Citations

OBJECTIVE—The purpose of this study was to determine the mechanism by which dipeptidyl peptidase-4 inhibitors lower postprandial glucose concentrations. RESEARCH DESIGN AND METHODS—We measured insulin secretion and action as well as glucose effectiveness in 14 subjects with type 2 diabetes who received vildagliptin (50 mg b.i.d.) or placebo for 10 days in random order separated by a 3-week washout. On day 9 of each period, subjects ate a mixed meal. Insulin sensitivity (SI), glucose effectiveness, and β-cell responsivity indexes were estimated using the oral glucose and C-peptide minimal models. At 300 min 0.02 unit/kg insulin was administered intravenously. RESULTS—Vildagliptin reduced postprandial glucose concentrations (905 ± 94 vs. 1,008 ± 104 mmol/6 h, P = 0.02). Vildagliptin did not alter net SI (7.71 ± 1.28 vs. 6.41 ± 0.84 10−4 dl · kg−1 · min−1 · μU−1 · ml−1, P = 0.13) or glucose effectiveness (0.019 ± 0.002 vs. 0.018 ± 0.002 dl · kg−1 · min−1, P = 0.65). However, the net β-cell responsivity index was increased (35.7 ± 5.2 vs. 28.9 ± 5.2 10−9 min−1, P = 0.03) as was total disposition index (381 ± 48 vs. 261 ± 35 10−14 dl · kg−1 · min−2 · pmol−1 · l−1, P = 0.006). Vildagliptin lowered postprandial glucagon concentrations (27.0 ± 1.1 vs. 29.7 ± 1.5 μg · l−1 · 6 h−1, P = 0.03), especially after administration of exogenous insulin (81.5 ± 6.4 vs. 99.3 ± 5.6 ng/l, P = 0.02). CONCLUSIONS—Vildagliptin lowers postprandial glucose concentrations by stimulating insulin secretion and suppressing glucagon secretion but not by altered insulin action or glucose effectiveness. A novel observation is that vildagliptin alters α-cell responsiveness to insulin administration, but the significance of this action is as yet unclear.

Abstract Background: The accurate and precise measurement of urinary albumin is critical, since even minor increases are diagnostically sensitive indicators of renal disease, cardiovascular events, and risk for death. To gain insights into potential measurement biases, we systematically compared urine albumin measurements performed by LC-MS, a clinically available immunoturbidimetric assay, and size-exclusion HPLC. Methods: We obtained unused clinical urine samples from 150 patients who were stratified by degrees of albuminuria (<20 mg/L, 20–250 mg/L, >250 mg/L) as determined by the immunoturbidimetric assay used in our clinical laboratory (Roche Hitachi 912). Urine albumin was then remeasured via LC-MS and HPLC (Accumin™) assays. Results: The immunoturbidimetric assay, calibrated using manufacturer-supplied serum-derived calibrators (Diasorin), underestimated albumin compared with LC-MS. After calibration with purified HSA, this immunoturbidimetric assay correlated well with LC-MS. HPLC overestimated albumin compared with both LC-MS and immunoturbidimetry. The current LC-MS and HPLC assays both performed poorly at concentrations <20 mg/L. Conclusions: Efforts are needed to establish gold-standard traceable calibrators for clinical assays. LC-MS is a specific method to quantify albumin in native urine when concentrations exceed 20 mg/L, and therefore could be employed for standardization among assays.

Abstract Background: We evaluated the sensitivity, precision, and concordance of 4 assays designed to detect aspirin responsiveness or resistance. Methods: Twenty-nine healthy laboratory volunteers took 80 mg aspirin for 7 days, and a subset of volunteers took 325 mg aspirin for an additional 7 days. We measured platelet function by light transmission aggregometry with arachidonic acid, PFA-100, and VerifyNow. PFA-100 and VerifyNow assays were performed in duplicate to assess method imprecision. Some volunteers had samples taken within 2–4 h of the final dose of aspirin and again within 20–24 h of the final dose. We measured urinary 11-dehydro-thromboxane B2 at baseline and after 80 or 325 mg aspirin. Results: No volunteers were nonresponsive to aspirin therapy as measured by the PFA-100. One of 29 participants demonstrated lack of response to aspirin as measured by VerifyNow and urinary 11-dehydro-thromboxane B2; 2 of 29 demonstrated lack of response as measured by light transmission aggregometry. Imprecision was <10% for the PFA-100 and VerifyNow. Concordance was high (>90%) between all assays. Neither aspirin dose (80 vs 325 mg) nor timing between final dose of aspirin and blood draw (2–4 vs 20–24 h) affected any of the assays. Conclusions: Light transmission aggregometry, PFA-100, VerifyNow, and urinary 11-dehydro-thromboxane B2 are all sensitive to the effects of aspirin in healthy individuals. Variables such as aspirin dose, timing between final dose of aspirin and blood collection, and imprecision do not affect the ability of the assays to detect aspirin effect on platelet function.