Clinical trial NCT02230839: Muscle Insulin Resistance in Aging (Mirage)
Official title: Muscle Insulin Resistance In Aging
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Insulin Resistance
Sarcopenia
Keywords: insulin resistance
muscle
health education
exercise
Lead sponsor: AdventHealth Translational Research Institute
Sponsor class: OTHER
First posted: 2014-09-03
Enrollment: 200
Sex: ALL
Minimum age (years): 65
Maximum age (years): 80
Standard ages: OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: The purpose of this study is to provide information regarding potential factors underlying metabolic dysfunction, insulin resistance, and loss of muscle mass in aging muscle.

Detailed description: Study Objectives:

1. To determine the effects of diet-induced weight loss with and without the addition of exercise on mitochondrial biogenesis and energetic capacity, cellular redox state and insulin resistance.
2. To determine the effects of diet-induced weight loss with and without the addition of exercise on intramyocellular lipid profiles.
3. To determine the effects of diet-induced weight loss with and without exercise on skeletal muscle proteins mediating a program of autophagy and either loss or maintenance of muscle mass.

Eligibility criteria: Inclusion Criteria:

* 65-80 years of age
* Stable weight (No Gain/Loss of \>10 lbs in 6 months)
* Sedentary (≤ 1 continuous exercise/week)
* Non-smoker
* BMI ≥ 30 kg/m2
* Resting Blood Pressure ≤ 150 millimeters of mercury systolic and ≤ 95 millimeters of mercury diastolic
* Note from Primary care physician/Cardiologist for exercise clearance if positive stress test symptoms were observed from exercise test
* Must be willing to washout for 14 days from all diabetes medication and independent in self blood glucose monitoring during the washout periods (those with diabetes only)

Exclusion Criteria:

* Clinically significant cardiovascular disease including history of myocardial infarction, within the past year
* Peripheral Vascular Disease
* Hepatic, renal, muscular/neuromuscular, or active hematologic/oncologic disease
* Clinically diminished pulse
* Presence of bruits in lower extremities
* Previous history of pulmonary emboli
* Peripheral Neuropathy

Primary outcomes:
measure: Measure of intramyocellular lipids
timeFrame: Visit 3 ~22 hours
Secondary outcomes:
measure: Measure of insulin sensitivity
timeFrame: Visit 3 ~22 hours
Other outcomes:
measure: Measure muscle strength and power
timeFrame: Visit 2 (baseline) and 6 months
Locations:
city: Orlando
country: United States
facility: Translational Research Institute for Metabolism and Diabetes
state: Florida
Study officials:
affiliation: Translational Research Institute for Metabolism and Diabetes
name: Bret Goodpaster, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Evans W. Functional and metabolic consequences of sarcopenia. J Nutr. 1997 May;127(5 Suppl):998S-1003S. doi: 10.1093/jn/127.5.998S.
citation: Evans WJ, Campbell WW. Sarcopenia and age-related changes in body composition and functional capacity. J Nutr. 1993 Feb;123(2 Suppl):465-8. doi: 10.1093/jn/123.suppl_2.465.
citation: Rosenberg IH. Sarcopenia: origins and clinical relevance. J Nutr. 1997 May;127(5 Suppl):990S-991S. doi: 10.1093/jn/127.5.990S.
citation: Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ, Flegal KM. Prevalence of overweight and obesity in the United States, 1999-2004. JAMA. 2006 Apr 5;295(13):1549-55. doi: 10.1001/jama.295.13.1549.
citation: Villareal DT, Apovian CM, Kushner RF, Klein S; American Society for Nutrition; NAASO, The Obesity Society. Obesity in older adults: technical review and position statement of the American Society for Nutrition and NAASO, The Obesity Society. Am J Clin Nutr. 2005 Nov;82(5):923-34. doi: 10.1093/ajcn/82.5.923.
citation: Goodpaster BH, Carlson CL, Visser M, Kelley DE, Scherzinger A, Harris TB, Stamm E, Newman AB. Attenuation of skeletal muscle and strength in the elderly: The Health ABC Study. J Appl Physiol (1985). 2001 Jun;90(6):2157-65. doi: 10.1152/jappl.2001.90.6.2157.
citation: Park SW, Goodpaster BH, Lee JS, Kuller LH, Boudreau R, de Rekeneire N, Harris TB, Kritchevsky S, Tylavsky FA, Nevitt M, Cho YW, Newman AB; Health, Aging, and Body Composition Study. Excessive loss of skeletal muscle mass in older adults with type 2 diabetes. Diabetes Care. 2009 Nov;32(11):1993-7. doi: 10.2337/dc09-0264. Epub 2009 Jun 23.
