Immune Therapy and β-Cell Death in Type 1 Diabetes

Lebastchi, Jasmin; Deng, Songyan; Lebastchi, Amir H.; Beshar, Isabel; Gitelman, Stephen E.; Willi, Steven M.; Gottlieb, Peter A.; Akirav, Eitan M.; Bluestone, Jeffrey A.; Herold, Kevan C.

doi:10.2337/db12-1207

Cited by 77 publications

(64 citation statements)

References 19 publications

(20 reference statements)

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“…We previously validated this approach in mice with diabetes induced by streptozotocin or in NOD mice with autoimmune diabetes (15). Using the same approach adapted to measurement of human INS DNA in serum, we found increased rates of β cell death in patients with recent-onset T1D compared with those in healthy control subjects (14). Patients with recent-onset T1D who were treated with anti-CD3 mAb showed improvement in C-peptide responses and also showed reduced levels of unmethylated INS DNA in the circulation.…”

Section: Demographic and Metabolic Features Of High-risk Participantsmentioning

confidence: 99%

“…The sample sizes were based on measurements of differences of unmethylated INS DNA in subjects with new-onset T1D that we have reported previously (14)(15)(16). Unless indicated otherwise, the data are presented as mean ± SEM.…”

Section: Methodsmentioning

confidence: 99%

“…However, it is possible that there were modest Our understanding of the kinetics of disease progression is limited because we do not have methods that directly measure β cell death, the primary pathologic process. We recently developed a method for assessing β cell death in vivo by measuring the relative amount of β cell-derived INS DNA in the circulation (14)(15)(16). The analysis involved quantitative PCR studies of INS DNA, with epigenetic marks that identify the DNA source as cells that actively transcribe insulin.…”

Section: Demographic and Metabolic Features Of High-risk Participantsmentioning

confidence: 99%

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β Cell death and dysfunction during type 1 diabetes development in at-risk individuals

Herold¹,

Usmani‐Brown²,

Ghazi³

et al. 2015

J. Clin. Invest.

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125

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BACKGROUND. The β cell killing that characterizes type 1 diabetes (T1D) is thought to begin years before patients present clinically with metabolic decompensation; however, this primary pathologic process of the disease has not been measured. METHODS.Here, we measured β cell death with an assay that detects β cell-derived unmethylated insulin (INS) DNA. Using this assay, we performed an observational study of 50 participants from 2 cohorts at risk for developing T1D from the TrialNet Pathway to Prevention study and of 4 subjects who received islet autotransplants. RESULTS.In at-risk subjects, those who progressed to T1D had average levels of unmethylated INS DNA that were elevated modestly compared with those of healthy control subjects. In at-risk individuals that progressed to T1D, the observed increases in unmethylated INS DNA were associated with decreases in insulin secretion, indicating that the changes in unmethylated INS DNA are indicative of β cell killing. Subjects at high risk for T1D had levels of unmethylated INS DNA that were higher than those of healthy controls and higher than the levels of unmethylated INS DNA in the at-risk progressor and at-risk nonprogressor groups followed for 4 years. Evaluation of insulin secretory kinetics also distinguished high-risk subjects who progressed to overt disease from those who did not. CONCLUSION.We conclude that a blood test that measures unmethylated INS DNA serves as a marker of active β cell killing as the result of T1D-associated autoimmunity. Together, the data support the concept that β cell killing occurs sporadically during the years prior to diagnosis of T1D and is more intense in the peridiagnosis period.TRIAL REGISTRATION. Clinicaltrials.gov NCT00097292. FUNDING.Funding was from the NIH, the Juvenile Diabetes Research Foundation, and the American Diabetes Association. University of Washington, Seattle, Washington, USA. cose tolerance and insulin secretion are normal. In the time period near presentation of clinical disease, β cell killing was consistently increased. In addition to β cell death, the progression to disease was indicated by a reversible delay in the kinetics of insulin secretion. Our findings suggest a new model of disease progression in which β cell destruction and metabolic dysfunction are events closely associated with disease onset. Conflict of interest: Results Demographic and metabolic features of high-risk participants in theTrialNet Natural History study. We studied 50 relatives of patients with T1D who were at risk for the disease, from 2 cohorts in the TrialNet Pathway to Prevention (PTP) study ( Figure 1). All of the individuals had normal HbA1c levels. We identified 10 at-risk participants who developed T1D over a 3-to 4-year follow-up period (progressors, n = 10) and a group of at-risk participants of similar age who were followed over a similar time period but did not develop T1D (nonprogressors, n = 10). The demographic and metabolic features of these two groups were comparable (Table 1), but the progressors had a hig...

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Section: Demographic and Metabolic Features Of High-risk Participantsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Demographic and Metabolic Features Of High-risk Participantsmentioning

confidence: 99%

See 1 more Smart Citation

β Cell death and dysfunction during type 1 diabetes development in at-risk individuals

Herold¹,

Usmani‐Brown²,

Ghazi³

et al. 2015

J. Clin. Invest.

Self Cite

125

123

View full text Add to dashboard Cite

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“…1,2 Typical symptoms (urination, excessive thirst and hunger) as the clinical signs result from the underlying hyperglycemia that is in turn caused by inadequate amounts of insulin. 1,3 Destruction course of insulin-producing β cells is caused by infiltration of dendritic cells, macrophages and T lymphocytes. 4 There are three conventional therapeutic options used for treating T1D, which are currently available: insulin therapy, transplantation and immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

New Approaches to the Immunotherapy of Type 1 Diabetes Mellitus Using Interleukin-27

et al. 2015

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“…Type 1 diabetes is caused by immune-mediated destruction of insulin-secreting islet b-cells in the pancreas (9,19). Pancreatic islet transplantation is currently being developed as a potential treatment for diabetes of various etiologies (30).…”

Section: Introductionmentioning

confidence: 99%

Engineered Hair Follicle Mesenchymal Stem Cells Overexpressing Controlled-Release Insulin Reverse Hyperglycemia in Mice with Type l Diabetes

Liu

et al. 2015

Cell Transplant

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Genetically engineered stem cells that overexpress genes encoding therapeutic products can be exploited to correct metabolic disorders by repairing and regenerating diseased organs or restoring their function. Hair follicles are readily accessible and serve as a rich source of autologous stem cells for cell-based gene therapy. Here we isolated mesenchymal stem cells from human hair follicles (HF-MSCs) and engineered them to overexpress the human insulin gene and release human insulin in a time-and dose-dependent manner in response to rapamycin. The engineered HF-MSCs retained their characteristic cell surface markers and retained their potential to differentiate into adipocytes and osteoblasts. When mice with streptozotocin-induced type 1 diabetes were engrafted with these engineered HF-MSCs, these cells expressed and released a dose of human insulin, dramatically reversed hyperglycemia, and significantly reduced death rate. Moreover, the engineered HF-MSCs did not form detectable tumors throughout the 120-day animal tests in our experiment. Our results show that HF-MSCs can be used to safely and efficiently express therapeutic transgenes and therefore show promise for cell-based gene therapy of human disease.

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Immune Therapy and β-Cell Death in Type 1 Diabetes

Cited by 77 publications

References 19 publications

β Cell death and dysfunction during type 1 diabetes development in at-risk individuals

β Cell death and dysfunction during type 1 diabetes development in at-risk individuals

New Approaches to the Immunotherapy of Type 1 Diabetes Mellitus Using Interleukin-27

Engineered Hair Follicle Mesenchymal Stem Cells Overexpressing Controlled-Release Insulin Reverse Hyperglycemia in Mice with Type l Diabetes

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