Macrophage: Key player in the pathogenesis of autoimmune diseases.

The macrophage is an essential part of the innate immune system and also serves as the bridge between innate immunity and adaptive immune response. As the initiator and executor of the adaptive immune response, macrophage plays an important role in various physiological processes such as immune tolerance, fibrosis, inflammatory response, angiogenesis and phagocytosis of apoptotic cells. Consequently, macrophage dysfunction is a vital cause of the occurrence and development of autoimmune diseases. In this review, we mainly discuss the functions of macrophages in autoimmune diseases, especially in systemic lupus erythematosus (SLE), rheumatic arthritis (RA), systemic sclerosis (SSc) and type 1 diabetes (T1D), providing references for the treatment and prevention of autoimmune diseases.

Comparison of long-term outcomes in simultaneous pancreas-kidney transplant versus simultaneous deceased donor pancreas and living donor kidney transplant.

Simultaneous deceased donor pancreas and living donor kidney transplant (SPLK) has certain advantages over conventional simultaneous pancreas-kidney transplant (SPK) and may be beneficial for overcoming the paucity of organs needed for diabetic patients requiring transplant. We compared the clinical outcomes of patients who underwent either SPK (n = 149) or SPLK (n = 46) in terms of pre- and post-transplantation variables, development of de novo DSA, occurrence of biopsy-proven acute rejection (BPAR), and graft survival rates. There were no significant differences in the baseline characteristics between the SPK and SPLK groups except for the shorter cold ischemic time of kidney grafts, shorter duration of diabetes, older age of pancreas graft-donors, and younger age of kidney graft-donors in the SPLK group. Our results showed that the death-censored pancreas graft survival rate was lower in the SPLK group. In addition, the incidence of BPAR of the pancreas graft was higher in the SPLK group. There was no significant difference in the presence of de novo DSA and the rates of kidney graft failure, kidney BPAR, and mortality. Our results show that SPLK can be considered an alternative option for SPK although higher incidences of BPAR and graft failure of pancreas after SPLK need to be overcome.

Fulminant Type 1 Diabetes Mellitus Caused by Long-Term Nivolumab Administration Followed by Nivolumab plus Cabozantinib Combination.

Nivolumab, an immune checkpoint inhibitor (ICI), is now used to treat many advanced cancers, including non-small cell lung cancer (NSCLC) and renal cancer. Immune-related adverse events are characteristic side effects of ICIs. Among them, fulminant type 1 diabetes mellitus is an infrequent but potentially life-threatening and clinically significant concern. Cabozantinib is known as a multikinase inhibitor. In recent years, combination therapy with nivolumab and cabozantinib has begun to be used to treat renal cell carcinoma. A 74-year-old man with no history of diabetes was treated with nivolumab for 5 years for NSCLC, followed by the combination of nivolumab and cabozantinib for clear cell renal cell carcinoma. He was diagnosed with fulminant type 1 diabetes 5 weeks after starting combination therapy, with symptoms of nausea and dry mouth. He was admitted to the intensive care unit and improved clinically with continuous insulin infusion and saline. The involvement of cabozantinib in the development of fulminant type 1 diabetes with long-term nivolumab use, which has not been reported previously, is unknown, but caution may be necessary in terms of glycemic control in combination therapy with nivolumab and cabozantinib.

Prenatal and early life factors and type 1 diabetes.

