Objective. Significant variation in interleukin-1␤ (IL-1␤) protein secretion between subjects has been observed when using a lipopolysaccharide (LPS)/ATPmediated ex vivo blood stimulation assay. To explore the potential relationships between genetic polymorphisms in the IL1B cytokine gene and cellular responses to inflammatory stimuli such as LPS, we investigated the hypothesis that polymorphisms within the promoter and exon 5 of the IL1B gene contribute to the observed differences in IL-1␤ protein secretion.Methods. The IL1B gene polymorphisms C؊511T, T؊31C, and C3954T were tested for association with LPS-induced secretion of IL-1␤ protein as measured by an ex vivo blood stimulation assay. Samples from 2 independent study populations (n ‫؍‬ 31 and n ‫؍‬ 25) were available for use in the ex vivo assay after consent was obtained to analyze the DNA.Results. A specific haplotype, composed of the T allele at ؊511 and the C allele at ؊31, was significantly associated with a 2-3-fold increase in LPS-induced IL-1␤ protein secretion. This association was observed in both of the independent study populations (P ‫؍‬ 0.0084 and P ‫؍‬ 0.0017).Conclusion. These data suggest that polymorphisms within the promoter region of the IL1B gene contribute to observed differences in LPS-induced IL-1␤ protein secretion.

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Abbreviations: (BG) blood glucose, (CGM) continuous glucose monitoring, (CI) confidence interval, (HbA1c) hemoglobin A1c, (RCT) randomized controlled trial, (SMBG) self-monitoring of blood glucose, (T1DM) type 1 diabetes mellitus

A short course of intensive lifestyle and drug therapy achieves on-treatment normoglycemia and promotes sustained weight loss. It may also achieve prolonged, drug-free diabetes remission and strongly supports ongoing studies of novel medical regimens targeting remission.

BACKGROUND Stability and transport challenges make hemoglobin (Hb) A1c measurement from EDTA whole blood (WB) inconvenient and costly for large-scale population studies. This study investigated Hb A1c measurement from WB blotted on filter paper (FP) in a Level I National Glycohemoglobin Standardization Program (NGSP)-accredited laboratory. METHODS Three Bio-Rad Variant™ II HPLC instruments and WB and FP specimens were used. Precision, accuracy, linearity, and readable total area of the 6.5-min (β-thalassemia method) Variant II HbA2/HbA1c Dual Program were assessed. Hb A1c stability was measured using in-house FP QC samples. The INTERHEART (a study of the effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries) and CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) studies provided chromatographs for morphometric analyses and interoperator variability experiments. Statistical analyses were performed to assess long-term sample stability, WB vs FP agreement, and significance of Hb A1c peak integration. RESULTS Intra- and interassay CVs were ≤2.00%. Total area counts between 0.8 and 5.5 × 106 μV/s produced accurate Hb A1c results. The regression equation for agreement between WB(x) and FP(y) was as follows: y = 0.933x + 0.4 (n = 85). FP QC samples stored at −70 °C and tested over approximately 3 years yielded CVs of 1.72%–2.73% and regression equations with slopes of −1.08 × 10−4 to 7.81 × 10−4. The CURE study, with better preanalytical preparation, achieved a 97% reportable rate, and the reportable rate of the INTERHEART study was 85%. CONCLUSIONS The FP collection method described provided accurate, robust, and reproducible measurement of Hb A1c using the Bio-Rad Variant II HPLC autoanalyzer when FP specimens were prepared according to standardized protocols, and analyses were performed in an NGSP-certified laboratory, supporting the use of FP collection cards in large multinational studies.

Background The Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) double blind randomized trial demonstrated that weekly subcutaneous dulaglutide 1.5 mg, a glucagon like peptide-1 receptor agonist, versus matched placebo reduced the first outcome of major adverse cardiovascular event (MACE), cardiovascular death, nonfatal myocardial infarction or nonfatal stroke (594 versus 663 events) in 9901 persons with type 2 diabetes and either chronic cardiovascular disease or risk factors, and followed during 5.4 years. These findings were based on a time-to-first-event analysis and preclude relevant information on the burden of total major events occurring during the trial. This analysis reports on the total cardiovascular or fatal events in the REWIND participants Methods We compared the total incidence of MACE or non-cardiovascular deaths, and the total incidence of expanded MACE (MACE, unstable angina, heart failure or revascularization) or non-cardiovascular deaths between participants randomized to dulaglutide and those randomized to placebo. Incidences were expressed as number per 1000 person-years. Hazard ratios (HR) were calculated using the conditional time gap and proportional means models. Results Participants had a mean age of 66.2 years, 46.3% were women and 31% had previous cardiovascular disease. During the trial there were 1972 MACE or non-cardiovascular deaths and 3673 expanded MACE or non-cardiovascular deaths. The incidence of total MACE or non-cardiovascular deaths in the dulaglutide and placebo groups was 35.8 and 40.3 per 1000 person-years, respectively [absolute reduction = 4.5 per 1000 person-years; conditional time gap HR 0.90 (95% CI, 0.82–0.98) p = 0.020, and proportional means HR 0.89 (95% CI, 0.80–0.98) p = 0.022]. The incidence of total expanded MACE or non-cardiovascular deaths in the dulaglutide and placebo groups was 67.1 and 74.7 per 1000 person-years, respectively [absolute reduction = 7.6 per 1000 person-years; conditional time gap HR 0.93 (95% CI, 0.87–0.99) p = 0.023, and proportional means HR 0.90 (95% CI, 0.82–0.99) p = 0.028]. Conclusions These findings suggest that weekly subcutaneous dulaglutide reduced total cardiovascular or fatal event burden in people with type 2 diabetes at moderate cardiovascular risk. Clinical Trial Registration:https://www.clinicaltrials.gouv. Unique Identifier NCT01394952).

The findings are consistent with a genetically based dose-dependent enhancement of cocaine reinforcement by C57BL/6J genes. These results suggest that heritable traits impart a substantial genetic load that facilitates the propensity for cocaine addiction among individuals in outbred populations.