Insulin Resistance in Adolescents with Type 2 Diabetes Is Associated with Impaired Exercise Capacity
ABSTRACT 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.
We hypothesized that cardiopulmonary fitness would be reduced in youth with T2D in association with insulin resistance (IR) and cardiovascular dysfunction.
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.
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.
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.
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.
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ABSTRACT: Cardiovascular disease risk and all-cause mortality is largely predicted by physical fitness. Exercise stimulates vascular mitochondrial biogenesis via endothelial nitric oxide synthase (eNOS), sirtuins (SIRTs), and PPARγ co-activator 1 alpha (PGC-1α), a response absent in diabetes and hypertension. We hypothesized that an agent regulating eNOS in the context of diabetes could reconstitute exercise mediated signaling to mitochondrial biogenesis. Glucagon-like peptide 1 (GLP-1) stimulates eNOS and blood flow; we employed saxagliptin, an inhibitor of GLP-1 degradation, to test whether vascular mitochondrial adaptation to exercise in diabetes could be restored. Goto-Kakizaki (GK) rats, a non-obese, type 2 diabetes model, and Wistar controls were exposed to an 8-day exercise intervention with or without saxagliptin (10mg/kg/d). We evaluated the impact of exercise and saxagliptin on mitochondrial proteins and signaling pathways in aorta. Mitochondrial protein expression increased with exercise in the Wistar aorta, and decreased or remained unchanged in the GK animals. GK rats treated with saxagliptin plus exercise showed increased expression of mitochondrial complexes, cytochrome c, eNOS, nNOS, PGC-1α, and UCP3 proteins. Notably, a three week saxagliptin plus exercise intervention significantly increased running time in the GK rats. These data suggest that saxagliptin restores vascular mitochondrial adaptation to exercise in a diabetic rodent model and may augment the impact of exercise on the vasculature.Journal of Cardiovascular Pharmacology 09/2014; DOI:10.1097/FJC.0000000000000170 · 2.11 Impact Factor
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ABSTRACT: Visceral fat (VF) is a source of pro-inflammatory adipokines implicated in cardiac remodeling. We sought to determine the impact of visceral fat (VF) and subcutaneous fat (SQ) depots on left ventricular (LV) structure, function, and geometry in the Multi-Ethnic Study of Atherosclerosis (MESA).Nutrition Metabolism and Cardiovascular Diseases 04/2015; DOI:10.1016/j.numecd.2015.03.016 · 3.88 Impact Factor
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ABSTRACT: OBJECTIVE Diabetic nephropathy and cardiovascular disease are strongly related in adults with type 1 diabetes, yet little is known about this relationship in adolescents prior to the onset of detectable clinical disease. We hypothesized that cardiopulmonary fitness would be directly associated with albumin-to-creatinine ratio (ACR) and inversely related to estimated glomerular filtration rate (eGFR) in adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS Sixty-nine adolescents with type 1 diabetes and 13 nondiabetic control subjects of similar pubertal stage and BMI had insulin sensitivity (glucose infusion rate [GIR]), measured by hyperinsulinemic-euglycemic clamp, and lean body mass, measured by DEXA. Cardiopulmonary fitness was measured by cycle ergometry to obtain peak volume of oxygen (VO2peak), and renal function was measured by eGFR using the Bouvet equation (measuring creatinine and cystatin C levels) and ACR. RESULTS Adolescents (15.5 ± 2.2 years of age) with type 1 diabetes (6.3 ± 3.8 years diabetes duration) had reduced VO2peak (31.5 ± 6.3 vs. 36.2 ± 7.9 mL/kg ⋅ min, P = 0.046) and VO2peak/lean kg (43.7 ± 7.0 vs. 51.0 ± 8.6 mL/lean kg ⋅ min, P = 0.007) compared with nondiabetic control subjects. eGFR was inversely associated with VO2peak and VO2peak/lean kg after adjusting for sex, Tanner stage, GIR, HbA1c level, systolic blood pressure, and LDL cholesterol level (β ± SE, VO2peak: −0.19 ± 0.07, P = 0.02; VO2peak/lean kg: −0.19 ± 0.09, P = 0.048). Moreover, participants in the highest tertile for eGFR had significantly lower sex- and Tanner-adjusted VO2peak and VO2peak/lean kg compared with participants in the lowest tertile. CONCLUSIONS Adolescents with type 1 diabetes had reduced exercise capacity, which was strongly associated with renal health, independent of insulin sensitivity. Future studies should examine the underlying interrelated pathophysiology in order to identify probable targets for treatment to reduce cardiovascular and renal complications.Diabetes Care 11/2014; 38(1). DOI:10.2337/dc14-1742 · 8.57 Impact Factor