Insulin resistance in adolescents with type 2 diabetes is associated with impaired exercise capacity.

CONTEXT The incidence of pediatric type 2 diabetes (T2D) is rising, with unclear effects on the cardiovascular system. Cardiopulmonary fitness, a marker of morbidity and mortality, is abnormal in adults with T2D, yet the mechanisms are incompletely understood. OBJECTIVE We hypothesized that cardiopulmonary fitness would be reduced in youth with T2D in association with insulin resistance (IR) and cardiovascular dysfunction. DESIGN, SETTING, AND PARTICIPANTS We conducted a cross-sectional study at an academic hospital that included 14 adolescents (age range, 12-19 yr) with T2D, 13 equally obese adolescents and 12 lean adolescents similar in age, pubertal stage, and activity level. MAIN OUTCOME MEASURES Cardiopulmonary fitness was measured by peak oxygen consumption (VO(2)peak) and oxygen uptake kinetics (VO(2)kinetics), IR by hyperinsulinemic clamp, cardiac function by echocardiography, vascular function by venous occlusion plethysmography, body composition by dual-energy x-ray absorptiometry, intramyocellular lipid by magnetic resonance spectroscopy, and inflammation by serum markers. RESULTS Adolescents with T2D had significantly decreased VO(2)peak and insulin sensitivity, and increased soleus intramyocellular lipid, C-reactive protein, and IL-6 compared to obese or lean adolescents. Adolescents with T2D also had significantly prolonged VO(2)kinetics, decreased work rate, vascular reactivity, and adiponectin, and increased left ventricular mass and fatty acids compared to lean adolescents. In multivariate linear regression analysis, IR primarily, and fasting free fatty acids and forearm blood flow secondarily, were significant independent predictors of VO(2)peak. CONCLUSIONS Given the strong relationship between decreased cardiopulmonary fitness and increased mortality, these findings in children are especially concerning and represent early signs of impaired cardiac function.

[1]  J. Hirsch,et al.  Reproducibility of single‐ and multi‐voxel 1H MRS measurements of intramyocellular lipid in overweight and lean subjects under conditions of controlled dietary calorie and fat intake , 2008, NMR in biomedicine.

[2]  J. Baldi,et al.  Impaired stroke volume and aerobic capacity in female adolescents with type 1 and type 2 diabetes mellitus , 2008, Diabetologia.

[3]  S. Daniels,et al.  Reversibility of cardiac abnormalities in morbidly obese adolescents. , 2008, Journal of the American College of Cardiology.

[4]  B. Braun,et al.  Impact of metformin on peak aerobic capacity. , 2008, Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme.

[5]  D. Allison,et al.  Intramyocellular lipid content is lower with a low-fat diet than with high-fat diets, but that may not be relevant for health. , 2007, The American journal of clinical nutrition.

[6]  T. Dresselaers,et al.  Evaluation of intramyocellular lipid breakdown during exercise by biochemical assay, NMR spectroscopy, and Oil Red O staining. , 2007, American journal of physiology. Endocrinology and metabolism.

[7]  P. Schrauwen.  High-fat diet, muscular lipotoxicity and insulin resistance , 2007, Proceedings of the Nutrition Society.

[8]  R. Schrier,et al.  Exercise capacity is a predictor of cardiovascular events in patients with type 2 diabetes mellitus , 2006, Diabetes & vascular disease research.

[9]  R. Doughty,et al.  The effect of type 2 diabetes on diastolic function. , 2006, Medicine and science in sports and exercise.

[10]  G. Boden.  Fatty acid—induced inflammation and insulin resistance in skeletal muscle and liver , 2006, Current diabetes reports.

[11]  J. Regensteiner,et al.  Rosiglitazone improves exercise capacity in individuals with type 2 diabetes. , 2005, Diabetes care.

[12]  J. Rimmer,et al.  Cardiovascular Endurance and Heart Rate Variability in Adolescents With Type 1 or Type 2 Diabetes , 2005, Biological research for nursing.

[13]  M. Goran,et al.  Cardiovascular fitness and the metabolic syndrome in overweight latino youths. , 2005, Medicine and science in sports and exercise.

[14]  Philip Zeitler,et al.  The global spread of type 2 diabetes mellitus in children and adolescents. , 2005, The Journal of pediatrics.

[15]  R. Kreis,et al.  Distribution of intramyocellular lipids in human calf muscles as determined by MR spectroscopic imaging , 2004, Magnetic resonance in medicine.

[16]  M. A. Ferguson,et al.  Intramyocellular lipid changes in men and women during aerobic exercise: a (1)H-magnetic resonance spectroscopy study. , 2003, The Journal of clinical endocrinology and metabolism.

[17]  S. Jaradeh,et al.  Evaluation of the autonomic nervous system. , 2003, Physical medicine and rehabilitation clinics of North America.

[18]  F. Schick,et al.  Intramyocellular lipids: anthropometric determinants and relationships with maximal aerobic capacity and insulin sensitivity. , 2003, The Journal of clinical endocrinology and metabolism.

