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Summary Transcriptional regulatory networks direct the development of specialized cell types. The transcription factors Stat4 and T-bet are required for the development of T helper 1 cells, although the hierarchy of activity by these factors has not been clearly defined. In this report we show that these factors are not in a linear pathway and that each factor plays a unique role in programming chromatin architecture for Th1 gene expression, with subsets of genes depending on Stat4, T-bet, or both for expression in Th1 cells. T-bet is not able to transactivate expression of Stat4-dependent genes in the absence of endogenous Stat4 expression. Thus, T-bet requires Stat4 to achieve complete Th1 fate determination.

Primary T helper 2 cells are heterogeneous, expressing subsets of cytokines at varying levels. Mechanisms controlling this spectrum of phenotypes are still unclear. The ETS family transcription factor PU.1 is expressed in Th2 but not Th1 cells. Th2 cytokine production is decreased in cultures transduced with a PU.1-expressing retrovirus and increased in Th2 cells following RNAi that decreases PU.1 expression. In primary cultures, PU.1 expression is restricted to a subpopulation of Th2 cells that express CCL22 and a subset of Th2 cytokines. PU.1 regulates the Th2 phenotype by interfering with GATA-3 DNA binding without altering GATA-3 protein levels. Thus, the expression of PU.1 in subsets of Th2 cells establishes a defined cytokine profile and contributes towards establishing the spectrum of cytokine production observed in Th2 populations.

AimsTo evaluate the efficacy and safety of dulaglutide 1.5 and 0.75 mg in patients with type 2 diabetes by subgroups of gender, duration of diabetes and baseline glycated haemoglobin (HbA1c) in the dulaglutide clinical development programme (AWARD‐1 to ‐6 and ‐8 clinical trials).MethodsChange in HbA1c was analysed by gender, duration of diabetes (<5, ≥5 years and <10, ≥10 years), and baseline HbA1c (<8.5%, ≥8.5%) in pooled and individual studies. Changes from baseline in weight, hypoglycaemia and gastrointestinal adverse events were evaluated for individual trials.ResultsIn the pooled analysis of patients treated with dulaglutide 1.5 mg at 6 months, the reductions in HbA1c from baseline were similar across gender (men: least squares [LS] mean −1.26% [95% confidence interval {CI} −1.36, −1.16]; women: LS mean −1.33% [95% CI −1.43, −1.24]) and among duration of diabetes subgroups (<5 years: LS mean −1.32% [95% CI −1.43, −1.22]; ≥5 and <10 years: LS mean −1.33% [95% CI −1.43, −1.22]; ≥10 years: −1.24% [95% CI −1.35, −1.14]). Patients with baseline HbA1c ≥8.5% had greater HbA1c reductions than patients with baseline HbA1c <8.5%, (≥8.5%: LS mean −1.86% [95% CI −1.97, −1.75]; <8.5%: LS mean −1.02% [95% CI −1.12, −0.93]). Reductions in fasting blood glucose (FBG) were consistent with HbA1c changes. Similar results were observed with dulaglutide 0.75 mg. In general, body weight changes were similar among duration of diabetes and in baseline HbA1c subgroups, respectively; women had a numerically greater weight loss or less weight gain than men with both dulaglutide doses. There was no clinically meaningful difference in hypoglycaemia trends by gender or duration of diabetes. Hypoglycaemia incidence and rate were generally lower in patients with baseline HbA1c ≥8.5% than in those with <8.5%, except for the AWARD‐4 study (combination with mealtime insulin).ConclusionsAcross the AWARD studies, dulaglutide demonstrated significant improvements in glycaemic control irrespective of gender, duration of diabetes, or baseline HbA1c, with greater HbA1c and FBG reductions in patients with a higher baseline HbA1c. Dulaglutide was well tolerated, with a safety profile similar to other glucagon‐like peptide‐1 receptor agonists.