BACKGROUND: The prevalence of type 1 diabetes is increasing worldwide, suggesting that unknown environmental factors are becoming increasingly important in its pathogenesis. AIM: The aim of the study was to investigate the possible role of a number of prenatal and perinatal factors in the aetiology of type 1 diabetes. METHODS: Mothers of patients diagnosed with type 1 diabetes (cases) and mothers of children born on the same day and of the same sex as type 1 diabetes patients (controls) were interviewed on a number of prenatal and perinatal factors of interest. RESULTS: Hand washing prior to eating, frequency of bathing and total stress score were found to be positively associated with the development of type 1 diabetes on univariate analyses. Hand-washing prior to eating and frequency of house cleaning were independently associated with an increased risk of type 1 diabetes, whilst getting dirty was associated with a reduced risk in multivariate analyses. There was no association of type 1 diabetes to removing of outdoor shoes indoors or to the age of first attendance to school or pre-school. There were also no significant associations to parental smoking, parental age, birth order, infant feeding, antibiotic use, mode of delivery or birth weight. CONCLUSION: Our data suggest that factors that affect the skin or gut microbiome might be more important than infections or factors affecting the microbiome at other sites.

Parental smoking, type 1 diabetes, and islet autoantibody positivity in the offspring: A systematic review and meta-analysis.

AIMS: Our aim was to synthesize current evidence on the association between parental smoking and incidence of type 1 diabetes and islet autoantibody positivity (IA) in the offspring by conducting a systematic review and meta-analysis. METHODS: We searched Medline, Embase, and Cochrane Library until January 21, 2021, for human studies with parental tobacco use as exposure, type 1 diabetes or IA as outcome, and hazard, risk, or odds ratios as effect estimates. Summary relative risks (RR) and 95% confidence intervals (CI) were estimated with random-effects models. Heterogeneity was quantified with the I2  statistic, bias with the ROBINS-I tool, and the certainty of evidence with the GRADE tool. RESULTS: We identified 535 records of which 23 were eligible including 25 927 cases of type 1 diabetes. Maternal smoking during pregnancy was associated with a reduced risk of type 1 diabetes (n = 22, RR 0.78, CI 0.71-0.86, I2 =69%). Including only studies with low to moderate risk of bias indicated similar results with less heterogeneity (n = 14, RR 0.73, CI 0.68-0.79, I2  = 44%). The certainty of evidence was graded as high. There was no clear association between type 1 diabetes and neither maternal (n = 6, RR 0.95, CI 0.78-1.14, I2  = 0%) nor paternal (n = 6, RR 0.90, 0.70-1.17, I2  = 68%) smoking during childhood. Furthermore, the association between maternal smoking during pregnancy and IA was weak (n = 4, RR 0.86, CI 0.44-1.65, I2  = 71%). CONCLUSIONS: Maternal smoking during pregnancy may reduce the risk of type 1 diabetes in the offspring. Further studies are needed to elucidate potential mechanisms underlying this association. REGISTRATION: Prospero CRD42021236717.

Using the T Cell Receptor as a Biomarker in Type 1 Diabetes.

T cell receptors (TCRs) are unique markers that define antigen specificity for a given T cell. With the evolution of sequencing and computational analysis technologies, TCRs are now prime candidates for the development of next-generation non-cell based T cell biomarkers, which provide a surrogate measure to assess the presence of antigen-specific T cells. Type 1 diabetes (T1D), the immune-mediated form of diabetes, is a prototypical organ specific autoimmune disease in which T cells play a pivotal role in targeting pancreatic insulin-producing beta cells. While the disease is now predictable by measuring autoantibodies in the peripheral blood directed to beta cell proteins, there is an urgent need to develop T cell markers that recapitulate T cell activity in the pancreas and can be a measure of disease activity. This review focuses on the potential and challenges of developing TCR biomarkers for T1D. We summarize current knowledge about TCR repertoires and clonotypes specific for T1D and discuss challenges that are unique for autoimmune diabetes. Ultimately, the integration of large TCR datasets produced from individuals with and without T1D along with computational 'big data' analysis will facilitate the development of TCRs as potentially powerful biomarkers in the development of T1D.

Sex-Related Differences in Cardiovascular Disease Risk Profile in Children and Adolescents with Type 1 Diabetes.