citation: Petersen KF, Befroy D, Dufour S, Dziura J, Ariyan C, Rothman DL, DiPietro L, Cline GW, Shulman GI. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science. 2003 May 16;300(5622):1140-2. doi: 10.1126/science.1082889.
citation: Amati F, Dube JJ, Coen PM, Stefanovic-Racic M, Toledo FG, Goodpaster BH. Physical inactivity and obesity underlie the insulin resistance of aging. Diabetes Care. 2009 Aug;32(8):1547-9. doi: 10.2337/dc09-0267. Epub 2009 Apr 28.
citation: Kelley DE, Goodpaster B, Wing RR, Simoneau JA. Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity, and weight loss. Am J Physiol. 1999 Dec;277(6):E1130-41. doi: 10.1152/ajpendo.1999.277.6.E1130.
citation: Kelley DE, Mintun MA, Watkins SC, Simoneau JA, Jadali F, Fredrickson A, Beattie J, Theriault R. The effect of non-insulin-dependent diabetes mellitus and obesity on glucose transport and phosphorylation in skeletal muscle. J Clin Invest. 1996 Jun 15;97(12):2705-13. doi: 10.1172/JCI118724.
citation: Lillioja S, Bogardus C. Obesity and insulin resistance: lessons learned from the Pima Indians. Diabetes Metab Rev. 1988 Aug;4(5):517-40. doi: 10.1002/dmr.5610040508.
citation: Devlin JT. Effects of exercise on insulin sensitivity in humans. Diabetes Care. 1992 Nov;15(11):1690-3. doi: 10.2337/diacare.15.11.1690.
citation: Bogardus C. Insulin resistance in the pathogenesis of NIDDM in Pima Indians. Diabetes Care. 1993 Jan;16(1):228-31. doi: 10.2337/diacare.16.1.228.
citation: Haffner SM, Valdez RA, Hazuda HP, Mitchell BD, Morales PA, Stern MP. Prospective analysis of the insulin-resistance syndrome (syndrome X). Diabetes. 1992 Jun;41(6):715-22. doi: 10.2337/diab.41.6.715.
citation: Rizza RA, Mandarino LJ, Gerich JE. Mechanism and significance of insulin resistance in non-insulin-dependent diabetes mellitus. Diabetes. 1981 Dec;30(12):990-5. doi: 10.2337/diab.30.12.990.
citation: Chavez JA, Knotts TA, Wang LP, Li G, Dobrowsky RT, Florant GL, Summers SA. A role for ceramide, but not diacylglycerol, in the antagonism of insulin signal transduction by saturated fatty acids. J Biol Chem. 2003 Mar 21;278(12):10297-303. doi: 10.1074/jbc.M212307200. Epub 2003 Jan 13.
citation: Stratford S, Hoehn KL, Liu F, Summers SA. Regulation of insulin action by ceramide: dual mechanisms linking ceramide accumulation to the inhibition of Akt/protein kinase B. J Biol Chem. 2004 Aug 27;279(35):36608-15. doi: 10.1074/jbc.M406499200. Epub 2004 Jun 25.
citation: Turinsky J, O'Sullivan DM, Bayly BP. 1,2-Diacylglycerol and ceramide levels in insulin-resistant tissues of the rat in vivo. J Biol Chem. 1990 Oct 5;265(28):16880-5.
citation: Holland WL, Brozinick JT, Wang LP, Hawkins ED, Sargent KM, Liu Y, Narra K, Hoehn KL, Knotts TA, Siesky A, Nelson DH, Karathanasis SK, Fontenot GK, Birnbaum MJ, Summers SA. Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metab. 2007 Mar;5(3):167-79. doi: 10.1016/j.cmet.2007.01.002.
citation: Adams JM 2nd, Pratipanawatr T, Berria R, Wang E, DeFronzo RA, Sullards MC, Mandarino LJ. Ceramide content is increased in skeletal muscle from obese insulin-resistant humans. Diabetes. 2004 Jan;53(1):25-31. doi: 10.2337/diabetes.53.1.25.
citation: Itani SI, Ruderman NB, Schmieder F, Boden G. Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha. Diabetes. 2002 Jul;51(7):2005-11. doi: 10.2337/diabetes.51.7.2005.
