Biomarkers of β-Cell Stress and Death in Type 1 Diabetes

Abstract

The hallmark of type 1 diabetes (T1D) is a decline in functional β-cell mass arising as a result of autoimmunity. Immunomodulatory interventions at disease onset have resulted in partial stabilization of β-cell function, but full recovery of insulin secretion has remained elusive. Revised efforts have focused on disease prevention through interventions administered at earlier disease stages. To support this paradigm, there is a parallel effort ongoing to identify circulating biomarkers that have the potential to identify stress and death of the islet β-cells. Whereas no definitive biomarker(s) have been fully validated, several approaches hold promise that T1D can be reliably identified in the pre-symptomatic phase, such that either β-cell preservation or immunomodulatory agents might be employed in at-risk populations. This review summarizes the most promising protein- and nucleic acid-based biomarkers discovered to date and reviews the context in which they have been studied.

Type 1 Diabetes: Disease Stratification

“…The environmental etiologies that trigger onset of islet autoimmunity are not well understood, but inflammation around the islets arising from various etiologies may lead to beta cell stress to precipitate immune-mediated beta cell dysfunction and destruction [56,57] . Several candidate biomarkers (proinsulin/C-peptide ratio, hsp90, noncoding RNAs) for detecting beta cell stress in the periphery are being investigated, and although have not been studied at pre-stage 1 T1D, have been evaluated in later stages of presymptomatic or new onset T1D [29,56,[58][59][60][61] .…”

“…Several candidate biomarkers (proinsulin/C-peptide ratio, hsp90, noncoding RNAs) for detecting beta cell stress in the periphery are being investigated, and although have not been studied at pre-stage 1 T1D, have been evaluated in later stages of presymptomatic or new onset T1D [29,56,[58][59][60][61] .…”

“…is likely the result of both the loss of beta cell mass and a decline in beta cell dysfunction [56] . Of note, emerging evidence suggests that beta cell mass may in fact be maintained until near the time of stage 2 to stage 3 transition [60] .…”

“…Alternative approaches to detect active disease include detection of pancreatic beta cell stress [56] , using assays described above, or detection of beta cell death. Multiple beta cell death assays are under development that are based on detection in peripheral blood of circulating beta cell DNA (insulin, amylin, and others) that is differentially methylated/demethylated [115][116][117][118] .…”

Persistent elevations in circulating INS DNA among subjects with longstanding type 1 diabetes

“…These initial analyses utilized nested PCR to calculate a demethylation index of circulating unmethylated INS DNA relative to methylated INS DNA, which was increased in serum from mouse models of T1D as well as in human subjects with new onset T1D . Subsequent modifications and variations of this assay have been reported by this group and others, including analysis of CpG sites in the insulin promoter, utilization of dual probe‐based detection strategies, use of droplet digital PCR (ddPCR) for absolute quantification of copy numbers, and performance of next‐generation sequencing to simultaneously analyse multiple CpG sites . In addition to an increase in the ratio of circulating unmethylated to methylated INS DNA, our group previously described absolute elevations in both serum unmethylated and methylated INS DNA in paediatric subjects with new onset T1D .…”