scholarly journals Checkpoint Inhibitor–Associated Autoimmune Diabetes Is Distinct From Type 1 Diabetes

2019 ◽  
Vol 104 (11) ◽  
pp. 5499-5506 ◽  
Author(s):  
Venessa H M Tsang ◽  
Rachel T McGrath ◽  
Roderick J Clifton-Bligh ◽  
Richard A Scolyer ◽  
Valerie Jakrot ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Checkpoint Inhibitor ◽  
Autoimmune Diabetes ◽  
Case Series ◽  
Acid Decarboxylase ◽  
Risk Haplotype ◽  
Β Cell ◽  
C Peptide

Abstract Context Checkpoint inhibitor–associated autoimmune diabetes mellitus (CIADM) is a rare illness, and little is known about its incidence, clinical features, or pathogenesis. Case Series Description Consecutive patients from a single quaternary melanoma center who developed new-onset insulin-requiring diabetes after commencing anti–programmed cell death-1 (PD-1) immunotherapy were studied to describe CIADM characteristics. Ten (1.9%) of 538 patients with metastatic melanoma treated with anti–PD-1–based immunotherapy from March 2015 to March 2018 developed CIADM. Nine patients had no history of diabetes, and one had pre-existing type 2 diabetes mellitus. Median time from immunotherapy start to CIADM diagnosis was 25 weeks [interquartile range (IQR), 17.5 to 34.5 weeks]. All patients had normal serum C-peptide shortly before CIADM onset and an inappropriately low level when measured soon after. At CIADM diagnosis, median hemoglobin A1c was 7.6% (IQR, 7.15% to 9.75%), median glucose level was 32.5 mmol/L (IQR, 21.6 to 36.7 mmol/L), and median C-peptide concentration was 0.35 nmol/L (IQR, 0.10 to 0.49 mmol/L). Type 1 diabetes (T1D)–associated autoantibodies (DAAs) were present in two patients (both of whom had anti–glutamic acid decarboxylase antibody); all were negative for insulin-associated protein 2, insulin, and ZnT8. Three patients were heterozygous for an HLA class II T1D-risk haplotype; two additional patients also carried protective haplotypes for T1D. All patients continued immunotherapy; eight (80%) had complete or partial oncological response, and all patients required ongoing insulin therapy. Conclusion CIADM is characterized by sudden permanent β-cell failure occurring after immunotherapy. It is distinct from T1D, usually lacks DAA or T1D-associated HLA-risk haplotypes, and is associated with difficult glycemic control from the onset. As such, CIADM represents a new model of auto-inflammatory β-cell failure.

scholarly journals Effects of incretin-based therapies on β-cell function in type 1 diabetes mellitus: a systematic review and meta-analysis

2021 ◽  
Vol 49 (12) ◽  
pp. 030006052110663
Author(s):  
Yucheng Wu ◽  
Yu Lu ◽  
Shufang Yang ◽  
Qingqing Zhang
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Plasma Glucose ◽  
Fasting Plasma Glucose ◽  
Cell Function ◽  
Meta Analysis ◽  
Β Cell ◽  
C Peptide ◽  
Β Cell Function

Aim To assess the effects of incretin-based therapies on β-cell function in patients with type 1 diabetes mellitus (T1DM). Methods We searched the PubMed, Cochrane Library, Embase, and Web of Knowledge databases for eligible randomized clinical trials published up to July 2021. The inclusion criteria were patients with T1DM or latent autoimmune diabetes in adults, patients treated with dipeptidyl peptidase-4 inhibitors or glucagon like peptide-1 receptor agonists, and outcomes included one of the following: fasting plasma glucose, fasting C-peptide, postprandial C-peptide, C-peptide area under the curve (AUC), homeostasis model assessment for β cell function, and insulin resistance. The effects were analyzed using a random effect model with STATA 11.0. Results Eight trials including 427 participants were included in the final analysis. A pooled analysis found no significant difference in fasting plasma glucose, fasting C-peptide, postprandial C-peptide, or C-peptide AUC between patients treated with incretin-based therapies and placebo. The two trials that reported changes in 2-hour postprandial C-peptide and two of the four trials that reported changes in C-peptide AUC reported increases after incretin-based therapies. Conclusion This meta-analysis showed that incretin-based therapies did not preserve β-cell function in patients with T1DM.

