Rosiglitazone (BRL 49653), a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist and potent insulin action-enhancing agent, was given in the diet (50 micromol/kg of diet) to male Zucker rats ages 6-7 weeks for 9 months (prevention group). In this treatment mode, rosiglitazone prolonged the time to onset of proteinuria from 3 to 6 months and markedly reduced the rate of its subsequent progression. Progression was also retarded when treatment was commenced (intervention group) after proteinuria had become established (4 months; ages 24-25 weeks). In either treatment mode, rosiglitazone normalized urinary N-acetyl-beta-D-glucosaminidase activity, a marker for renal proximal tubular damage, and ameliorated the rise in systolic blood pressure that occurred coincidentally with the development of proteinuria in Zucker fatty control rats. The renal protective action of rosiglitazone was verified morphologically. Thus in the prevention group there was an absence of the various indexes of chronic nephropathy that were prominent in the Zucker fatty control group, namely, glomerulosclerosis, dilated tubules containing proteinaceous casts, a loss of functional microvilli on the tubular epithelium, and varying degrees of chronic interstitial nephritis. An intermediate pathology was observed in the intervention group. Also, pancreatic islet hyperplasia, ultrastructural evidence of beta-cell work hypertrophy, and derangement of alpha-cell distribution within the islet were prominent features of Zucker fatty control rats, but these adaptive changes were ameliorated (intervention group) or prevented (prevention group) by rosiglitazone treatment. These data demonstrate that treatment of Zucker fatty rats with rosiglitazone produced substantial protection over a prolonged period against the development and progression of renal injury and the adaptive changes to pancreatic islet morphology caused by sustained hyperinsulinemia.
Common, but weakly penetrant, functional polymorphisms probably account for most of the genetic risk for breast cancer in the general population. Current polygenic risk models assume that component genes act independently. To test for potential gene-gene interactions, single nucleotide polymorphisms in ten genes with known or predicted roles in breast carcinogenesis were examined in a case-control study of 631 Caucasian women diagnosed with breast cancer under the age of 53 years and 1,504 controls under the age of 53 years. Association of breast cancer risk with individual genes and with two- and three-gene combinations was analyzed. Sixty-nine oligogenotypes from 37 distinct two- and three-gene combinations met stringent criteria for significance. Significant odds ratios (ORs) covered a 12-fold range: 0.5-5.9. Of the observed ORs, 17% differed significantly from the ORs predicted by a model of independent gene action, suggesting epistasis, i.e., that these genes interact to affect breast cancer risk in a manner not predictable from single gene effects. Exploration of the biological basis for these oligogenic interactions might reveal etiologic or therapeutic insights into breast cancer and other cancers.
OBJECTIVEDiabetic nephropathy (DN) remains the most common cause of end-stage renal disease and is a major cause of mortality in type 2 diabetes. Insulin sensitivity is an important determinant of renal health in adults with type 2 diabetes, but limited data exist in adolescents. We hypothesized that measured insulin sensitivity (glucose infusion rate [GIR]) would be associated with early markers of DN reflected by estimated glomerular filtration rate (eGFR) and albumin-creatinine ratio (ACR) in adolescents with type 2 diabetes.RESEARCH DESIGN AND METHODSType 2 diabetic (n = 46), obese (n = 29), and lean (n = 19) adolescents (15.1 ± 2.2 years) had GIR measured by hyperinsulinemic-euglycemic clamps. ACR was measured and GFR was estimated by the Bouvet equation (combined creatinine and cystatin C).RESULTSAdolescents with type 2 diabetes had significantly lower GIR, and higher eGFR and ACR than obese or lean adolescents. Moreover, 34% of type 2 diabetic adolescents had albuminuria (ACR ≥30 mg/g), and 24% had hyperfiltration (≥135 mL/min/1.73 m2). Stratifying ACR and eGFR into tertiles, adolescents with type 2 diabetes in the highest tertiles of ACR and eGFR had respectively lower GIR than those in the mid and low tertiles, after adjusting for age, sex, Tanner stage, BMI, and HbA1c (P = 0.02 and P = 0.04). GIR, but not HbA1c, LDL, or systolic blood pressure, was also associated with eGFR after adjusting for sex and Tanner stage (β ± SE: −2.23 ± 0.87; P = 0.02).CONCLUSIONSA significant proportion of adolescents with type 2 diabetes showed evidence of early DN, and insulin sensitivity, rather than HbA1c, blood pressure, or lipid control, was the strongest determinant of renal health.
Introduction Insulin resistance (IR) is increasingly prevalent in children, and may be related to muscle mitochondrial dysfunction, necessitating development of mitochondrial assessment techniques. Recent studies used 31Phosphorus magnetic resonance spectroscopy (31P-MRS), a non-invasive technique appealing for clinical research. 31P-MRS requires exercise at a precise percentage of maximum volitional contraction (MVC). MVC measurement in children, particularly with disease, is problematic due to variability in perception of effort and motivation. We therefore developed a method to predict MVC, using maximal calf muscle cross-sectional area (MCSA) to assure controlled and reproducible muscle metabolic perturbations. Methods Data were collected from 66 sedentary 12–20 year-olds. Plantar flexion-volitional MVC was assessed using a MRI-compatible exercise treadle device. MCSA of the calf muscles were measured from MRI images. Data from the first 26 participants were utilized to model the relationship between MVC and MCSA (predicted MVC = 24.763+0.0047*MCSA). This model was then applied to the subsequent 40 participants. Results Volitional vs. model-predicted mean MVC was 43.9±0.8 kg vs. 44.2±1.81 (P=0.90). 31P-MRS results when predicted and volitional MVC were similar showed expected changes during volitional MVC-based exercise. In contrast, volitional MVC was markedly lower than predicted in 4 participants, and produced minimal metabolic perturbation. Upon repeat testing, these individuals could perform their predicted MVC with coaching, which produced expected metabolic perturbations. Conclusions Compared to using MVC testing alone, utilizing MRI to predict muscle strength allows for a more accurate and standardized 31P-MRS protocol during exercise in children. This method overcomes a major obstacle in assessing mitochondrial function in youth. These studies have importance as we seek to determine the role of mitochondrial function in youth with IR and diabetes and response to interventions.
The purpose of this study was to compare the effectiveness of 3 treatment modes (Anti-Gravity Treadmill [G-trainer], stationary cycling [CompuTrainer], and static stretching) on the physiological and psychological recovery after an acute bout of exhaustive exercise. In a crossover design, 12 aerobically trained men (21.3 ± 2.3 years, 72.1 ± 8.1 kg, 178.4 ± 6.3 cm, (Equation is included in full-text article.): 53.7 ± 6.3 ml·kg·min) completed a 29-km stationary cycling time trial. Immediately after the time trial, subjects completed 30 minutes of G-trainer or CompuTrainer (40% (Equation is included in full-text article.)) or static stretching exercises. A significant time effect was detected for plasma lactate (p = 0.010) and serum cortisol (p = 0.039) after exercise. No treatment or treatment by time interaction was identified for lactate or cortisol, respectively. No main effects for time, treatment, or treatment by time interaction were identified for interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α). No differences were observed among treatments in skeletal muscle peak power output, mean power output, time to peak power, and rate to fatigue at 24 hours postexercise bout. Finally, no significant changes in mood status were observed after exercise and between treatment groups. When compared with stationary cycling and static stretching, exercise recovery performed on the G-trainer was unable to reduce systemic markers of stress and inflammation, blood lactate, or improve anaerobic performance and psychological mood states after an exhaustive bout of endurance exercise. Further research is warranted that includes individualized recovery modalities to create balances between the stresses of training and competition.
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