Cardiovascular disease (CVD) is the primary cause of higher and earlier morbidity and mortality in people with type 1 diabetes (T1D) compared to people without diabetes. In addition, women with T1D are at an even higher relative risk for CVD than men. However, the underlying pathophysiology is not well understood. Atherosclerotic changes are known to progress early in life among people with T1D, yet it is less clear when excess CVD risk begins in females with T1D. This review explores the prevalence of classical CVD risk factors (such as glycemic control, hypertension, dyslipidemia, obesity, albuminuria, smoking, diet, physical inactivity), as well as of novel biomarkers (such as chronic inflammation), in children and adolescents with T1D with particular regard to sex-related differences in risk profile. We also summarize gaps where further research and clearer clinical guidance are needed to better address this issue. Considering that girls with T1D might have a more adverse CVD risk profile than boys, the early identification of and sex-specific intervention in T1D would have the potential to reduce later CVD morbidity and excess mortality in females with T1D. To conclude, based on an extensive review of the existing literature, we found a clear difference between boys and girls with T1D in the presence of individual CVD risk factors as well as in overall CVD risk profiles; the girls were on the whole more impacted.

Prenatal cadmium exposure does not induce greater incidence or earlier onset of autoimmunity in the offspring.

We previously demonstrated that exposure of adult mice to environmental levels of cadmium (Cd) alters immune cell development and function with increases in anti-streptococcal antibody levels, as well as decreases in splenic natural regulatory T cells (nTreg) in the adult female offspring. Based on these data, we hypothesized that prenatal Cd exposure could predispose an individual to developing autoimmunity as adults. To test this hypothesis, the effects of prenatal Cd on the development of autoimmune diabetes and arthritis were investigated. Non-obese diabetic (NOD) mice were exposed to Cd in a manner identical to our previous studies, and the onset of diabetes was assessed in the offspring. Our results showed a similar time-to-onset and severity of disease to historical data, and there were no statistical differences between Cd-exposed and control offspring. Numerous other immune parameters were measured and none of these parameters showed biologically-relevant differences between Cd-exposed and control animals. To test whether prenatal Cd-exposure affected development of autoimmune arthritis, we used SKG mice. While the levels of arthritis were similar between Cd-exposed and control offspring of both sexes, the pathology of arthritis determined by micro-computed tomography (µCT) between Cd-exposed and control animals, showed some statistically different values, especially in the female offspring. However, the differences were small and thus, the biological significance of these changes is open to speculation. Overall, based on the results from two autoimmune models, we conclude that prenatal exposure to Cd did not lead to a measurable propensity to develop autoimmune disease later in life.

Disfunción tiroidea y diabetes mellitus tipo 1 / Thyroid dysfunction and type 1 diabetes mellitus

Introducción: La diabetes mellitus tipo 1 es una enfermedad autoinmunitaria que se relaciona con alteraciones tiroideas. Objetivo: Describir la relación que existe entre diabetes mellitus tipo 1 y enfermedad tiroidea autoinmune. Métodos: Se realizó una revisión de la literatura nacional e internacional de los últimos 15 años en bases de datos, en español y en inglés. Se utilizaron las siguientes palabras clave: diabetes mellitus tipo 1, autoinmunidad, enfermad tiroidea autoinmune, disfunción tiroidea y anticuerpos antitiroideos. Análisis e integración de la información: La alteración más frecuente es el hipotiroidismo subclínico y se presenta con mayor frecuencia en el sexo femenino, por lo que se sugiere realizar periódicamente el perfil tiroideo a estos pacientes. Conclusiones: Se debe tener en cuenta en la práctica clínica estas implicaciones para brindar un tratamiento oportuno, mejorar complicaciones derivadas como las enfermedades cardiovasculares y disminuir las cifras de morbilidad y mortalidad(AU)

