RNA Sequencing of All Transcripts and How Islet β-Cells Fail

  1. Viviane Delghingaro-Augusto2
  1. 1Department of Endocrinology, The Canberra Hospital, Garran, ACT, Australia
  2. 2The Australian National University Medical School, Acton, ACT, Australia
  1. Corresponding author: Christopher J. Nolan, christopher.nolan{at}anu.edu.au.

In this issue, Cnop et al. (1) report on using RNA-sequencing methodology and the response of the whole transcriptome of human islets to 48-h exposure to saturated free fatty acid (FFA) palmitate. They demonstrated that palmitate altered the expression of 1,325 genes and shifted alternate splicing of 3,525 transcripts. This follows on from a similar study by the same group on the effects on human islets of 48-h exposure to the proinflammatory cytokines interleukin-1β and interferon-γ in which 3,065 (16%) of transcripts were modified and, again, alternate splicing of transcripts was commonly seen (2). However, islet β-cell failure causing diabetes, particularly type 2 diabetes, develops over years and not 48 h. So how do these technically remarkable in vitro experiments on human islets help us to understand islet β-cell failure?

Islet β-cell failure causing diabetes is due to impaired β-cell function and/or loss of β-cell mass. The pathways to islet β-cell failure, however, are very heterogeneous, requiring interaction between extrinsic stressors, such as cytokines or nutrient oversupply, and genetic or acquired islet susceptibility factors (3,4) (Fig. 1). In some circumstances, islet susceptibility may predominant such that extrinsic stressors are less important (e.g., some forms of monogenic diabetes [5]); while at the other end of the spectrum, severe extrinsic insults may be enough to cause failure of quite robust β-cells (e.g., aggressive autoimmune attack of type 1 diabetes or as a consequence of morbid obesity) (Fig. 1). Very often though, it will be the interaction of extrinsic and intrinsic factors that will result in the β-cell failure. Of note, the separation of type 1 from type 2 diabetes is becoming more blurred with overweight and insulin resistance possibly underlying some of the increasing prevalence of type 1 diabetes (4,6). Complex interactions …

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