Insulin Clamp Ancillary Study for Assessment of Insulin Resistance

Summary

Insulin Clamp Ancillary study for Assessment of Insulin Resistance will be conducted as a sub-study to the main protocol, Metformin Therapy for Overweight Adolescents With Type 1 Diabetes (NCT01881828). The purpose of this ancillary study is to assess if metformin will improve tissue-specific insulin resistance (IR) in type 1 diabetes using a hyperinsulinemic euglycemic clamp; a 3-month randomized trial comparing metformin versus placebo in 12 to \<20 year olds with BMI \>85th percentile ( total daily insulin dose \>0.7 units/kg, and HbA1c 7.0%-9.9%).

Timeline

Start

2014-01

Primary completion

2016-02-15

Completion

2016-02-15

Publications

• Background Snell-Bergeon JK, Hokanson JE, Jensen L, MacKenzie T, Kinney G, Dabelea D, Eckel RH, Ehrlich J, Garg S, Rewers M. Progression of coronary artery calcification in type 1 diabetes: the importance of glycemic control. Diabetes Care. 2003 Oct;26(10):2923-8. doi: 10.2337/diacare.26.10.2923.
• Background Maahs DM, Kinney GL, Wadwa P, Snell-Bergeon JK, Dabelea D, Hokanson J, Ehrlich J, Garg S, Eckel RH, Rewers MJ. Hypertension prevalence, awareness, treatment, and control in an adult type 1 diabetes population and a comparable general population. Diabetes Care. 2005 Feb;28(2):301-6. doi: 10.2337/diacare.28.2.301.
• Background Wadwa RP, Kinney GL, Maahs DM, Snell-Bergeon J, Hokanson JE, Garg SK, Eckel RH, Rewers M. Awareness and treatment of dyslipidemia in young adults with type 1 diabetes. Diabetes Care. 2005 May;28(5):1051-6. doi: 10.2337/diacare.28.5.1051.
• Background Borch-Johnsen K, Kreiner S. Proteinuria: value as predictor of cardiovascular mortality in insulin dependent diabetes mellitus. Br Med J (Clin Res Ed). 1987 Jun 27;294(6588):1651-4. doi: 10.1136/bmj.294.6588.1651.
• Background Krolewski AS, Kosinski EJ, Warram JH, Leland OS, Busick EJ, Asmal AC, Rand LI, Christlieb AR, Bradley RF, Kahn CR. Magnitude and determinants of coronary artery disease in juvenile-onset, insulin-dependent diabetes mellitus. Am J Cardiol. 1987 Apr 1;59(8):750-5. doi: 10.1016/0002-9149(87)91086-1.
• Background Snell-Bergeon JK, Hokanson JE, Kinney GL, Dabelea D, Ehrlich J, Eckel RH, Ogden L, Rewers M. Measurement of abdominal fat by CT compared to waist circumference and BMI in explaining the presence of coronary calcium. Int J Obes Relat Metab Disord. 2004 Dec;28(12):1594-9. doi: 10.1038/sj.ijo.0802796.
• Background Maahs DM, Ogden LG, Kinney GL, Wadwa P, Snell-Bergeon JK, Dabelea D, Hokanson JE, Ehrlich J, Eckel RH, Rewers M. Low plasma adiponectin levels predict progression of coronary artery calcification. Circulation. 2005 Feb 15;111(6):747-53. doi: 10.1161/01.CIR.0000155251.03724.A5. Epub 2005 Feb 7.
• Background Orchard TJ, Olson JC, Erbey JR, Williams K, Forrest KY, Smithline Kinder L, Ellis D, Becker DJ. Insulin resistance-related factors, but not glycemia, predict coronary artery disease in type 1 diabetes: 10-year follow-up data from the Pittsburgh Epidemiology of Diabetes Complications Study. Diabetes Care. 2003 May;26(5):1374-9. doi: 10.2337/diacare.26.5.1374.
