Abstract
Type 2 diabetes (T2D) typically occurs in the setting of obesity and insulin resistance, where hyperglycemia is associated with decreased pancreatic β-cell mass and function. Loss of β-cell mass has variably been attributed to β-cell dedifferentiation and/or death. In recent years, it has been proposed that circulating epigenetically modified DNA fragments arising from β cells might be able to report on the potential occurrence of β-cell death in diabetes. Here, we review published literature of DNA-based β-cell death biomarkers that have been evaluated in human cohorts of islet transplantation, type 1 diabetes, and obesity and type 2 diabetes. In addition, we provide new data on the applicability of one of these biomarkers (cell free unmethylated INS DNA) in adult cohorts across a spectrum from obesity to T2D, in which no significant differences were observed, and compare these findings to those previously published in youth cohorts where differences were observed. Our analysis of the literature and our own data suggest that β-cell death may occur in subsets of individuals with obesity and T2D, however a more sensitive method or refined study designs are needed to provide better alignment of sampling with disease progression events.
Highlights
As a group, showed statistically greater levels of unmethylated CHTOP and both unmethylated and methylated in blood glucose levels qPCR (INS) compared to lean control youth—findings suggestive of β-cell death in youth with obesity. When these subjects were further stratified into five subgroups, no statistical differences in unmethylated INS or CHTOP were observed across these cross-sectional cohorts
1) The epigenetic landscape at the INS gene, or the rate of clearance of DNA fragments from circulation, might be altered by the aging process such that the assay itself is unable to pick up evidence of β-cell death in adults, 2) the prevalence and/or rate of β-cell death in adults might be below the detection limits of the assay, 3) they might reflect an accelerated inflammatory state across the spectrum from obesity to Type 2 diabetes (T2D) in childhood, where stress and death of β cells may predominate in youth, and 4) it remains possible, as in mouse models [22], that β-cell death is an episodic phenomenon and that the cross-sectional nature of these studies miss the timing of cellular death
It is notable that a recent study could not verify this occurrence using a sensitive PCR+sequencing approach [29], suggesting that either differences in assay sensitivity, the populations examined, or the CpG sites interrogated may be crucial variables to consider in the course of assay development
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. There are several proposed mechanisms underlying the inadequacy of insulin production in T2D (reviewed in [2]): (1) β-cell dysfunction arising from cellular stress resulting in failure to produce and secrete adequate insulin, (2). Β-cell death resulting in reduced cellular mass; and (3) β-cell dedifferentiation resulting in loss of β-cell identity and failure to secrete insulin. Whether these three mechanisms are independent of one another or are mutually exclusive remains an unresolved issue. Under conditions of stress such as increased insulin demand or inflammation in the context of insulin resistance, the capacity of the endoplasmic reticulum (ER) can be overwhelmed resulting initially in inadequate protein production and loss of function; more prolonged ER stress can lead to the activation of apoptotic pathways, resulting in cellular death [3,4]. Other recent reviews offer synopses using other type of nucleic acids, such as RNA species, as biomarkers of β-cell death [9,11,12,13]
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