The current study evaluated both the time course of insulin resistance associated with feeding dogs a high-fat diet and the relationship between the development of insulin resistance and the increase in blood pressure that also occurs. Twelve adult mongrel dogs were chronically instrumented and randomly assigned to either a control diet group (n = 4) or a high-fat diet group (n = 8). Insulin resistance was assessed by a weekly, single-dose (2 mU.kg-1.min-1) euglycemic-hyperinsulinemic clamp on all dogs. Feeding dogs a high-fat diet was associated with a 3.7 +/- 0.5 kg increase in body weight, a 20 +/- 4 mmHg increase in mean blood pressure, a reduction in insulin-mediated glucose uptake [(in mumol-kg-1.min-1) decreasing from 72 +/- 6 before to 49 +/- 7 at 1 wk, 29 +/- 3 at 3 wk, and 30 +/- 2 at 6 wk of the high-fat diet, P < 0.01]. and a reduced insulin-mediated increase in cardiac output. In eight dogs (4 high fat and 4 control), the dose-response relationship of insulin-induced glucose uptake also was studied. The whole body glucose uptake dose-response curve was shifted to the right, and the rate of maximal whole body glucose uptake was significantly decreased (P < 0.001). Finally, we observed a direct relationship between the high-fat diet-induced weekly increase in mean arterial pressure and the degree to which insulin resistance developed. In summary, the current study documents that feeding dogs a high-fat diet causes the rapid development of insulin resistance that is the result of both a reduced sensitivity and a reduced responsiveness to insulin.
While lung transplant is an effective therapy for advanced lung disease, chronic allograph rejection remains a primary basis for lower survival rates than those for other solid organ transplants. This study used carefully controlled Zip-Tip extraction of bronchoalveolar lavage fluid (BALF) followed by MALDI-TOF MS to identify biomarkers of chronic lung transplant rejection. Many differences were observed between controls, those who did not develop chronic rejection within 100 months, and patients who had developed chronic rejection, diagnosed as bronchiolitis obliterans syndrome (BOS). Intensity ratios of peaks within the same MALDI-TOF profile were used to quantify the result. One of the best identifiers of BOS was a lowered ratio of clara cell protein (CCP m/z = 15,835) to lysozyme (m/z = 14,700), which gave 94% specificity and 74% sensitivity for diagnosis. Furthermore, low values for CCP/Lysozyme (<0.3) were observed in 66% of samples taken at 1 to 15 months prior to the diagnosis of BOS. Many other components of the profile gave similar or better outcomes for diagnosis but tended to be less valuable for the prediction of future disease. Overall, this study demonstrated the feasibility of this approach for the detection of disease biomarkers.
This study evaluated both cardiac hemodynamic and metabolic effects of a graded intracoronary artery infusion of insulin in four normal and five obese anesthetized dogs. Dogs were anesthetized with isoflurane, a catheter was advanced under fluoroscopic guidance into the coronary sinus and great cardiac vein, and a 20-MHz 3F coronary Doppler catheter was advanced into either the mid left anterior descending or circumflex coronary artery. A graded intracoronary insulin infusion was administered (starting at 0.3 mU/min and doubling every 40 minutes until a maximum dose of 2.4 mU/min was achieved). Coronary glucose extraction, coronary blood flow velocity, and coronary artery size were measured at each infusion rate. An intracoronary artery infusion of insulin stimulated myocardial glucose uptake in normal dogs. However, in high-fat-fed dogs, weight gain was associated with a reduction in the ability of insulin to promote glucose uptake by cardiac muscle and a rightward shift in the dose-response curve. In normal dogs, an intracoronary insulin infusion resulted in an increase in coronary blood flow and coronary vasodilation (with insulin coronary vascular resistance index decreases to 0.72 +/- 0.06, P<.01), whereas with weight gain the vasodilator response to insulin was lost. The loss of coronary artery vasodilation to local hyperinsulinemia in fat-fed dogs is consistent with other reports in obese or hypertensive humans that document an impairment in the action of insulin to increase skeletal muscle blood flow.
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Context Our previous case-control study identified human neutrophil peptide (HNP) as a potential biomarker for bronchiolitis obliterans syndrome (BOS) in lung transplant recipients. Objective To prospectively validate HNP as a biomarker for BOS. Materials and Methods HNP was measured by ELISA in bronchoalveolar lavage (BAL) fluid in lung transplant recipients. Results The first HNP measurement after reaching baseline pulmonary function was predictive of developing BOS ≥2 (p=0.0419). HNP remained elevated in those that developed BOS. The effect of potential confounders did not significantly impact BOS-free survival time. Conclusion HNP levels are elevated early and persistently in those that develop BOS.
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