We applaud the thoughtful letter from Vialettes and Valéro (1) bringing attention to endoplasmic reticulum (ER) stress as a potential mechanism influencing the decline in β-cell function observed in individuals with type 1 diabetes. We agree that it is a plausible mechanism underlying the preservation of C-peptide seen with aggressive correction of metabolic dysregulation and look forward to the results of the DirectNet/Type 1 Diabetes TrialNet study this year testing the effects of state-of-the-art glycemic control including closed-loop therapy at time of diagnosis on C-peptide. Intriguingly, the current studies referred to by Vialettes and Valéro in the NOD mouse suggest that ER stress antedate the onset of hyperglycemia (2). Previous work in animal models suggested that putting the β-cell to rest with diaxozide or insulin would prevent disease progression (3–5). In humans, although the Diabetes Prevention Trial–Type 1 parenteral insulin study was unable to demonstrate an effect of insulin therapy to prevent type 1 diabetes (6), the β-cell rest hypothesis in that trial was not fully tested as β-cell rest outside the yearly 4-day period of intravenous insulin infusion did not occur. Whether β-cell rest would be sufficient to repair or reduce ER stress in humans is unknown. The current challenge is to identify and evaluate biomarkers of β-cell ER stress in peripheral blood of individuals at risk for or with type 1 diabetes. In this way the role of β-cell ER stress in humans can be studied and appropriate intervention trials designed.
No potential conflicts of interest relevant to this article were reported.