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John P. Kirwan, Ph.D.
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Research Programs:
My laboratory focuses on discovering physiological and cellular mechanisms that cause insulin resistance, diabetes, and obesity and contribute to regulating human performance.
Increasing exercise and modifying diet are first-line treatments for insulin resistance and diabetes. We found that the combination of exercise and a low glycemic diet is three times more effective at reversing insulin resistance than standard exercise and diet therapy. Our ongoing NIH-funded clinical study examines the underlying cellular mechanisms that may explain these observations.
These studies combine clinical measures of insulin resistance (clamp infusions, tracer isotopes, glucose tolerance testing), body composition (dual-energy X-ray absorptiometry, computed tomographic scanning, magnetic resonance imaging) and exercise (VO2max testing) with cellular measures (protein and mRNA expression, enzyme activity, insulin signaling) in skeletal muscle and adipose tissue samples. Our clinical studies are conducted in Cleveland Clinic’s General Clinical Research Center; bench analyses are performed in the Institute.
In addition to our exercise/diet studies in older adults, we are working on research questions related to lipid-induced insulin resistance (in vivo and in silico) and on energy metabolism and insulin resistance in conditions such as the metabolic syndrome, fatty liver disease, colon cancer, and hepatitis C and in bariatric surgery.
Work is also ongoing to develop a new in vitro model to measure the metabolic effects of contraction in muscle cells (exercise in a Petri dish!).
Specific Projects:
- Aging and Insulin Resistance
- Role of Exercise and Nutrition in Reversing Insulin Resistance in Skeletal Muscle
- Insulin Signaling Pathways in Skeletal Muscle
- In Vitro Cell Models of Skeletal Muscle Insulin Resistance
- In Silico Models of Skeletal Muscle Insulin Resistance
- Role of Inflammation in Insulin Resistance and Type 2 Diabetes
- Biomarkers of Insulin Resistance and Type 2 Diabetes
- Insulin Resistence and Fatty Liver Disease
- Obesity and the Metabolic Effects of Bariatric Surgery
Investigators:
- Marc Cook, M.Sc., Exercise Physiologist
- Ciaran Fealy, Undergraduate Research Student
- Julianne Filion, B.Sc., R.N., Clinical Research Nurse Coordinator
- Jacob Haus, Postdoctoral Fellow
- Hazel Huang, M.Sc., Lead Technologist
- Karen Kelly, Postdoctoral Fellow
- Takhar Kasumov, Staff
- Yanjun Li, M.S. (BME), Graduate Student
- Aimee Patrick-Melin, M.Sc., Graduate Student
- Thomas Solomon, Ph.D., Postdoctoral Fellow
Collaborators
- Hope Barkoukis, Ph.D., Dept. of Nutrition, CASE
- Chris Flask, Ph.D., Dept. of Radiology, CASE
- Art McCullough, Dept. of Gastroenterology/Hepatology, CCF
- Nizar Zein, M.D., Dept. of Gastroenterology/Hepatology, CCF
- Srinivasan Dasarathy, M.D., Dept. of Gastroenterology/Hepatology, CCF
- Gerry Saidel, Ph.D., Dept. of Biomedical Engineering, CASE
- Marco Cabrera, Ph.D., Dept. of Pediatrics, CASE
- Sangeeta Kashyap, M.D., Dept. of Endocrinology, CCF
- Nora Nock, Ph.D., Dept. of Epidemiology and Biostatistics, CASE
- Claudia Zein, M.D., Dept. of Gastroenterology, VA
- Patrick Catalano, M.D., Dept of Ob/Gyn, MetroHealth
- Jed Friedman, Ph.D., Dept. of Peds., Biochem. & Molec. Gen., Univ of Colorado, Aurora
- Ted Ciaraldi, Ph.D., Dept. of Endocrinology, Univ California, San Diego
- Michael Kalinski, Ph.D., School of Exercise, Kent State Univ.
- Ken Sparks, Dept of Exercise Physiology, Cleveland State University
- Richard Hanson, Dept. of Biochemistry, CASE
- Charles Hoppel, Dept. of Pharmacology, CASE
Grant Support:
- National Institutes of Health - R01 AG12834-08
Age, Exercise, Diet: Effects on Insulin Resistance
This study will determine the effects of high- and low-glycemic diets combined with exercise on insulin resistance, body composition and skeletal muscle insulin signaling in elderly obese men and women. - National Institutes of Health - U54CA116867 - PILOT GRANT (PI:Nock)
Improving Energy Balance Assessment Using Biomarkers and Genetic Determinants of Resting Metabolic Rate (RMR)
This is a pilot study to generate preliminary data aimed at determining genetic profiles that predict obesity-related cancers. - National Istitutes of Health - U54CA116867 - PILOT GRANT (PI: Thompson)
Retinol Binding Protein-4 (RBP4): A Novel Biomarker for Colon Neoplasia
This is a pilot study to generate preliminary data aimed at determining genetic profiles that predict obesity-related cancers.
