediated skeletal muscle vasodilation contributes to both insulin sensitivity and responsiveness in lean humans. J Clin Invest. 1995 Aug;96(2):786-92. doi: 10.1172/JCI118124.
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• Background Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G, Baron AD. Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. J Clin Invest. 1996 Jun 1;97(11):2601-10. doi: 10.1172/JCI118709.
• Background Rossi R, Cioni E, Nuzzo A, Origliani G, Modena MG. Endothelial-dependent vasodilation and incidence of type 2 diabetes in a population of healthy postmenopausal women. Diabetes Care. 2005 Mar;28(3):702-7. doi: 10.2337/diacare.28.3.702.
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• Background Baron AD. Hemodynamic actions of insulin. Am J Physiol. 1994 Aug;267(2 Pt 1):E187-202. doi: 10.1152/ajpendo.1994.267.2.E187.
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• Background Laakso M, Edelman SV, Brechtel G, Baron AD. Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. A novel mechanism for insulin resistance. J Clin Invest. 1990 Jun;85(6):1844-52. doi: 10.1172/JCI114644.
• Background Laakso M, Edelman SV, Brechtel G, Baron AD. Impaired insulin-mediated skeletal muscle blood flow in patients with NIDDM. Diabetes. 1992 Sep;41(9):1076-83. doi: 10.2337/diab.41.9.1076.
• Background Vollenweider P, Tappy L, Randin D, Schneiter P, Jequier E, Nicod P, Scherrer U. Differential effects of hyperinsulinemia and carbohydrate metabolism on sympathetic nerve activity and muscle blood flow in humans. J Clin Invest. 1993 Jul;92(1):147-54. doi: 10.1172/JCI116542.
• Background Raitakari M, Knuuti MJ, Ruotsalainen U, Laine H, Makea P, Teras M, Sipila H, Niskanen T, Raitakari OT, Iida H, Harkonen R, Wegelius U, Yki-Jarvinen H, Nuutila P, et al. Insulin increases blood volume in human skeletal muscle: studies using [15O]CO and positron emission tomography. Am J Physiol. 1995 Dec;269(6 Pt 1):E1000-5. doi: 10.1152/ajpendo.1995.269.6.E1000.
• Background Raitakari M, Nuutila P, Knuuti J, Raitakari OT, Laine H, Ruotsalainen U, Kirvela O, Takala TO, Iida H, Yki-Jarvinen H. Effects of insulin on blood flow and volume in skeletal muscle of patients with IDDM: studies using [15O]H2O, [15O]CO, and positron emission tomography. Diabetes. 1997 Dec;46(12):2017-21. doi: 10.2337/diab.46.12.2017.
• Background Tack CJ, Ong MK, Lutterman JA, Smits P. Insulin-induced vasodilatation and endothelial function in obesity/insulin resistance. Effects of troglitazone. Diabetologia. 1998 May;41(5):569-76. doi: 10.1007/s001250050948.
• Background Yki-Jarvinen H, Utriainen T. Insulin-induced vasodilatation: physiology or pharmacology? Diabetologia. 1998 Apr;41(4):369-79. doi: 10.1007/s001250050919. No abstract available.
• Background Taddei S, Virdis A, Mattei P, Natali A, Ferrannini E, Salvetti A. Effect of insulin on acetylcholine-induced vasodilation in normotensive subjects and patients with essential hypertension. Circulation. 1995 Nov 15;92(10):2911-8. doi: 10.1161/01.cir.92.10.2911.
• Background Bonadonna RC, Saccomani MP, Del Prato S, Bonora E, DeFronzo RA, Cobelli C. Role of tissue-specific blood flow and tissue recruitment in insulin-mediated glucose uptake of human skeletal muscle. Circulation. 1998 Jul 21;98(3):234-41. doi: 10.1161/01.cir.98.3.234.
• Background Steinberg HO, Brechtel G, Johnson A, Fineberg N, Baron AD. Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent. A novel action of insulin to increase nitric oxide release. J Clin Invest. 1994 Sep;94(3):1172-9. doi: 10.1172/JCI117433.
• Background Baron AD, Brechtel-Hook G, Johnson A, Cronin J, Leaming R, Steinberg HO. Effect of perfusion rate on the time course of insulin-mediated skeletal muscle glucose uptake. Am J Physiol. 1996 Dec;271(6 Pt 1):E1067-72. doi: 10.1152/ajpendo.1996.271.6.E1067.
• Background Zhang L, Vincent MA, Richards SM, Clerk LH, Rattigan S, Clark MG, Barrett EJ. Insulin sensitivity of muscle capillary recruitment in vivo. Diabetes. 2004 Feb;53(2):447-53. doi: 10.2337/diabetes.53.2.447.
• Background Eggleston EM, Jahn LA, Barrett EJ. Hyperinsulinemia rapidly increases human muscle microvascular perfusion but fails to increase muscle insulin clearance: evidence that a saturable process mediates muscle insulin uptake. Diabetes. 2007 Dec;56(12):2958-63. doi: 10.2337/db07-0670. Epub 2007 Aug 24.