• Background Libby P, Nathan DM, Abraham K, Brunzell JD, Fradkin JE, Haffner SM, Hsueh W, Rewers M, Roberts BT, Savage PJ, Skarlatos S, Wassef M, Rabadan-Diehl C; National Heart, Lung, and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases Working Group on Cardiovascular Complications of Type 1 Diabetes Mellitus. Report of the National Heart, Lung, and Blood Institute-National Institute of Diabetes and Digestive and Kidney Diseases Working Group on Cardiovascular Complications of Type 1 Diabetes Mellitus. Circulation. 2005 Jun 28;111(25):3489-93. doi: 10.1161/CIRCULATIONAHA.104.529651. No abstract available.
• Background Lloyd CE, Kuller LH, Ellis D, Becker DJ, Wing RR, Orchard TJ. Coronary artery disease in IDDM. Gender differences in risk factors but not risk. Arterioscler Thromb Vasc Biol. 1996 Jun;16(6):720-6. doi: 10.1161/01.atv.16.6.720.
• Background Soedamah-Muthu SS, Chaturvedi N, Toeller M, Ferriss B, Reboldi P, Michel G, Manes C, Fuller JH; EURODIAB Prospective Complications Study Group. Risk factors for coronary heart disease in type 1 diabetic patients in Europe: the EURODIAB Prospective Complications Study. Diabetes Care. 2004 Feb;27(2):530-7. doi: 10.2337/diacare.27.2.530.
• Background Amiel SA, Sherwin RS, Simonson DC, Lauritano AA, Tamborlane WV. Impaired insulin action in puberty. A contributing factor to poor glycemic control in adolescents with diabetes. N Engl J Med. 1986 Jul 24;315(4):215-9. doi: 10.1056/NEJM198607243150402.
• Background Arslanian S, Heil BV, Kalhan SC. Hepatic insulin action in adolescents with insulin-dependent diabetes mellitus: relationship with long-term glycemic control. Metabolism. 1993 Mar;42(3):283-90. doi: 10.1016/0026-0495(93)90075-y.
• Background Arslanian S, Nixon PA, Becker D, Drash AL. Impact of physical fitness and glycemic control on in vivo insulin action in adolescents with IDDM. Diabetes Care. 1990 Jan;13(1):9-15. doi: 10.2337/diacare.13.1.9.
• Background Heptulla RA, Stewart A, Enocksson S, Rife F, Ma TY, Sherwin RS, Tamborlane WV, Caprio S. In situ evidence that peripheral insulin resistance in adolescents with poorly controlled type 1 diabetes is associated with impaired suppression of lipolysis: a microdialysis study. Pediatr Res. 2003 May;53(5):830-5. doi: 10.1203/01.PDR.0000059552.08913.B7.
• Background Nadeau KJ, Regensteiner JG, Bauer TA, Brown MS, Dorosz JL, Hull A, Zeitler P, Draznin B, Reusch JE. Insulin resistance in adolescents with type 1 diabetes and its relationship to cardiovascular function. J Clin Endocrinol Metab. 2010 Feb;95(2):513-21. doi: 10.1210/jc.2009-1756. Epub 2009 Nov 13.
• Background Purnell JQ, Hokanson JE, Marcovina SM, Steffes MW, Cleary PA, Brunzell JD. Effect of excessive weight gain with intensive therapy of type 1 diabetes on lipid levels and blood pressure: results from the DCCT. Diabetes Control and Complications Trial. JAMA. 1998 Jul 8;280(2):140-6. doi: 10.1001/jama.280.2.140.
• Background Regensteiner JG. Type 2 diabetes mellitus and cardiovascular exercise performance. Rev Endocr Metab Disord. 2004 Aug;5(3):269-76. doi: 10.1023/B:REMD.0000032416.13070.01. No abstract available.
• Background Regensteiner JG, Bauer TA, Reusch JE, Brandenburg SL, Sippel JM, Vogelsong AM, Smith S, Wolfel EE, Eckel RH, Hiatt WR. Abnormal oxygen uptake kinetic responses in women with type II diabetes mellitus. J Appl Physiol (1985). 1998 Jul;85(1):310-7. doi: 10.1152/jappl.1998.85.1.310.
• Background Regensteiner JG, Bauer TA, Reusch JE, Quaife RA, Chen MY, Smith SC, Miller TM, Groves BM, Wolfel EE. Cardiac dysfunction during exercise in uncomplicated type 2 diabetes. Med Sci Sports Exerc. 2009 May;41(5):977-84. doi: 10.1249/MSS.0b013e3181942051.