citation: Bruce CR, Thrush AB, Mertz VA, Bezaire V, Chabowski A, Heigenhauser GJ, Dyck DJ. Endurance training in obese humans improves glucose tolerance and mitochondrial fatty acid oxidation and alters muscle lipid content. Am J Physiol Endocrinol Metab. 2006 Jul;291(1):E99-E107. doi: 10.1152/ajpendo.00587.2005. Epub 2006 Feb 7.
citation: Bergman BC, Perreault L, Hunerdosse DM, Koehler MC, Samek AM, Eckel RH. Increased intramuscular lipid synthesis and low saturation relate to insulin sensitivity in endurance-trained athletes. J Appl Physiol (1985). 2010 May;108(5):1134-41. doi: 10.1152/japplphysiol.00684.2009. Epub 2010 Mar 18.
citation: Perreault L, Bergman BC, Hunerdosse DM, Playdon MC, Eckel RH. Inflexibility in intramuscular triglyceride fractional synthesis distinguishes prediabetes from obesity in humans. Obesity (Silver Spring). 2010 Aug;18(8):1524-31. doi: 10.1038/oby.2009.454. Epub 2009 Dec 24.
citation: Bergman BC, Perreault L, Hunerdosse DM, Koehler MC, Samek AM, Eckel RH. Intramuscular lipid metabolism in the insulin resistance of smoking. Diabetes. 2009 Oct;58(10):2220-7. doi: 10.2337/db09-0481. Epub 2009 Jul 6.
citation: Lowell BB, Shulman GI. Mitochondrial dysfunction and type 2 diabetes. Science. 2005 Jan 21;307(5708):384-7. doi: 10.1126/science.1104343.
citation: Holloszy JO. "Deficiency" of mitochondria in muscle does not cause insulin resistance. Diabetes. 2013 Apr;62(4):1036-40. doi: 10.2337/db12-1107.
citation: Li J, Romestaing C, Han X, Li Y, Hao X, Wu Y, Sun C, Liu X, Jefferson LS, Xiong J, Lanoue KF, Chang Z, Lynch CJ, Wang H, Shi Y. Cardiolipin remodeling by ALCAT1 links oxidative stress and mitochondrial dysfunction to obesity. Cell Metab. 2010 Aug 4;12(2):154-65. doi: 10.1016/j.cmet.2010.07.003.
citation: Lee HY, Choi CS, Birkenfeld AL, Alves TC, Jornayvaz FR, Jurczak MJ, Zhang D, Woo DK, Shadel GS, Ladiges W, Rabinovitch PS, Santos JH, Petersen KF, Samuel VT, Shulman GI. Targeted expression of catalase to mitochondria prevents age-associated reductions in mitochondrial function and insulin resistance. Cell Metab. 2010 Dec 1;12(6):668-74. doi: 10.1016/j.cmet.2010.11.004.
citation: Reznick RM, Zong H, Li J, Morino K, Moore IK, Yu HJ, Liu ZX, Dong J, Mustard KJ, Hawley SA, Befroy D, Pypaert M, Hardie DG, Young LH, Shulman GI. Aging-associated reductions in AMP-activated protein kinase activity and mitochondrial biogenesis. Cell Metab. 2007 Feb;5(2):151-6. doi: 10.1016/j.cmet.2007.01.008.
citation: Masiero E, Agatea L, Mammucari C, Blaauw B, Loro E, Komatsu M, Metzger D, Reggiani C, Schiaffino S, Sandri M. Autophagy is required to maintain muscle mass. Cell Metab. 2009 Dec;10(6):507-15. doi: 10.1016/j.cmet.2009.10.008.
citation: Wenz T, Rossi SG, Rotundo RL, Spiegelman BM, Moraes CT. Increased muscle PGC-1alpha expression protects from sarcopenia and metabolic disease during aging. Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20405-10. doi: 10.1073/pnas.0911570106. Epub 2009 Nov 16.
citation: Romanello V, Guadagnin E, Gomes L, Roder I, Sandri C, Petersen Y, Milan G, Masiero E, Del Piccolo P, Foretz M, Scorrano L, Rudolf R, Sandri M. Mitochondrial fission and remodelling contributes to muscle atrophy. EMBO J. 2010 May 19;29(10):1774-85. doi: 10.1038/emboj.2010.60. Epub 2010 Apr 16.
citation: Civitarese AE, Carling S, Heilbronn LK, Hulver MH, Ukropcova B, Deutsch WA, Smith SR, Ravussin E; CALERIE Pennington Team. Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. PLoS Med. 2007 Mar;4(3):e76. doi: 10.1371/journal.pmed.0040076.
