Pancreatic β-Cell Death in Response to Pro-Inflammatory Cytokines Is Distinct from Genuine Apoptosis

A reduction in functional β-cell mass leads to both major forms of diabetes; pro-inflammatory cytokines, such as interleukin-1beta (IL-1β) and gamma-interferon (γ-IFN), activate signaling pathways that direct pancreatic β-cell death and dysfunction. However, the molecular mechanism of β-cell death in this context is not well understood. In this report, we tested the hypothesis that individual cellular death pathways display characteristic phenotypes that allow them to be distinguished by the precise biochemical and metabolic responses that occur during stimulus-specific initiation. Using 832/13 and INS-1E rat insulinoma cells and isolated rat islets, we provide evidence that apoptosis is unlikely to be the primary pathway underlying β-cell death in response to IL-1β+γ-IFN. This conclusion was reached via the experimental results of several different interdisciplinary strategies, which included: 1) tandem mass spectrometry to delineate the metabolic differences between IL-1β+γ-IFN exposure versus apoptotic induction by camptothecin and 2) pharmacological and molecular interference with either NF-κB activity or apoptosome formation. These approaches provided clear distinctions in cell death pathways initiated by pro-inflammatory cytokines and bona fide inducers of apoptosis. Collectively, the results reported herein demonstrate that pancreatic β-cells undergo apoptosis in response to camptothecin or staurosporine, but not pro-inflammatory cytokines

Vps34 PI 3-kinase inactivation enhances insulin sensitivity through reprogramming of mitochondrial metabolism

Postdoctoral fellowships were from EU Marie Curie (PIEF-GA-2009–252916) and EMBO (ALTF 753–2010) for SA and EU Marie Curie (PIIF-GA-2009–252846) for C.C. J. M.H. was a recipient of a doctoral fellowship from Eisai UK Ltd. Work in our laboratories was supported as follows: BV: MRC [G0700755], BBSRC (BB/I007806/1 and BB/ M013278/1), CRUK (C23338/A15965), the Ludwig Institute for Cancer Research and the National Institute for Health Research (NIHR) UCL Hospitals Biomedical Research Centre; J.M.B.: NIH AG039632, GM112524. and the Albert Einstein Diabetes Research and Training Center Animal Physiology Core DK020541; E.G.: Barry Reed Cancer Research fund; G.S.: BBSRC (BB/L020874/1) and B.H.F.; S.S.: Anatomical Society of Great Britain (GT) and a Wellcome Trust Career Development Fellowship 074246/Z04/Z (S.S.); R.K.S.: Wellcome Trust (WT098498) and M.R.C. (MRC_MC_UU_12012/5); S.A. T. and L.C.: the Francis Crick Institute, which receives its core funding from CRUK (FC001187), MRC (FC001187), and the Wellcome Trust (FC001187); Y.-L.C.: the CRUK Cancer Imaging Centre in association with the MRC and DoH (England) grant C1060/ A10334, C1060/A16464, NHS funding to the NIHR BRC; B.P.: Inserm and the Fondation pour la recherche médicale

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation