Precision and accuracy of hyperglycemic clamps in a multicenter study.

Application of glucose clamp methodologies in multicenter studies brings challenges for standardization. The Restoring Insulin Secretion (RISE) Consortium implemented a hyperglycemic clamp protocol across seven centers using a combination of technical and management approaches to achieve standardization. Two-stage hyperglycemic clamps with glucose targets of 200 mg/dL and >450 mg/dL were performed utilizing a centralized spreadsheet-based algorithm that guided dextrose infusion rates using bedside plasma glucose measurements. Clamp operators received initial and repeated training with ongoing feedback based on surveillance of clamp performance. The precision and accuracy of the achieved stage-specific glucose targets were evaluated, including differences by study center. We also evaluated robustness of the method to baseline physiologic differences and on-study treatment effects. The RISE approach produced high overall precision (3%-9% variance in achieved plasma glucose from target at various times across the procedure) and accuracy (SD < 10% overall). Statistically significant but numerically small differences in achieved target glucose concentrations were observed across study centers, within the magnitude of the observed technical variability. Variation of the achieved target glucose over time in placebo-treated individuals was low (<3% variation), and the method was robust to differences in baseline physiology (youth vs. adult, IGT vs. diabetes status) and differences in physiology induced by study treatments. The RISE approach to standardization of the hyperglycemic clamp methodology across multiple study centers produced technically excellent standardization of achieved glucose concentrations. This approach provides a reliable method for implementing glucose clamp methodology across multiple study centers.NEW & NOTEWORTHY The Restoring Insulin Secretion (RISE) study centers undertook hyperglycemic clamps using a simplified methodology and a decision guidance algorithm implemented in an easy-to-use spreadsheet. This approach, combined with active management including ongoing central data surveillance and routine feedback to study centers, produced technically excellent standardization of achieved glucose concentrations on repeat studies within and across study centers.

Within-Trial Cost-Effectiveness of a Structured Lifestyle Intervention in Adults With Overweight/Obesity and Type 2 Diabetes: Results From the Action for Health in Diabetes (Look AHEAD) Study.

OBJECTIVE: To assess the cost-effectiveness (CE) of an intensive lifestyle intervention (ILI) compared with standard diabetes support and education (DSE) in adults with overweight/obesity and type 2 diabetes, as implemented in the Action for Health in Diabetes study. RESEARCH DESIGN AND METHODS: Data were from 4,827 participants during their first 9 years of study participation from 2001 to 2012. Information on Health Utilities Index Mark 2 (HUI-2) and HUI-3, Short-Form 6D (SF-6D), and Feeling Thermometer (FT), cost of delivering the interventions, and health expenditures was collected during the study. CE was measured by incremental CE ratios (ICERs) in costs per quality-adjusted life year (QALY). Future costs and QALYs were discounted at 3% annually. Costs were in 2012 U.S. dollars. RESULTS: Over the 9 years studied, the mean cumulative intervention costs and mean cumulative health care expenditures were $11,275 and $64,453 per person for ILI and $887 and $68,174 for DSE. Thus, ILI cost $6,666 more per person than DSE. Additional QALYs gained by ILI were not statistically significant measured by the HUIs and were 0.07 and 0.15, respectively, measured by SF-6D and FT. The ICERs ranged from no health benefit with a higher cost based on HUIs to $96,458/QALY and $43,169/QALY, respectively, based on SF-6D and FT. CONCLUSIONS: Whether ILI was cost-effective over the 9-year period is unclear because different health utility measures led to different conclusions.

Association of Habitual Daily Physical Activity With Glucose Tolerance and ß-Cell Function in Adults With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes From the Restoring Insulin Secretion (RISE) Study.

OBJECTIVE: We examined the relationship between habitual daily physical activity and measures of glucose tolerance, insulin sensitivity, and ß-cell responses in adults with impaired glucose tolerance (IGT) or drug-naive, recently diagnosed type 2 diabetes. RESEARCH DESIGN AND METHODS: Participants included 230 adults (mean ± SD age 54.5 ± 8.5 years, BMI 35 ± 5.5 kg/m2; 42.6% women) who underwent a 3-h oral glucose tolerance test (OGTT) and hyperglycemic clamp. Wrist accelerometers worn for 7 consecutive days measured total physical activity counts (TAC) (daily mean 233,460 [∼50th percentile for age]). We evaluated whether TAC was associated with fasting plasma glucose, OGTT 2-h plasma glucose or glucose incremental area under the curve (G-iAUC), hyperglycemic clamp measures of insulin sensitivity (steady-state glucose infusion rate/insulin [M/I]) and ß-cell responses (acute C-peptide response to glucose, steady-state C-peptide, and maximal ß-cell response), and OGTT C-peptide index (ΔC-peptide0-30/Δglucose0-30). RESULTS: After adjustments for confounders, there was no association of TAC with fasting plasma glucose, 2-h glucose, or G-iAUC. Higher TAC was associated with higher insulin sensitivity (M/I). After adjusting for M/I, higher TAC was not associated with measures of ß-cell response. CONCLUSIONS: In adults with IGT or drug-naive, recently diagnosed type 2 diabetes, higher levels of habitual physical activity are associated with higher insulin sensitivity. Further studies are needed to understand why higher levels of physical activity are not associated with better ß-cell response.