Introduction: Type 1 diabetes mellitus is an autoimmune disease that is related to thyroid abnormalities. Objective: Describe the relationship between type 1 diabetes mellitus and autoimmune thyroid disease. Methods: A review of the national and international literature of the last 15 years was carried out in databases, in Spanish and in English. The following keywords were used: type 1 diabetes mellitus, autoimmune, autoimmune thyroid disease, thyroid dysfunction and antithyroid antibodies. Analysis and integration of information: The most common alteration is subclinical hypothyroidism and it occurs most often in the female sex, so it is suggested to periodically perform the thyroid profile to these patients. Conclusions: These implications should be taken into account in clinical practice to provide timely treatment, improve complications such as cardiovascular disease and reduce morbidity and mortality figures(AU)

Hemoglobin A1c Is a Predictor of New Insulin Dependence After Partial Pancreatectomy: A Multi-Institutional Analysis.

BACKGROUND: Pancreatic diseases have long been associated with impaired glucose control. This study sought to identify the incidence of new insulin-dependent diabetes mellitus (IDDM) after pancreatectomy and the predictive accuracy of hemoglobin A1c (HbA1c) or blood glucose. METHODS: Patients who underwent partial pancreatectomy and had preoperative HbA1c available at two academic institutions were assessed for new IDDM on discharge in relation to complication rates and survival. RESULTS: Of the 267 patients analyzed, 67% had abnormal HbA1c levels prior to surgery (mean 6.8%, glucose 135 mg/dL). Two hundred eight (77.9%) were not insulin-dependent prior to surgery, and 35 (16.8%) developed new IDDM after resection. On multivariable regression, increasing HbA1c and preoperative glucose were the only significant predictors for new IDDM. Optimal predictive cutoffs (HbA1c of 6.25% and glucose of 121 mg/dL) were determined in a discovery group (n = 143) and confirmed in a validation group (n = 124) with a diagnostic sensitivity of 72.7% and specificity of 84.8%. Patients with new IDDM after resection had higher rates of severe complications (OR 3.39), increased TPN at discharge (OR 4.32), and increased rates of discharge to nursing facilities (OR 2.57) (all P < 0.05). New IDDM was also associated with a decreased cancer-specific survival. CONCLUSION: Preoperative HbA1c ≥ 6.25% and blood glucose ≥ 121 mg/dL can accurately identify patients at increased risk of IDDM. These diagnostics may help identify patients in a preoperative setting that may benefit from interventions such as diabetes education or enhanced glucose control preoperatively.

From virus to diabetes therapy: Characterization of a specific insulin-degrading enzyme inhibitor for diabetes treatment.

Inhibition of insulin-degrading enzyme (IDE) is a possible target for treating diabetes. However, it has not yet evolved into a medical intervention, mainly because most developed inhibitors target the zinc in IDE's catalytic site, potentially causing toxicity to other essential metalloproteases. Since IDE is a cellular receptor for the varicella-zoster virus (VZV), we constructed a VZV-based inhibitor. We computationally characterized its interaction site with IDE showing that the peptide specifically binds inside IDE's central cavity, however, not in close proximity to the zinc ion. We confirmed the peptide's effective inhibition on IDE activity in vitro and showed its efficacy in ameliorating insulin-related defects in types 1 and 2 diabetes mouse models. In addition, we suggest that inhibition of IDE may ameliorate the pro-inflammatory profile of CD4+ T-cells toward insulin. Together, we propose a potential role of a designed VZV-derived peptide to serve as a selectively-targeted and as an efficient diabetes therapy.

Predictors of sinonasal disease onset, progression, and severity in pediatric cystic fibrosis patients.

