Beta cells in type 1 diabetes: mass and function; sleeping or dead?

Abstract

Histological analysis of donor pancreases coupled with measurement of serum C-peptide in clinical cohorts has challenged the idea that all beta cells are eventually destroyed in type 1 diabetes. These findings have raised a number of questions regarding how the remaining beta cells have escaped immune destruction, whether pools of 'sleeping' or dysfunctional beta cells could be rejuvenated and whether there is potential for new growth of beta cells. In this Review, we describe histological and in vivo evidence of persistent beta cells in type 1 diabetes and discuss the limitations of current methods to distinguish underlying beta cell mass in comparison with beta cell function. We highlight that evidence for new beta cell growth in humans many years from diagnosis is limited, and that this growth may be very minimal if at all present. We review recent contributions to the debate around beta cell abnormalities contributing to the pathogenesis of type 1 diabetes. We also discuss evidence for restoration of beta cell function, as opposed to mass, in recent-onset type 1 diabetes, but highlight the absence of data supporting functional recovery in the setting of long-duration diabetes. Finally, future areas of research are suggested to help resolve the source and phenotype of residual beta cells that persist in some, but not all, people with type 1 diabetes.

Keywords: Beta cell function; Beta cell mass; C-peptide; Network for Pancreatic Organ Donors with Diabetes; Proinsulin; Review; Type 1 diabetes.

Fig. 1

Persistent beta cells in type 1 diabetes. Histological and in vivo analyses (e.g. serum C-peptide, insulin and proinsulin studies) have provided evidence for the persistence of insulin-producing beta cells in long-duration type 1 diabetes. Potential explanations for this phenomenon include: (1) new beta cell growth via neogenesis, transdifferentiation and cell regeneration/turnover; (2) variation in intensity of autoimmune response, e.g. regulation of immune responses or a diminishing immune response may reduce beta cell destruction; and (3) that heterogeneity of beta cells may lead to beta cell protection. The histological image for nPOD donor 6328 was provided by S. J. Richardson (personal communication; University of Exeter Medical School, Exeter, UK) and shows an insulin-containing pancreatic islet from a 39-year-old organ donor with type 1 diabetes for 20 years (diagnosed aged 19). Insulin is stained in brown and glucagon in red. The histological image for nPOD donor 6038 was provided by T. L. Mastracci (personal communication; Indiana Biosciences Research Institute and the Indiana University School of Medicine, Indianapolis, IN, USA) and shows a pancreatic islet from an individual with type 1 diabetes for 20 years, in which beta cells have not been lost and continue to express both proinsulin and insulin (proinsulin, green; insulin, red; DAPI, blue [nuclei]). T1D, type 1 diabetes. Copyright details: the serum C-peptide graph is derived from [2], published under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.Org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium; the image for the generation of new beta cells is from [19], adapted by permission from Springer Nature © 2005; the image for altered/variable autoimmunity is from [20], adapted by permission from Springer Nature © 2014. This figure is available as a downloadable slide