β Cell dysfunction exists more than 5 years before type 1 diabetes diagnosis

Evans‐Molina, Carmella; Sims, Emily K.; DiMeglio, Linda A.; Ismail, Heba M.; Steck, Andrea K.; Palmer, Jerry P.; Krischer, Jeffrey P.; Geyer, Susan; Xu, Ping; Sosenko, Jay M.

doi:10.1172/jci.insight.120877

Cited by 84 publications

(62 citation statements)

References 33 publications

(28 reference statements)

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“…Type 1 diabetes is classified as an autoimmune disease based on the associated risk with other endocrine autoimmune diseases, such as Addison's disease and Hashimoto's thyroiditis, genetic linkage to HLA subtypes and the presence of autoantibodies with diabetes-predictive value [1,2]. Prospective studies of individuals at risk of developing type 1 diabetes have established the time course between the initiation of autoimmunity, as defined by detectable autoantibodies, and diabetes onset [3]. This time course is often surprisingly slow, taking as long as 10 years.…”

Section: Introductionmentioning

confidence: 99%

Activation of the HIF1α/PFKFB3 stress response pathway in beta cells in type 1 diabetes

et al. 2019

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Aims/hypothesis The conserved hypoxia inducible factor 1 α (HIF1α) injury-response pro-survival pathway has recently been implicated in early beta cell dysfunction but slow beta cell loss in type 2 diabetes. We hypothesised that the unexplained prolonged prediabetes phase in type 1 diabetes may also be, in part, due to activation of the HIF1α signalling pathway. Methods RNA sequencing (RNA-Seq) data from human islets with type 1 diabetes or after cytokine exposure in vitro was evaluated for activation of HIF1α targets. This was corroborated by immunostaining human pancreases from individuals with type 1 diabetes for 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), the key effector of HIF1α-mediated metabolic remodelling, and by western blotting of islets and INS-1 832/13 cells exposed to cytokines implicated in type 1 diabetes. Results HIF1α signalling is activated (p = 4.5 × 10 −9) in islets from individuals with type 1 diabetes, and in human islets exposed in vitro to cytokines implicated in type 1 diabetes (p = 1.1 × 10 −14). Expression of PFKFB3 is increased fivefold (p < 0.01) in beta cells in type 1 diabetes and in human and rat islets exposed to cytokines that induced increased lactate production. HIF1α attenuates cytokine-induced cell death in beta cells. Conclusions/interpretation The conserved pro-survival HIF1α-mediated injury-response signalling is activated in beta cells in type 1 diabetes and likely contributes to the relatively slow rate of beta cell loss at the expense of early defective glucose-induced insulin secretion.

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Section: Introductionmentioning

confidence: 99%

Activation of the HIF1α/PFKFB3 stress response pathway in beta cells in type 1 diabetes

et al. 2019

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“…Here, despite similar glucose values to nonprogressors, progressors had significantly lower FPIR starting around 4–6 years prior to T1D diagnosis [23]. In Ab+ relatives monitored through the TrialNet PTP for at least 5 years before diabetes progression (mean age of diagnosis of 21.6 years), compared to Ab- relatives, abnormalities in fasting and stimulated C-peptide levels were already present at the initial OGTT, a mean of 6.6 ± 1.3 years before diagnosis [66].…”

Section: Beta Cell Dysfunction Is Present Long Before T1d Onsetmentioning

confidence: 90%

Cause or effect? A review of clinical data demonstrating beta cell dysfunction prior to the clinical onset of type 1 diabetes

Sims

DiMeglio

2019

Molecular Metabolism

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BackgroundLimited successes of conventional approaches to type 1 diabetes (T1D) prevention and treatment have highlighted the need for improved understanding of risk factors contributing to or hastening progression to clinical diagnosis.Scope of reviewThis review summarizes beta cell function metabolic phenotyping data from clinical studies conducted in at-risk individuals before T1D onset and healthy controls. Data are drawn from studies comparing at-risk individuals who progress to T1D to at-risk individuals who do not progress to T1D, as well as from studies comparing at-risk individuals to controls without a T1D family history.Major conclusionsRapid loss of beta cell insulin secretion occurs in the months immediately preceding clinical onset. However, evidence of beta cell dysfunction is present even years earlier. Comparisons to controls without a family history suggest that many individuals in families impacted by T1D have evidence of beta cell dysfunction, even individuals who are unlikely to develop clinical disease. These findings may mean that underlying metabolic beta cell dysfunction contributes to T1D development and may explain some of the heterogeneity observed in the disease.

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“…Progressors with <5 years of follow-up were younger at study entry had a younger age of diabetes diagnosis compared to progressors with ≥5 years of follow-up (median of 11.6 yrs at T1D onset in progressors<5 vs. a median of 17.0 yrs in progressors≥5). Remarkably, patterns of C-peptide loss and increased glycemia within three years of diagnosis were nearly identical between the two groups, raising the possibility that within this proximity to diagnosis, metabolic progression follows a stereotypical course of decline that is independent of age (21).…”

Section: Age and Metabolic Progression In T1dmentioning

confidence: 97%

The Effect of Age on the Progression and Severity of Type 1 Diabetes: Potential Effects on Disease Mechanisms

et al. 2018

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Purpose of review:To explore the impact of age on type 1 diabetes (T1D) pathogenesis. Recent findings:Children progress more rapidly from autoantibody positivity to T1D and have lower C-peptide levels compared to adults. In histological analysis of post-mortem pancreata, younger age of diagnosis is associated with reduced numbers of insulin containing islets and a hyper-immune CD20 hi infiltrate. Compared to adults, children exhibit decreased immune regulatory function and increased engagement and trafficking of autoreactive CD8 + T-cells, and age-related differences in β-cell vulnerability may also contribute to the more aggressive immune phenotype observed in children. HLA and non-HLA genetic loci that influence multiple disease characteristics, including age of onset, are being increasingly characterized. Summary:The exception of T1D as an autoimmune disease more prevalent in children than adults results from a combination of immune, metabolic, and genetic factors. Age-related differences in T1D pathology have important implications for better tailoring of immunotherapies.

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β Cell dysfunction exists more than 5 years before type 1 diabetes diagnosis

Cited by 84 publications

References 33 publications

Activation of the HIF1α/PFKFB3 stress response pathway in beta cells in type 1 diabetes

Activation of the HIF1α/PFKFB3 stress response pathway in beta cells in type 1 diabetes

Cause or effect? A review of clinical data demonstrating beta cell dysfunction prior to the clinical onset of type 1 diabetes

The Effect of Age on the Progression and Severity of Type 1 Diabetes: Potential Effects on Disease Mechanisms

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