PURPOSE: Pediatric cystic fibrosis (CF) patients have a variable onset, severity, and progression of sinonasal disease. The objective of this study was to identify genotypic and phenotypic factors associated with CF that are predictive of sinonasal disease, recurrent nasal polyposis, and failure to respond to standard treatment. METHODS: A retrospective case series was conducted of 30 pediatric patients with CF chronic rhinosinusitis with and without polyps. Patient specific mutations were divided by class and categorized into high risk (Class I-III) and low risk (Class IV-V). Severity of pulmonary and pancreatic manifestations of CF, number of sinus surgeries, nasal polyposis and recurrence, age at presentation to Otolaryngology, and Pediatric Sinonasal Symptom Survey (SN-5)/Sinonasal Outcome Test (SNOT-22) scores were examined. RESULTS: 27/30 patients (90%) had high risk mutations (Class I-III). 21/30 (70.0%) patients had nasal polyposis and 10/30 (33.3%) had recurrent nasal polyposis. Dependence on pancreatic enzymes (23/27, 85.2% vs 0/3, 0.0%, p = 0.009) and worse forced expiratory volumes (FEV1%) (mean 79, SD 15 vs mean 105, SD 12, p = 0.009) were more common in patients with high risk mutations. Insulin-dependence was more common in those with recurrent polyposis (5/10, 50% vs 2/20, 10%, p = 0.026). There was no statistical difference in ages at presentation, first polyps, or sinus surgery, or in polyposis presence, recurrence, or extent of sinus surgery based on high risk vs. low risk classification. CONCLUSION: CF-related diabetes was associated with nasal polyposis recurrence. Patients with more severe extra-pulmonary manifestations of CF may also be at increased risk of sinonasal disease.

Case Report: Refractory Autoimmune Gastritis Responsive to Abatacept in LRBA Deficiency.

Primary immunodeficiency (PID) with immune dysregulation may present with early onset gastrointestinal autoimmune disorders. When gastrointestinal autoimmunity is associated with multiple extraintestinal immune system dysfunction the diagnosis of PID is straightforward. However, with the advent of next generation sequencing technologies, genetic defects in PID genes have been increasingly recognized even when a single or no extraintestinal signs of immune dysregulation are present. A genetic diagnosis is especially important considering the expanding armamentarium of therapies designed to inhibit specific molecular pathways. We describe a boy with early-onset severe, refractory autoimmune gastritis and biallelic mutations in the LRBA gene causing a premature STOP-codon who was successfully treated with CTLA4-Ig, abatacept, with long term clinical and endoscopic remission. The case underscores the importance to consider a monogenetic defect in early onset autoimmune disorders, since the availability of targeted treatments may significantly improve patient prognosis.

Risk of cause-specific death, its sex and age differences, and life expectancy in post-pancreatitis diabetes mellitus.

AIMS: The aim was to investigate sex- and age-stratified risks of cause-specific death and life expectancy in individuals with post-pancreatitis diabetes mellitus (PPDM). METHODS: Nationwide data on mortality in New Zealand were obtained. For two head-to-head comparisons (PPDM versus type 2 diabetes mellitus [T2DM]; PPDM versus type 1 diabetes mellitus [T1DM]), the groups were matched on age, sex, and calendar year of diabetes diagnosis. Multivariable Cox regression analyses were conducted to estimate risks of vascular, cancer, and non-vascular non-cancer mortality. Remaining life expectancy at age of diabetes diagnosis was estimated using the Chiang II method. RESULTS: A total of 15,848 individuals (1,132 PPDM, 3,396 T1DM, and 11,320 T2DM) were included. The risks of vascular mortality and non-vascular non-cancer mortality did not differ significantly between PPDM and T2DM or T1DM. PPDM was associated with a significantly higher risk of cancer mortality compared with T2DM (adjusted hazard ratio, 1.32; 95% confidence interval, 1.08-1.63) or T1DM (adjusted hazard ratio, 1.65; 95% confidence interval, 1.27-2.13). The risk of cancer mortality associated with PPDM (versus T2DM) was significantly higher in women than in men (p for interaction = 0.003). This sex difference in cancer mortality risk was also significant in the comparison between PPDM and T1DM (p for interaction = 0.006). Adults of both sexes with PPDM had the lowest remaining life expectancy (in comparison with T2DM or T1DM) up to 64 years of age. CONCLUSIONS: People with PPDM have a higher risk of cancer mortality compared with those with T2DM or T1DM. This is especially pronounced in women. Young and middle-aged adults with PPDM have a lower life expectancy compared with their counterparts with T2DM or T1DM.

