Persistent elevations in circulating <i>INS</i> DNA among subjects with longstanding type 1 diabetes

Neyman, Anna; Nelson, Jennifer B.; Tersey, Sarah A.; Mirmira, Raghavendra G.; Evans‐Molina, Carmella; Sims, Emily K.

doi:10.1111/dom.13489

Cited by 9 publications

(4 citation statements)

References 43 publications

(152 reference statements)

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“…Husseiny et al found that unmethylated INS DNA was also elevated following islet transplant [63]. Other recent studies have largely confirmed these initial observations and indicate that increased rates of β-cell death occur in T1D, aging, and islet transplantation [64,65].…”

Section: Considerations For Quantifying β-Cell Death In Human Diabetesmentioning

confidence: 86%

β-Cell Death in Diabetes: Past Discoveries, Present Understanding, and Potential Future Advances

et al. 2021

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β-cell death is regarded as a major event driving loss of insulin secretion and hyperglycemia in both type 1 and type 2 diabetes mellitus. In this review, we explore past, present, and potential future advances in our understanding of the mechanisms that promote β-cell death in diabetes, with a focus on the primary literature. We first review discoveries of insulin insufficiency, β-cell loss, and β-cell death in human diabetes. We discuss findings in humans and mouse models of diabetes related to autoimmune-associated β-cell loss and the roles of autoreactive T cells, B cells, and the β cell itself in this process. We review discoveries of the molecular mechanisms that underlie β-cell death-inducing stimuli, including proinflammatory cytokines, islet amyloid formation, ER stress, oxidative stress, glucotoxicity, and lipotoxicity. Finally, we explore recent perspectives on β-cell death in diabetes, including: (1) the role of the β cell in its own demise, (2) methods and terminology for identifying diverse mechanisms of β-cell death, and (3) whether non-canonical forms of β-cell death, such as regulated necrosis, contribute to islet inflammation and β-cell loss in diabetes. We believe new perspectives on the mechanisms of β-cell death in diabetes will provide a better understanding of this pathological process and may lead to new therapeutic strategies to protect β cells in the setting of diabetes.

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Section: Considerations For Quantifying β-Cell Death In Human Diabetesmentioning

confidence: 86%

β-Cell Death in Diabetes: Past Discoveries, Present Understanding, and Potential Future Advances

et al. 2021

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“…Yet, only a few have examined evidence of β-cell death in subjects with either long-standing diabetes or in those at-risk for T1D. Using banked sera from subjects in the T1D Exchange registry, one study demonstrated elevations in both unmethylated INS and methylated INS in subjects from both C-peptide-positive and C-peptide-negative subjects with longstanding (≥9 years) T1D [ 37 ]. These findings seem indicative of the persistence of β cells in such subjects, where ongoing β-cell death may give rise to circulating unmethylated INS signals and ongoing systemic autoimmunity/inflammation may give rise to elevated methylated INS signals [ 38 ].…”

Section: Development Of Dna-based Biomarkers Of β-Cell Deathmentioning

confidence: 99%

Cell-Free DNA Fragments as Biomarkers of Islet β-Cell Death in Obesity and Type 2 Diabetes

Arosemena

Meah

Mather

et al. 2021

IJMS

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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.

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“…Even direct evidence of beta cell death, using histological studies, has been difficult to demonstrate consistently [11, 23]. Recently, circulating cell-free unmethylated preproinsulin DNA (a proposed biomarker of beta cell death [51–53]) was found to be elevated in a cross-section of 90 individuals with long-standing type 1 diabetes [54]. Although this marker may theoretically allow for analysis of beta cell death in living individuals, given the limitations of the sensitivity and specificity of this assay, combined with the likely tiny number of cells dying at any one time, interpretation of these data are challenging without longitudinal analyses in the same individuals.…”

Section: What Is the Source Of Persistent Beta Cells In Long-durationmentioning

confidence: 99%

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

2019

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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.

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

Abstract: These results could reflect ongoing β cell death in individuals with longstanding T1D, even in the absence of detectable C-peptide production, suggesting that therapies targeting β cell survival could be beneficial among individuals with longstanding T1D.

Cited by 9 publications

References 43 publications

β-Cell Death in Diabetes: Past Discoveries, Present Understanding, and Potential Future Advances

β-Cell Death in Diabetes: Past Discoveries, Present Understanding, and Potential Future Advances

Cell-Free DNA Fragments as Biomarkers of Islet β-Cell Death in Obesity and Type 2 Diabetes

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

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