Rapid Point-of-Care Test for Determination of C-Peptide Levels

2021 ◽  
pp. 193229682199555
Author(s):  
Paturi V. Rao ◽  
Eric Bean ◽  
Dhanalakshmi Nair-Schaef ◽  
Siting Chen ◽  
Steven C. Kazmierczak ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Cell Function ◽  
Late Onset ◽  
Autoimmune Diabetes ◽  
Point Of Care ◽  
Cell Mass ◽  
Hepatic Clearance ◽  
Β Cell ◽  
C Peptide

C-peptide is co-secreted with insulin and is not subject to hepatic clearance and thus reflects functional β-cell mass. Assessment of C-peptide levels can identify individuals at risk for or with type 1 diabetes with residual β-cell function in whom β cell-sparing interventions can be evaluated, and can aid in distinguishing type 2 diabetes from Latent Autoimmune Diabetes in Adults and late-onset type 1 diabetes. To facilitate C-peptide testing, we describe a quantitative point-of-care C-peptide test. C-peptide levels as low as 0.2 ng/ml were measurable in a fingerstick sample, and the test was accurate over a range of 0.17 to 12.0 ng/ml. This test exhibited a correlation of r = 0.98 with a high-sensitivity commercial ELISA assay and a correlation of r = 0.90 between matched serum and fingerstick samples.

scholarly journals Unravelling Checkpoint Inhibitor Associated Autoimmune Diabetes: From Bench to Bedside

2021 ◽  
Vol 12 ◽  
Author(s):  
Linda Wu ◽  
Venessa H. M. Tsang ◽  
Sarah C. Sasson ◽  
Alexander M. Menzies ◽  
Matteo S. Carlino ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Autoimmune Diabetes ◽  
Management Strategies ◽  
Therapeutic Strategies ◽  
Β Cell

Immune checkpoint inhibitors have transformed the landscape of oncological therapy, but at the price of a new array of immune related adverse events. Among these is β-cell failure, leading to checkpoint inhibitor-related autoimmune diabetes (CIADM) which entails substantial long-term morbidity. As our understanding of this novel disease grows, parallels and differences between CIADM and classic type 1 diabetes (T1D) may provide insights into the development of diabetes and identify novel potential therapeutic strategies. In this review, we outline the knowledge across the disciplines of endocrinology, oncology and immunology regarding the pathogenesis of CIADM and identify possible management strategies.

scholarly journals SAT-674 Anti PD1 Induced Type 1 Diabetes

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Maria Belen Naranjo ◽  
David S Rosenthal ◽  
Salini Chellappan Kumar ◽  
Amal Shariff
Keyword(s):  
Systematic Review ◽  
Type 1 Diabetes ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Autoimmune Diabetes ◽  
C Peptide

Abstract Introduction: Pembrolizumab t is used to treat various cancers. It is associated with immune related adverse events (IRAEs) that can be life threatening [1,4]. We describe a patient who presented autoimmune Diabetes after the use of Pembrolizumab. Case: 64 y/o African American female PMHX of lung non-small cell lung cancer diagnosed in 2017 Clinical stage IV with gluteal metastasis, and dementia. Pt was referred by Oncology. The patient had a family history of Type 1 DM. and complained of dizziness, and unintentional weight loss (30 pounds) over a year. She had received 2 cycles of Pembrolizumab. The last cycle given 5 weeks before presentation to Endocrinology.Physical examination revealed cachectic female (weight 35 kg, height 147cm), dry mouth, BP 135/82, Plasma glucose 383mg%, A1c 7, negative Islet cell antibodies, positive anti-GAD, undetectableserum C-peptide. Cortisol 27, Acth 21 at 8 am and TSH 2.3. Discussion: In a systematic literature review, the early pattern of Diabetes onset with the use of checkpoint inhibitors was evaluated and on average after 4.5 treatment cycles [4].The incidence of immune checkpoint inhibitor-induced Type 1 Diabetes is estimated at 1% [3].This appeared to be earlier for the combination of anti-cytotoxic T-Lymphocyte associated antigen 4 monoclonal antibody and PD-1 therapy. The onset of β cell inflammation is often fulminant, suggested by the relatively low glycated hemoglobin levels, while C-peptide levels are usually low or undetectable at diagnosis and mostly positive GAD antibodies [5]. This side effect is predominantly found in patients exposed to blockade of the PD-1/PD-Ligand pathway. The IRAEs are primarily managed by immunosuppression with corticosteroids and discontinuation of immunotherapy except in autoimmune Diabetes which is irreversible. Physicians should be aware of and patients educated about the important multiorgan side effects since a growing number of patients are treated with checkpoint blockade.Azoury SC, Straughan DM, Shukla V. Immune checkpoint inhibitors for cancer therapy: clinical efficacy and safety. Curr Cancer Drug Targets 2015;15: 452-462Weber JS, Postow M, Lao CD, et al. Management of adverse events following treatment with anti-programmed death-1 agents. Oncologist 2016;21:1230-40Stamatouli AM, Quandt Z, Perdigoto AL, Clark PL, Kluger H,Weiss SA et al Collateral damage: insulin-dependent diabetes induced with checkpoint inhibitors. Diabetes 2018;67(8):1471-1480de Filette JMK, Pen JJ, Decoster L, et al. Immune checkpoint inhibitors and Type 1 Diabetes mellitus: a case report and systematic review. Eur J Endocrinol. 2019;181(3):363–374.Akturk HK, Kahramangil D, Sarwal A, Hoffecker L, Murad MH, Michels AW. Immune checkpoint inhibitor-induced Type 1 Diabetes: a systematic review and meta-analysis. Diabet Med. 2019;36(9):1075–1081.