Gut microbiota in pancreatic diseases: possible new therapeutic strategies.

Pancreatic diseases such as pancreatitis, type 1 diabetes and pancreatic cancer impose substantial health-care costs and contribute to marked morbidity and mortality. Recent studies have suggested a link between gut microbiota dysbiosis and pancreatic diseases; however, the potential roles and mechanisms of action of gut microbiota in pancreatic diseases remain to be fully elucidated. In this review, we summarize the evidence that supports relationship between alterations of gut microbiota and development of pancreatic diseases, and discuss the potential molecular mechanisms of gut microbiota dysbiosis in the pathogenesis of pancreatic diseases. We also propose current strategies toward gut microbiota to advance a developing research field that has clinical potential to reduce the cost of pancreatic diseases.

Refractive Error and Retinopathy Outcomes in Type 1 Diabetes: The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study.

PURPOSE: To determine the relationship between refractive error and diabetic retinopathy (DR). DESIGN: Clinical trial. PARTICIPANTS: Type I diabetes individuals with serial refractive error and DR stage measurements over 30 years in the Diabetes Control and Complications Trial (DCCT) and Epidemiology of Diabetes Interventions and Complications (EDIC) follow-up study. METHODS: Stage of DR was measured every 6 months from standard fundus photographs, and refractive error was measured annually during the 6.5 years of DCCT; then, both were staggered every fourth year during EDIC with the full cohort measured at EDIC years 4 and 10. Outcomes of DR were 2- or 3-step progression, presence of proliferative DR (PDR), clinically significant macular edema (CSME), diabetic macular edema (DME), or ocular surgery. Myopia, emmetropia, and hyperopia were defined as a spherical equivalent of ≤-0.5, >-0.5 and <0.5, and ≥0.5, respectively. MAIN OUTCOME MEASURES: For each outcome separately, Cox proportional hazard (PH) models assessed the association between the refractive error status and the subsequent risk of that outcome, both without and with adjustment for potential risk factors. RESULTS: Hyperopia was associated with a higher risk of 2-step progression (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.05-1.59), 3-step progression (HR, 1.35; 95% CI, 1.05-1.73), and PDR (HR, 1.40; 95% CI, 1.02-1.92) compared with emmetropia in unadjusted models. These associations remained significant after adjustment for DCCT treatment group, cohort, age, sex, smoking, duration of diabetes, systolic and diastolic blood pressures, pulse, low-density lipoprotein, high-density lipoprotein, triglycerides, albumin excretion rate, and DCCT/EDIC mean updated hemoglobin A1c (HbA1c) (2-step progression: HR, 1.28; 95% CI, 1.03-1.58; 3-step progression: HR, 1.30; 95% CI, 1.00-1.68; PDR: HR, 1.38; 95% CI, 1.00-1.90). Myopia was not associated with any of the 5 DR outcomes in the unadjusted models and only marginally associated with 2-step progression (HR, 1.11; 95% CI, 1.00-1.24) in the adjusted models. CONCLUSIONS: Myopia is not associated with DR progression risk. Hyperopia is an independent risk factor for 2-step and 3-step DR progression and PDR.

Sintilimab-Induced Autoimmune Diabetes in a Patient With the Anti-tumor Effect of Partial Regression.