[19]  K. Petersen,et al.  Assessment of skeletal muscle triglyceride content by (1)H nuclear magnetic resonance spectroscopy in lean and obese adolescents: relationships to insulin sensitivity, total body fat, and central adiposity. , 2002, Diabetes.

[20]  Thomas W. Storer,et al.  Exercise Testing and Interpretation: A Practical Approach , 2001 .

[21]  D. Molnár,et al.  Low physical performance in obese adolescent boys with metabolic syndrome , 2001, International Journal of Obesity.

[22]  S Mierisová,et al.  MR spectroscopy quantitation: a review of frequency domain methods , 2001, NMR in biomedicine.

[23]  S. Provencher.  Automatic quantitation of localized in vivo 1H spectra with LCModel , 2001, NMR in biomedicine.

[24]  Steven Blair,et al.  Low Cardiorespiratory Fitness and Physical Inactivity as Predictors of Mortality in Men with Type 2 Diabetes , 2000, Annals of Internal Medicine.

[25]  P. Scifo,et al.  Intramyocellular triglyceride content is a determinant of in vivo insulin resistance in humans: a 1H-13C nuclear magnetic resonance spectroscopy assessment in offspring of type 2 diabetic parents. , 1999, Diabetes.

[26]  Elizabeth J. Mayer-Davis,et al.  Validity and reproducibility of a food frequency interview in a Multi-Cultural Epidemiology Study. , 1999, Annals of epidemiology.

[27]  P. Tothill,et al.  Measurement of abdominal fat by magnetic resonance imaging, dual-energy X-ray absorptiometry and anthropometry in non-obese men and women , 1999, International Journal of Obesity.

[28]  G. Borg.  Borg's Perceived Exertion and Pain Scales , 1998 .

[29]  R. Eckel,et al.  Abnormal oxygen uptake kinetic responses in women with type II diabetes mellitus. , 1998, Journal of applied physiology.

[30]  P. Mortimer,et al.  Forearm blood flow measured by venous occlusion plethysmography in healthy subjects and in women with postmastectomy oedema , 1998, Vascular medicine.

[31]  C Boesch,et al.  In vivo determination of intra‐myocellular lipids in human muscle by means of localized 1H‐MR‐spectroscopy , 1997, Magnetic resonance in medicine.

[32]  Randolph P. Martin,et al.  Canadian consensus recommendations for the measurement and reporting of diastolic dysfunction by echocardiography: from the Investigators of Consensus on Diastolic Dysfunction by Echocardiography. , 1996, Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography.

[33]  S. Daniels,et al.  Increased incidence of non-insulin-dependent diabetes mellitus among adolescents. , 1996, The Journal of pediatrics.

[34]  R. Eckel,et al.  Relationship Between Habitual Physical Activity and Insulin Area Among Individuals With Impaired Glucose Tolerance: The San Luis Valley Diabetes Study , 1995, Diabetes Care.

[35]  D. Jullien,et al.  Abnormalities suggestive of cardiomyopathy in patients with type 2 diabetes of relatively short duration. , 1994, Diabete & metabolisme.

[36]  S. Provencher.  Estimation of metabolite concentrations from localized in vivo proton NMR spectra , 1993, Magnetic resonance in medicine.

[37]  F Schick,et al.  Comparison of localized proton NMR signals of skeletal muscle and fat tissue in vivo: Two lipid compartments in muscle tissue , 1993, Magnetic resonance in medicine.

[38]  S. Daniels,et al.  Left ventricular mass and body size in normotensive children and adults: assessment of allometric relations and impact of overweight. , 1992, Journal of the American College of Cardiology.

[39]  G. D. Johnston,et al.  Impaired endothelium-dependent and independent vasodilation in patients with Type 2 (non-insulin-dependent) diabetes mellitus , 1992, Diabetologia.

[40]  D. Molnár,et al.  The effect of fasting hyperinsulinaemia on physical fitness in obese children , 1990, European Journal of Pediatrics.

[41]  R. DeFronzo,et al.  Glucose clamp technique: a method for quantifying insulin secretion and resistance. , 1979, The American journal of physiology.

[42]  W L Beaver,et al.  Anaerobic threshold and respiratory gas exchange during exercise. , 1973, Journal of applied physiology.

[43]  J. Regensteiner,et al.  Skeletal Muscle Deoxygenation Following the Onset of Moderate Exercise Suggests Slowed Microvascular Blood Flow Kinetics in Type 2 Diabetes , 2007 .

[44]  M. Goran,et al.  Insulin sensitivity, cardiorespiratory fitness, and physical activity in overweight Hispanic youth. , 2004, Obesity research.

[45]  J. Harrell,et al.  Effects of improvement in aerobic power on resting insulin and glucose concentrations in children , 2000, European Journal of Applied Physiology.

[46]  R. Pate,et al.  Validation of an instrument for measurement of physical activity in youth. , 1997, Medicine and science in sports and exercise.