citation: Fontana L, Villareal DT, Weiss EP, Racette SB, Steger-May K, Klein S, Holloszy JO; Washington University School of Medicine CALERIE Group. Calorie restriction or exercise: effects on coronary heart disease risk factors. A randomized, controlled trial. Am J Physiol Endocrinol Metab. 2007 Jul;293(1):E197-202. doi: 10.1152/ajpendo.00102.2007. Epub 2007 Mar 27.
citation: Heilbronn LK, de Jonge L, Frisard MI, DeLany JP, Larson-Meyer DE, Rood J, Nguyen T, Martin CK, Volaufova J, Most MM, Greenway FL, Smith SR, Deutsch WA, Williamson DA, Ravussin E; Pennington CALERIE Team. Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: a randomized controlled trial. JAMA. 2006 Apr 5;295(13):1539-48. doi: 10.1001/jama.295.13.1539.
citation: Santanasto AJ, Glynn NW, Newman MA, Taylor CA, Brooks MM, Goodpaster BH, Newman AB. Impact of weight loss on physical function with changes in strength, muscle mass, and muscle fat infiltration in overweight to moderately obese older adults: a randomized clinical trial. J Obes. 2011;2011:516576. doi: 10.1155/2011/516576. Epub 2010 Oct 10.
citation: Messier SP, Loeser RF, Mitchell MN, Valle G, Morgan TP, Rejeski WJ, Ettinger WH. Exercise and weight loss in obese older adults with knee osteoarthritis: a preliminary study. J Am Geriatr Soc. 2000 Sep;48(9):1062-72. doi: 10.1111/j.1532-5415.2000.tb04781.x.
citation: Weiss EP, Racette SB, Villareal DT, Fontana L, Steger-May K, Schechtman KB, Klein S, Ehsani AA, Holloszy JO; Washington University School of Medicine CALERIE Group. Lower extremity muscle size and strength and aerobic capacity decrease with caloric restriction but not with exercise-induced weight loss. J Appl Physiol (1985). 2007 Feb;102(2):634-40. doi: 10.1152/japplphysiol.00853.2006. Epub 2006 Nov 9.
citation: Goodpaster BH, He J, Watkins S, Kelley DE. Skeletal muscle lipid content and insulin resistance: evidence for a paradox in endurance-trained athletes. J Clin Endocrinol Metab. 2001 Dec;86(12):5755-61. doi: 10.1210/jcem.86.12.8075.
citation: Kelley DE, He J, Menshikova EV, Ritov VB. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes. 2002 Oct;51(10):2944-50. doi: 10.2337/diabetes.51.10.2944.
citation: Ritov VB, Menshikova EV, Kelley DE. Analysis of cardiolipin in human muscle biopsy. J Chromatogr B Analyt Technol Biomed Life Sci. 2006 Feb 2;831(1-2):63-71. doi: 10.1016/j.jchromb.2005.11.031. Epub 2005 Dec 6.
citation: Ritov VB, Menshikova EV, Kelley DE. High-performance liquid chromatography-based methods of enzymatic analysis: electron transport chain activity in mitochondria from human skeletal muscle. Anal Biochem. 2004 Oct 1;333(1):27-38. doi: 10.1016/j.ab.2004.05.014.
citation: Dube JJ, Amati F, Stefanovic-Racic M, Toledo FG, Sauers SE, Goodpaster BH. Exercise-induced alterations in intramyocellular lipids and insulin resistance: the athlete's paradox revisited. Am J Physiol Endocrinol Metab. 2008 May;294(5):E882-8. doi: 10.1152/ajpendo.00769.2007. Epub 2008 Mar 4.
citation: Goodpaster BH, Katsiaras A, Kelley DE. Enhanced fat oxidation through physical activity is associated with improvements in insulin sensitivity in obesity. Diabetes. 2003 Sep;52(9):2191-7. doi: 10.2337/diabetes.52.9.2191.
citation: Pruchnic R, Katsiaras A, He J, Kelley DE, Winters C, Goodpaster BH. Exercise training increases intramyocellular lipid and oxidative capacity in older adults. Am J Physiol Endocrinol Metab. 2004 Nov;287(5):E857-62. doi: 10.1152/ajpendo.00459.2003. Epub 2004 Jun 29.
citation: Dube JJ, Amati F, Toledo FG, Stefanovic-Racic M, Rossi A, Coen P, Goodpaster BH. Effects of weight loss and exercise on insulin resistance, and intramyocellular triacylglycerol, diacylglycerol and ceramide. Diabetologia. 2011 May;54(5):1147-56. doi: 10.1007/s00125-011-2065-0. Epub 2011 Feb 17.