scholarly journals Caspase-3-Dependent β-Cell Apoptosis in the Initiation of Autoimmune Diabetes Mellitus

2005 ◽  
Vol 25 (9) ◽  
pp. 3620-3629 ◽  
Author(s):  
Nicole Liadis ◽  
Kiichi Murakami ◽  
Mohamed Eweida ◽  
Alisha R. Elford ◽  
Laura Sheu ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Apoptosis ◽  
Cell Activation ◽  
Caspase 3 ◽  
Autoimmune Diabetes ◽  
Β Cell

ABSTRACT β-Cell apoptosis is a key event contributing to the pathogenesis of type 1 diabetes mellitus. In addition to apoptosis being the main mechanism by which β cells are destroyed, β-cell apoptosis has been implicated in the initiation of type 1 diabetes mellitus through antigen cross-presentation mechanisms that lead to β-cell-specific T-cell activation. Caspase-3 is the major effector caspase involved in apoptotic pathways. Despite evidence supporting the importance of β-cell apoptosis in the pathogenesis of type 1 diabetes, the specific role of caspase-3 in this process is unknown. Here, we show that Caspase-3 knockout (Casp3 − /−) mice were protected from developing diabetes in a multiple-low-dose streptozotocin autoimmune diabetes model. Lymphocyte infiltration of the pancreatic islets was completely absent in Casp3 − /− mice. To determine the role of caspase-3-dependent apoptosis in disease initiation, a defined antigen-T-cell receptor transgenic system, RIP-GP/P14 double-transgenic mice with Casp3 null mutation, was examined. β-cell antigen-specific T-cell activation and proliferation were observed only in the pancreatic draining lymph node of RIP-GP/P14/Casp3 + /− mice, but not in mice lacking caspase-3. Together, our findings demonstrate that caspase-3-mediated β-cell apoptosis is a requisite step for T-cell priming, a key initiating event in type 1 diabetes.

scholarly journals Slowly evolving, immune-mediated diabetes in 14-year-old patient: a case report

2021 ◽  
Vol 24 (1) ◽  
pp. 70-73
Author(s):  
M. R. Ragimov ◽  
D. D. Omelchuk ◽  
L. I. Ibragimova ◽  
O. S. Derevyanko ◽  
T. V. Nikonova
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Insulin Therapy ◽  
Type 1 Diabetes Mellitus ◽  
Autoimmune Diabetes ◽  
Tyrosine Phosphatase ◽  
Acid Decarboxylase ◽  
Latent Autoimmune Diabetes ◽  
Immune Mediated

Slowly developing immune-mediated diabetes, often called latent autoimmune diabetes in adults, is characterized by the presence of autoantibodies (ATs) to glutamic acid decarboxylase (GADA), the patient's age at the onset over 35 years, and the absence of the need for insulin therapy for 6-12 months to 6 years from the moment of diagnosis, according to the WHO classification of 2019, refers to hybrid forms of diabetes mellitus (DM). In this article, we present a case history of slowly developing immune-mediated diabetes in a 14-year-old boy who was transferred from metformin monotherapy and a diet with restriction of digestible carbohydrates to the intensified insulin therapy only 4 years after the onset of diabetes mellitus with a glycated hemoglobin (HbA1c) level of less than 6.5% throughout the disease. As a result of the studies, the patient was found to have a homozygous genotype highly predisposing to the development of Type 1 Diabetes Mellitus (T1DM), as well as increased levels of ATs to GADA and tyrosine phosphatase (IA-2A). The initially preserved level of basal C-peptide and the clinical course of the disease in this patient do not allow us to classify this case as a classic variant of the course of Type 1 Diabetes Mellitus.