• Background Inyard AC, Clerk LH, Vincent MA, Barrett EJ. Contraction stimulates nitric oxide independent microvascular recruitment and increases muscle insulin uptake. Diabetes. 2007 Sep;56(9):2194-200. doi: 10.2337/db07-0020. Epub 2007 Jun 11.
• 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 Vincent MA, Barrett EJ, Lindner JR, Clark MG, Rattigan S. Inhibiting NOS blocks microvascular recruitment and blunts muscle glucose uptake in response to insulin. Am J Physiol Endocrinol Metab. 2003 Jul;285(1):E123-9. doi: 10.1152/ajpendo.00021.2003.
• Background Clerk LH, Vincent MA, Barrett EJ, Lankford MF, Lindner JR. Skeletal muscle capillary responses to insulin are abnormal in late-stage diabetes and are restored by angiotensin-converting enzyme inhibition. Am J Physiol Endocrinol Metab. 2007 Dec;293(6):E1804-9. doi: 10.1152/ajpendo.00498.2007. Epub 2007 Oct 2.
• Background Rattigan S, Clark MG, Barrett EJ. Acute vasoconstriction-induced insulin resistance in rat muscle in vivo. Diabetes. 1999 Mar;48(3):564-9. doi: 10.2337/diabetes.48.3.564.
• Background Lauer T, Heiss C, Balzer J, Kehmeier E, Mangold S, Leyendecker T, Rottler J, Meyer C, Merx MW, Kelm M, Rassaf T. Age-dependent endothelial dysfunction is associated with failure to increase plasma nitrite in response to exercise. Basic Res Cardiol. 2008 May;103(3):291-7. doi: 10.1007/s00395-008-0714-3. Epub 2008 Mar 17.
• 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.
• Background Agarwal N, Rice SP, Bolusani H, Luzio SD, Dunseath G, Ludgate M, Rees DA. Metformin reduces arterial stiffness and improves endothelial function in young women with polycystic ovary syndrome: a randomized, placebo-controlled, crossover trial. J Clin Endocrinol Metab. 2010 Feb;95(2):722-30. doi: 10.1210/jc.2009-1985. Epub 2009 Dec 8.
• Background Naka KK, Kalantaridou SN, Kravariti M, Bechlioulis A, Kazakos N, Calis KA, Makrigiannakis A, Katsouras CS, Chrousos GP, Tsatsoulis A, Michalis LK. Effect of the insulin sensitizers metformin and pioglitazone on endothelial function in young women with polycystic ovary syndrome: a prospective randomized study. Fertil Steril. 2011 Jan;95(1):203-9. doi: 10.1016/j.fertnstert.2010.06.058. Epub 2010 Aug 4.
• Background Zou MH, Kirkpatrick SS, Davis BJ, Nelson JS, Wiles WG 4th, Schlattner U, Neumann D, Brownlee M, Freeman MB, Goldman MH. Activation of the AMP-activated protein kinase by the anti-diabetic drug metformin in vivo. Role of mitochondrial reactive nitrogen species. J Biol Chem. 2004 Oct 15;279(42):43940-51. doi: 10.1074/jbc.M404421200. Epub 2004 Jul 19.
• Background Xie Z, Zhang J, Wu J, Viollet B, Zou MH. Upregulation of mitochondrial uncoupling protein-2 by the AMP-activated protein kinase in endothelial cells attenuates oxidative stress in diabetes. Diabetes. 2008 Dec;57(12):3222-30. doi: 10.2337/db08-0610. Epub 2008 Oct 3.
• Background Katzmarzyk PT, Church TS, Blair SN. Cardiorespiratory fitness attenuates the effects of the metabolic syndrome on all-cause and cardiovascular disease mortality in men. Arch Intern Med. 2004 May 24;164(10):1092-7. doi: 10.1001/archinte.164.10.1092.
• Background Allen JD, Geaghan JP, Greenway F, Welsch MA. Time course of improved flow-mediated dilation after short-term exercise training. Med Sci Sports Exerc. 2003 May;35(5):847-53. doi: 10.1249/01.MSS.0000064931.62916.8A.
• Background Sugawara J, Otsuki T, Tanabe T, Hayashi K, Maeda S, Matsuda M. Physical activity duration, intensity, and arterial stiffening in postmenopausal women. Am J Hypertens. 2006 Oct;19(10):1032-6. doi: 10.1016/j.amjhyper.2006.03.008.
• Background Miyaki A, Maeda S, Yoshizawa M, Misono M, Saito Y, Sasai H, Endo T, Nakata Y, Tanaka K, Ajisaka R. Effect of weight reduction with dietary intervention on arterial distensibility and endothelial function in obese men. Angiology. 2009 Jun-Jul;60(3):351-7. doi: 10.1177/0003319708325449. Epub 2008 Nov 19.

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