Abstract
Aims/hypothesisBeta cell death is a hallmark of diabetes. It is not known whether specific cellular stresses associated with type 1 or type 2 diabetes require specific factors to protect pancreatic beta cells. No systematic comparison of endogenous soluble factors in the context of multiple pro-apoptotic conditions has been published.MethodsPrimary mouse islet cells were cultured in conditions mimicking five type 1 or type 2 diabetes-related stresses: basal 5 mmol/l glucose, cytokine cocktail (25 ng/ml TNF-α, 10 ng/ml IL-1β, 10 ng/ml IFN-γ), 1 μmol/l thapsigargin, 1.5 mmol/l palmitate and 20 mmol/l glucose (all in the absence of serum). We surveyed the effects of a library of 206 endogenous factors (selected based on islet expression of their receptors) on islet cell survival through multi-parameter, live-cell imaging.ResultsOur survey pointed to survival factors exhibiting generalised protective effects across conditions meant to model different types of diabetes and stages of the diseases. For example, our survey and follow-up experiments suggested that OLFM1 is a novel protective factor for mouse and human beta cells across multiple conditions. Most strikingly, we also found specific protective survival factors for each model stress condition. For example, semaphorin4A (SEMA4A) was toxic to islet cells in the serum-free baseline and serum-free 20 mmol/l glucose conditions, but protective in the context of lipotoxicity. Rank product testing supported the consistency of our observations.Conclusions/interpretationCollectively, our survey reveals previously unidentified islet cell survival factors and suggest their potential utility in individualised medicine.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-015-3552-5) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
Highlights
The loss of functional beta cell mass is critical in diabetes pathogenesis [1]
Research aimed at discovering beta cell survival factors has typically been conducted one at a time and Diabetologia (2015) 58:1239–1249 has been limited by prior knowledge [2,3,4]
Analysis of dispersed mouse insulin-1 promoter-green fluorescent protein (MIP-GFP) islet cells suggested that beta cells were more sensitive to these stress conditions compared with the non-beta cell population within the same cultures (ESM Fig. 1c,d)
Summary
Research aimed at discovering beta cell survival factors has typically been conducted one at a time and Diabetologia (2015) 58:1239–1249 has been limited by prior knowledge [2,3,4]. Glucagon-like peptide 1 (GLP1) is considered a gold standard for beta cell protective factors [5]. Local GLP1 increases islet transplant success in animals [6], clinical evidence to support its efficacy to durably increase human beta cell mass is lacking. There is an unmet need to identify more and better beta cell survival factors. We recently developed high-throughput, kinetic, live-cell imaging methods that allow the effects of hundreds of factors on multiple cell death parameters to be simultaneously evaluated in dispersed primary islet cells over relatively long periods of time in culture [10]
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