Type 1 Diabetes-related Autoantibodies in Different Forms of Diabetes

2019 ◽  
Vol 15 (3) ◽  
pp. 199-204 ◽  
Author(s):  
Elin Pettersen Sørgjerd
Keyword(s):  
Type 2 Diabetes ◽  
Type 1 Diabetes ◽  
Autoimmune Diabetes ◽  
Acid Decarboxylase ◽  
Adult Onset ◽  
Latent Autoimmune Diabetes ◽  
Childhood Type 1 Diabetes ◽  
Childhood Type

Autoantibodies against Glutamic Acid Decarboxylase (GADA), insulinoma antigen-2 (IA- 2A), insulin (IAA) and the most recently Zinc Transporter 8 (ZnT8A) are one of the most reliable biomarkers for autoimmune diabetes in both children and adults. They are today the only biomarkers that can distinguish Latent Autoimmune Diabetes in Adults (LADA) from phenotypically type 2 diabetes. As the frequency of autoantibodies at diagnosis in childhood type 1 diabetes depends on age, GADA is by far the most common in adult onset autoimmune diabetes, especially LADA. Being multiple autoantibody positive have also shown to be more common in childhood diabetes compared to adult onset diabetes, and multiple autoantibody positivity have a high predictive value of childhood type 1 diabetes. Autoantibodies have shown inconsistent results to predict diabetes in adults. Levels of autoantibodies are reported to cause heterogeneity in LADA. Reports indicate that individuals with high levels of autoantibodies have a more type 1 diabetes like phenotype and individuals with low levels of autoantibody positivity have a more type 2 diabetes like phenotype. It is also well known that autoantibody levels can fluctuate and transient autoantibody positivity in adult onset autoimmune diabetes have been reported to affect the phenotype.

scholarly journals One repeated transplantation of allogeneic umbilical cord mesenchymal stromal cells in type 1 diabetes: an open parallel controlled clinical study

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jing Lu ◽  
Shan-mei Shen ◽  
Qing Ling ◽  
Bin Wang ◽  
Li-rong Li ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Stromal Cells ◽  
Treated Group ◽  
Control Group ◽  
Adult Onset ◽  
Β Cell ◽  
Juvenile Onset ◽  
C Peptide

Abstract Background The preservation or restoration of β cell function in type 1 diabetes (T1D) remains as an attractive and challengeable therapeutic target. Mesenchymal stromal cells (MSCs) are multipotent cells with high capacity of immunoregulation, which emerged as a promising cell-based therapy for many immune disorders. The objective of this study was to examine the efficacy and safety of one repeated transplantation of allogeneic MSCs in individuals with T1D. Methods This was a nonrandomized, open-label, parallel-armed prospective study. MSCs were isolated from umbilical cord (UC) of healthy donors. Fifty-three participants including 33 adult-onset (≥ 18 years) and 20 juvenile-onset T1D were enrolled. Twenty-seven subjects (MSC-treated group) received an initial systemic infusion of allogeneic UC-MSCs, followed by a repeat course at 3 months, whereas the control group (n = 26) only received standard care based on intensive insulin therapy. Data at 1-year follow-up was reported in this study. The primary endpoint was clinical remission defined as a 10% increase from baseline in the level of fasting and/or postprandial C-peptide. The secondary endpoints included side effects, serum levels of HbA1c, changes in fasting and postprandial C-peptide, and daily insulin doses. Results After 1-year follow-up, 40.7% subjects in MSC-treated group achieved the primary endpoint, significantly higher than that in the control arm. Three subjects in MSC-treated group, in contrast to none in control group, achieved insulin independence and maintained insulin free for 3 to 12 months. Among the adult-onset T1D, the percent change of postprandial C-peptide was significantly increased in MSC-treated group than in the control group. However, changes in fasting or postprandial C-peptide were not significantly different between groups among the juvenile-onset T1D. Multivariable logistic regression assay indicated that lower fasting C-peptide and higher dose of UC-MSC correlated with achievement of clinical remission after transplantation. No severe side effects were observed. Conclusion One repeated intravenous dose of allogeneic UC-MSCs is safe in people with recent-onset T1D and may result in better islet β cell preservation during the first year after diagnosis compared to standard treatment alone. Trial registration ChiCTR2100045434. Registered on April 15, 2021—retrospectively registered, http://www.chictr.org.cn/

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