Key References:
Gonzalez, F., J. Minium, N.S. Rote, and J.P. Kirwan. Reactive oxygen species induced oxidative stress in the development of insulin resistance and hyperandrogenism in polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 91: 336-340, 2006. PDF
O’Leary, V.B., C.M. Marchetti, R.K. Krishnan, B.P. Stetzer, F. Gonzalez, and J.P. Kirwan. Exercise-induced reversal of insulin resistance in obese elderly is associated with reduced visceral fat. J. Appl. Physiol. 100: 1584-1589, 2006. PDF
O’Connor, A.M., S. Pola, B.M. Ward, D. Fillmore, K.D. Buchanan, and J.P. Kirwan. The gastroenteroinsular response to glucose ingestion during postexercise recovery. Am. J. Physiol. Endocrinol. Metab. 290: E1155-1161, 2006. PDF
Gonzalez, F., J. Minium, N.S. Rote, and J.P. Kirwan. Increased activation of nuclear factor kB may trigger inflammation and insulin resistance in polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 91: 1508-1512, 2006. PDF
Volek, J.S., R. Silvestre, J.P. Kirwan, M.J. Sharman, D.A. Judelson, B.A. Spiering, J.L. Vingren, C.M. Maresh, J.L. VanHeest, and W.J. Kraemer. Effects of chromium supplementation on glycogen synthesis after high-intensity exercise. Med. Sci. Sports Exerc. 38: 1-9, 2006. PDF
Kim, J., G.M. Saidel, J.P. Kirwan, and M.E. Cabrera. Computational model of glucose homeostasis during exercise. Conf Proc IEEE Eng Med Biol Soc. 1: 311-4, 2006.
O’Leary, V.B., A.E. Nardi, C.M. Marchetti, F. Gonzalez, S.A. Phillips, T.P. Ciaraldi, and J.P. Kirwan. Enhanced adiponectin multimer ratio and skeletal muscle adiponectin receptor expression following exercise training and diet in older insulin resistant adults. Am. J. Physiol. Endocrinol. Metab. 293: E421-E427, 2007. PDF
Barbour, L.A., C.E. McCurdy, T.L. Hernandez, J.P. Kirwan, P.M. Catalano, and J.E. Friedman. Cellular mechanisms of insulin resistance in normal pregnancy and gestational diabetes. Diabetes Care. Suppl 2: S112-S119, 2007. PDF
Hakimi, P., J. Yang, G. Casadesus, D. Massillon, F. Tolentino-Silva, C.K. Nye, M.E. Cabrera, D.R. Hagen, C.B. Utter, Y. Baghdy, D.H. Johnson, D.L. Wilson, J.P. Kirwan, S.C. Kalhan, and R.W. Hanson. Over-expression of the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) in skeletal muscle repatterns energy metabolism in the mouse. J. Biol. Chem. 282: 32844-55, 2007. PDF
Gonzalez, F., N.S. Rote, J. Minium, V.B. O’Leary, and J.P. Kirwan. Obese reproductive age women exhibit a proatherogenic inflammatory response to hyperglycemia. Obesity. 15: 2436-2444, 2007.
Barkoukis, H, C.M. Marchetti, B. Nolan, S.N. Sistrun, R.K. Krishnan, and J.P. Kirwan. A high glycemic meal suppresses the postprandial leptin response in normal healthy adults. Ann. Nutr. Metab. 51: 512-518, 2007. PDF
Friedman, J.E., J.P. Kirwan, M. Jing, L. Presley, and P.M. Catalano. Increased skeletal muscle TNF-a and impaired insulin signaling persists in obese GDM women 1 year postpartum. Diabetes. 57:606-13, 2008. PDF
Solomon TP, Marchetti CM, Krishnan RK, Gonzalez F, Kirwan JP.Effects of aging on basal fat oxidation in obese humans. Metabolism. 57(8):1141-7, 2008. PDF
Solomon TP, Sistrun SN, Krishnan RK, Del Aguila LF, Marchetti CM, O'Carroll SM, O'Leary VB, Kirwan JP.Exercise and diet enhance fat oxidation and reduce insulin resistance in older obese adults. J Appl Physiol. 104(5):1313-9, 2008. PDF