Context: Immune checkpoint blockades (ICBs) have been approved widely to treat various malignancies. Autoimmune diabetes mellitus, which can be caused by programmed cell death protein 1 (PD-1) inhibitors, is rare. Sintilimab, a monoclonal anti-PD-1 antibody, has been approved in China for the treatment of Hodgkin's lymphoma and was used in our clinical trial for patients with unresectable hepatocellular carcinoma (HCC). Case Presentation: We present the first case of autoimmune diabetes during Sintilimab treatment in a patient with unresectable HCC, accompanied by a remarkable anti-tumor effect of partial regression. A 56-year-old male with typical symptoms presented with diabetic ketoacidosis (DKA) at 24 weeks after Sintilimab initiation. His fasting plasma glucose level was 22.2 mmol/L, HbA1c was 7.8%, fasting insulin was 1.5 mIU/L, and fasting C-peptide was 1.12 ng/mL, which further decreased to 0.21 ng/mL 4 days later. The patient was diagnosed with new-onset diabetes mellitus using the oral glucose tolerance test. The anti-glutamic acid decarboxylase 65 antibody, anti-islet cell antibody, and anti-insulin antibody tests were all negative. For the type 1 diabetes-associated alleles of human leukocyte antigen (HLA) class I and II, the most relevant type was identified as HLA-A∗0201. A diagnosis of PD-1 inhibitor-induced autoimmune diabetes was made. After rectification of DKA, he was treated with insulin therapy daily, which has since controlled his plasma glucose well. Thereafter, Sintilimab was been continued with sustained therapeutic effect. Conclusion: Due to unpredictability of this rare immune related adverse event (irAE), diabetes-related autoantibodies and C-peptide are recommended to be tested before immunotherapy, and plasma glucose monitoring should be performed. After plasma glucose is well controlled using insulin therapy, PD-1 inhibitor treatment might be continued, especially when the immunotherapy is effective.

Upregulation of FOXO3 in New-Onset Type 1 Diabetes Mellitus.

Forkhead box O (FOXO) transcription factors have been implicated in the development and differentiation of the immune cells. FOXO3 plays a crucial role in physiologic and pathologic immune response. FOXO3, cooperatively with FOXO1, control the development and function of Foxp3+ regulatory T cells (Treg). Since the lack of Treg-mediated control has fundamental impact on type 1 diabetes mellitus (T1DM) development, we investigated FOXO3 expression in patients with T1DM. FOXO3 expression was estimated in peripheral blood mononuclear cells (PBMCs) from newly diagnosed T1DM pediatric patients (n = 28) and age-matched healthy donors (n = 27) by reahavel-time PCR and TaqMan gene expression assays. Expression analysis revealed significant upregulation of FOXO3 in T1DM (P = 0.0005). Stratification of the T1DM group according to the presence of initial diabetic ketoacidosis (DKA) did not indicate differences in FOXO3 expression in patients with DKA compared to a mild T1DM onset (P > 0.05). In conclusion, overexpression of FOXO3 is correlated with the ongoing islet autoimmune destruction and might suggest a potential role for this gene in the pathogenesis of type 1 diabetes mellitus.

Adverse events associated with immune checkpoint inhibitors: a new era in autoimmune diabetes.

PURPOSE OF REVIEW: To summarize a new form of autoimmune diabetes as an adverse event of specific cancer immunotherapies. Immune checkpoint inhibitors are revolutionary treatments in advanced cancers; however, they can cause type 1 diabetes following treatment with these state-of-the-art therapies. RECENT FINDINGS: A review of the literature showed that this new form of autoimmune diabetes has significant similarities with childhood-onset type 1 diabetes but also some distinctions. It frequently presents with severe diabetic ketoacidosis and almost half of the patients have type 1 diabetes-associated antibodies at presentation. Rapid loss of residual beta-cell function with a lack of honeymoon phase is typical. Certain human leukocyte antigen risk genes for prototypical type 1 diabetes that develops in children and young adults are also commonly found in patients with immune checkpoint inhibitor-induced type 1 diabetes. SUMMARY: Immune checkpoint inhibitor-induced type 1 diabetes presenting with diabetic ketoacidosis is a life-threatening adverse event of cancer immunotherapy. Healthcare providers should be aware of this adverse event to prevent morbidity and mortality related to diabetic ketoacidosis. Developing guidelines to identify and monitor risk groups are of utmost importance.