• Background Rewers M, Zaccaro D, D'Agostino R, Haffner S, Saad MF, Selby JV, Bergman R, Savage P; Insulin Resistance Atherosclerosis Study Investigators. Insulin sensitivity, insulinemia, and coronary artery disease: the Insulin Resistance Atherosclerosis Study. Diabetes Care. 2004 Mar;27(3):781-7. doi: 10.2337/diacare.27.3.781.
• Background Haffner SM, D'Agostino R Jr, Mykkanen L, Tracy R, Howard B, Rewers M, Selby J, Savage PJ, Saad MF. Insulin sensitivity in subjects with type 2 diabetes. Relationship to cardiovascular risk factors: the Insulin Resistance Atherosclerosis Study. Diabetes Care. 1999 Apr;22(4):562-8. doi: 10.2337/diacare.22.4.562.
• Background Nadeau KJ, Zeitler PS, Bauer TA, Brown MS, Dorosz JL, Draznin B, Reusch JE, Regensteiner JG. Insulin resistance in adolescents with type 2 diabetes is associated with impaired exercise capacity. J Clin Endocrinol Metab. 2009 Oct;94(10):3687-95. doi: 10.1210/jc.2008-2844. Epub 2009 Jul 7.
• Background Perseghin G, Lattuada G, Danna M, Sereni LP, Maffi P, De Cobelli F, Battezzati A, Secchi A, Del Maschio A, Luzi L. Insulin resistance, intramyocellular lipid content, and plasma adiponectin in patients with type 1 diabetes. Am J Physiol Endocrinol Metab. 2003 Dec;285(6):E1174-81. doi: 10.1152/ajpendo.00279.2003. Epub 2003 Aug 21.
• Background Greenfield JR, Samaras K, Chisholm DJ. Insulin resistance, intra-abdominal fat, cardiovascular risk factors, and androgens in healthy young women with type 1 diabetes mellitus. J Clin Endocrinol Metab. 2002 Mar;87(3):1036-40. doi: 10.1210/jcem.87.3.8324.
• Background Taskinen MR. Quantitative and qualitative lipoprotein abnormalities in diabetes mellitus. Diabetes. 1992 Oct;41 Suppl 2:12-7. doi: 10.2337/diab.41.2.s12.
• Background Nijs HG, Radder JK, Frolich M, Krans HM. The course and determinants of insulin action in type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1989 Jan;32(1):20-7. doi: 10.1007/BF00265399.
• Background Yang X, Ongusaha PP, Miles PD, Havstad JC, Zhang F, So WV, Kudlow JE, Michell RH, Olefsky JM, Field SJ, Evans RM. Phosphoinositide signalling links O-GlcNAc transferase to insulin resistance. Nature. 2008 Feb 21;451(7181):964-9. doi: 10.1038/nature06668.
• Background Dentin R, Hedrick S, Xie J, Yates J 3rd, Montminy M. Hepatic glucose sensing via the CREB coactivator CRTC2. Science. 2008 Mar 7;319(5868):1402-5. doi: 10.1126/science.1151363.
• Background Koivisto VA, Yki-Jarvinen H. Changes in muscle glucose metabolism in type 1 diabetes. Ann Med. 1990 Jun;22(3):201-5. doi: 10.3109/07853899009147270.
• Background Chibalin AV, Leng Y, Vieira E, Krook A, Bjornholm M, Long YC, Kotova O, Zhong Z, Sakane F, Steiler T, Nylen C, Wang J, Laakso M, Topham MK, Gilbert M, Wallberg-Henriksson H, Zierath JR. Downregulation of diacylglycerol kinase delta contributes to hyperglycemia-induced insulin resistance. Cell. 2008 Feb 8;132(3):375-86. doi: 10.1016/j.cell.2007.12.035.
• Background Jensen MD, Caruso M, Heiling V, Miles JM. Insulin regulation of lipolysis in nondiabetic and IDDM subjects. Diabetes. 1989 Dec;38(12):1595-601. doi: 10.2337/diab.38.12.1595.
• Background Nadeau KJ, Ehlers LB, Zeitler PS, Love-Osborne K. Treatment of non-alcoholic fatty liver disease with metformin versus lifestyle intervention in insulin-resistant adolescents. Pediatr Diabetes. 2009 Feb;10(1):5-13. doi: 10.1111/j.1399-5448.2008.00450.x. Epub 2008 Aug 20.