citation: Goodpaster BH, Chomentowski P, Ward BK, Rossi A, Glynn NW, Delmonico MJ, Kritchevsky SB, Pahor M, Newman AB. Effects of physical activity on strength and skeletal muscle fat infiltration in older adults: a randomized controlled trial. J Appl Physiol (1985). 2008 Nov;105(5):1498-503. doi: 10.1152/japplphysiol.90425.2008. Epub 2008 Sep 25.
citation: LIFE Study Investigators; Pahor M, Blair SN, Espeland M, Fielding R, Gill TM, Guralnik JM, Hadley EC, King AC, Kritchevsky SB, Maraldi C, Miller ME, Newman AB, Rejeski WJ, Romashkan S, Studenski S. Effects of a physical activity intervention on measures of physical performance: Results of the lifestyle interventions and independence for Elders Pilot (LIFE-P) study. J Gerontol A Biol Sci Med Sci. 2006 Nov;61(11):1157-65. doi: 10.1093/gerona/61.11.1157.
citation: Goodpaster BH, Theriault R, Watkins SC, Kelley DE. Intramuscular lipid content is increased in obesity and decreased by weight loss. Metabolism. 2000 Apr;49(4):467-72. doi: 10.1016/s0026-0495(00)80010-4.
citation: Gnaiger E. Capacity of oxidative phosphorylation in human skeletal muscle: new perspectives of mitochondrial physiology. Int J Biochem Cell Biol. 2009 Oct;41(10):1837-45. doi: 10.1016/j.biocel.2009.03.013. Epub 2009 Apr 2.
citation: Hutter E, Unterluggauer H, Garedew A, Jansen-Durr P, Gnaiger E. High-resolution respirometry--a modern tool in aging research. Exp Gerontol. 2006 Jan;41(1):103-9. doi: 10.1016/j.exger.2005.09.011. Epub 2005 Nov 23.
citation: Goodpaster BH, Kelley DE, Wing RR, Meier A, Thaete FL. Effects of weight loss on regional fat distribution and insulin sensitivity in obesity. Diabetes. 1999 Apr;48(4):839-47. doi: 10.2337/diabetes.48.4.839.
citation: Goodpaster BH, Thaete FL, Kelley DE. Thigh adipose tissue distribution is associated with insulin resistance in obesity and in type 2 diabetes mellitus. Am J Clin Nutr. 2000 Apr;71(4):885-92. doi: 10.1093/ajcn/71.4.885.
citation: Toledo FG, Menshikova EV, Ritov VB, Azuma K, Radikova Z, DeLany J, Kelley DE. Effects of physical activity and weight loss on skeletal muscle mitochondria and relationship with glucose control in type 2 diabetes. Diabetes. 2007 Aug;56(8):2142-7. doi: 10.2337/db07-0141. Epub 2007 May 29.
citation: Toledo FG, Watkins S, Kelley DE. Changes induced by physical activity and weight loss in the morphology of intermyofibrillar mitochondria in obese men and women. J Clin Endocrinol Metab. 2006 Aug;91(8):3224-7. doi: 10.1210/jc.2006-0002. Epub 2006 May 9.
citation: Bielawski J, Szulc ZM, Hannun YA, Bielawska A. Simultaneous quantitative analysis of bioactive sphingolipids by high-performance liquid chromatography-tandem mass spectrometry. Methods. 2006 Jun;39(2):82-91. doi: 10.1016/j.ymeth.2006.05.004.
citation: Sun D, Cree MG, Wolfe RR. Quantification of the concentration and 13C tracer enrichment of long-chain fatty acyl-coenzyme A in muscle by liquid chromatography/mass spectrometry. Anal Biochem. 2006 Feb 1;349(1):87-95. doi: 10.1016/j.ab.2005.10.006. Epub 2005 Oct 26.
citation: Jubrias SA, Crowther GJ, Shankland EG, Gronka RK, Conley KE. Acidosis inhibits oxidative phosphorylation in contracting human skeletal muscle in vivo. J Physiol. 2003 Dec 1;553(Pt 2):589-99. doi: 10.1113/jphysiol.2003.045872. Epub 2003 Sep 26.
citation: Blei ML, Conley KE, Kushmerick MJ. Separate measures of ATP utilization and recovery in human skeletal muscle. J Physiol. 1993 Jun;465:203-22. doi: 10.1113/jphysiol.1993.sp019673.