• Background Moreau KL, Donato AJ, Seals DR, DeSouza CA, Tanaka H. Regular exercise, hormone replacement therapy and the age-related decline in carotid arterial compliance in healthy women. Cardiovasc Res. 2003 Mar;57(3):861-8. doi: 10.1016/s0008-6363(02)00777-0.
• Background Ekstrand AV, Groop PH, Gronhagen-Riska C. Insulin resistance precedes microalbuminuria in patients with insulin-dependent diabetes mellitus. Nephrol Dial Transplant. 1998 Dec;13(12):3079-83. doi: 10.1093/ndt/13.12.3079.
• Background DeFronzo RA, Simonson D, Ferrannini E. Hepatic and peripheral insulin resistance: a common feature of type 2 (non-insulin-dependent) and type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1982 Oct;23(4):313-9. doi: 10.1007/BF00253736.
• Background Van Pelt RE, Gozansky WS, Hickner RC, Schwartz RS, Kohrt WM. Acute modulation of adipose tissue lipolysis by intravenous estrogens. Obesity (Silver Spring). 2006 Dec;14(12):2163-72. doi: 10.1038/oby.2006.253.
• Background Druet C, Tubiana-Rufi N, Chevenne D, Rigal O, Polak M, Levy-Marchal C. Characterization of insulin secretion and resistance in type 2 diabetes of adolescents. J Clin Endocrinol Metab. 2006 Feb;91(2):401-4. doi: 10.1210/jc.2005-1672. Epub 2005 Nov 15.
• Background Gilker CD, Pesola GR, Matthews DE. A mass spectrometric method for measuring glycerol levels and enrichments in plasma using 13C and 2H stable isotopic tracers. Anal Biochem. 1992 Aug 15;205(1):172-8. doi: 10.1016/0003-2697(92)90595-x.
• Background STEELE R. Influences of glucose loading and of injected insulin on hepatic glucose output. Ann N Y Acad Sci. 1959 Sep 25;82:420-30. doi: 10.1111/j.1749-6632.1959.tb44923.x. No abstract available.
• Background Finegood DT, Bergman RN, Vranic M. Estimation of endogenous glucose production during hyperinsulinemic-euglycemic glucose clamps. Comparison of unlabeled and labeled exogenous glucose infusates. Diabetes. 1987 Aug;36(8):914-24. doi: 10.2337/diab.36.8.914.
• Background Kamel EG, McNeill G, Han TS, Smith FW, Avenell A, Davidson L, Tothill P. Measurement of abdominal fat by magnetic resonance imaging, dual-energy X-ray absorptiometry and anthropometry in non-obese men and women. Int J Obes Relat Metab Disord. 1999 Jul;23(7):686-92. doi: 10.1038/sj.ijo.0800904.
• Background Sarnblad S, Kroon M, Aman J. Metformin as additional therapy in adolescents with poorly controlled type 1 diabetes: randomised placebo-controlled trial with aspects on insulin sensitivity. Eur J Endocrinol. 2003 Oct;149(4):323-9. doi: 10.1530/eje.0.1490323.
• Background Martin FI, Hopper JL. The relationship of acute insulin sensitivity to the progression of vascular disease in long-term type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1987 Mar;30(3):149-53. doi: 10.1007/BF00274219.
• Background Regensteiner JG, Sippel J, McFarling ET, Wolfel EE, Hiatt WR. Effects of non-insulin-dependent diabetes on oxygen consumption during treadmill exercise. Med Sci Sports Exerc. 1995 Jun;27(6):875-81.
• Cree-Green M, Bergman BC, Cengiz E, Fox LA, Hannon TS, Miller K, Nathan B, Pyle L, Kahn D, Tansey M, Tichy E, Tsalikian E, Libman I, Nadeau KJ. Metformin Improves Peripheral Insulin Sensitivity in Youth With Type 1 Diabetes. J Clin Endocrinol Metab. 2019 Aug 1;104(8):3265-3278. doi: 10.1210/jc.2019-00129.

Drugs

Indications