Profiling the Gut Microbiome Unraveled Signature Bacterial Groups in Autoimmune Diabetes, which Remain Unperturbed by the Low Ionic Strength of the Drinking Water in NOD mice.

BACKGROUND: Non-obese diabetic (NOD) mice develop type 1 diabetes (T1D) spontaneously and serve as a good model for investigating the underlying pathological mechanisms and devising novel treatment procedures. Although acid water consumption has been reported to exaggerate or reduce diabetes incidence in female NOD mice by two groups, the causative bacteria responsible for these contrasting changes remain unclear. On the contrary, we and others failed to observe the effect of acid water consumption on diabetes incidence. This study aimed to determine whether the consumption of low-pH drinking water could alter the frequencies of prominent bacterial groups independent of diabetes manifestation. METHODS: Six-week-old female NOD mice maintained on acidified drinking water at the Jackson Laboratories were transferred to neutral pH water or continuously provided with low pH drinking water at our facility. Diabetes was monitored weekly using a glucometer. Using the 454-pyrosequencing methodology, we profiled the gut microbiome of mice transferred to neutral water and developed diabetes. Further, we performed quantitative real-time polymerase chain reactions (qRT-PCR) using primers specific for prominent 16S rRNA genes on the fecal DNA of mice provided with low pH or neutral water and displayed diabetes similarly. RESULTS: Consistent with our earlier report, the incidence of T1D was robust (80-100%) regardless of whether female NOD mice consumed acid (~pH 2.9) or neutral water. The 454-pyrosequencing of fecal DNA indicated no substantial influence of transferring mice to neutral pH drinking water on the gut microbiome. To validate these findings, we conducted qRT-PCR on the fecal DNA of mice longitudinally from six weeks of age to adulthood that consumed acidic or neutral pH water and developed diabetes similarly. Among the 15 selected bacterial groups examined, the frequency of Lactobacillus sp. remained consistently lower (p < 0.05) throughout the life of NOD mice compared to that found in young (6-week-old) mice, regardless of the pH of the drinking water. The relative frequencies of the Firmicutes Ruminococcaceae and the Bactereoidetes members Anaerophaga sp. and Paludibacter sp. increased significantly (p < 0.05) during the transition to the overtly diabetic stage irrespective of the ionic strength of the drinking water. Interestingly, the Firmicutes members Clostridium coccoides, C. leptum, and Lachnospiraceae and the Bacteroidetes members Bacteroides sp. and Prevottella sp. remained unchanged throughout the analysis irrespective of the pH of the drinking water. Paradoxically, the representations of Akkermansia muciniphila and the segmented filamentous bacteria implicated in diabetes protection did not differ regardless of the age or the ionic strength of the drinking water. CONCLUSIONS: The data presented herein validate the lack of influence of acidic drinking water on T1D development in female NOD mice. Diabetes was associated with the lower representation of Lactobacillus sp. throughout life, which was not influenced by the differing pH of the drinking water. Significantly, segmented filamentous bacteria and A. muciniphila, previously implicated in protection against T1D, were not perturbed by the varying pH of the water consumed. These data indicate that although acidified water consumption was reported previously to diminish specific gastrointestinal pathogens, it failed to perturb gut commensals that influence diabetes development.

Dietary emulsifier consumption accelerates type 1 diabetes development in NOD mice.

The rapidly increasing prevalence of type 1 diabetes (T1D) underscores the role of environmental (i.e. non-genetic) determinants of T1D development. Such factors include industrialized diets as well as the intestinal microbiota with which they interact. One component of industrialized diets that deleteriously impact gut microbiota is dietary emulsifiers, which perturb intestinal microbiota to encroach upon their host promoting chronic low-grade intestinal inflammation and metabolic syndrome. Hence, we investigated whether 2 dietary emulsifiers, carboxymethylcellulose (CMC) and polysorbate-80 (P80), might influence the development of T1D in NOD mice, which spontaneously develop this disorder. We observed that chronic emulsifier exposure accelerated T1D development in NOD mice, which was associated with increased insulin autoantibody levels. Such accelerated T1D development was accompanied by compositional and functional alterations of the intestinal microbiota as well as low-grade intestinal inflammation. Moreover, machine learning found that the severity of emulsifier-induced microbiota disruption had partial power to predict subsequent disease development, suggesting that complex interactions occur between the host, dietary factors, and the intestinal microbiota. Thus, perturbation of host-microbiota homeostasis by dietary emulsifiers may have contributed to the post-mid-20th-century increase in T1D.

Cumulative incidence of type 1 diabetes in two cohorts of children with different national gluten recommendations in infancy.

AIMS: Between 1985 and 1996, Sweden experienced an "epidemic" of celiac disease with a fourfold increase in incidence in young children. Timing and amount of gluten introduced during infancy have been thought to explain this "epidemic". We aimed to study whether the cumulative incidence of type 1 diabetes differs between children born during the "epidemic" compared to children born after. METHODS: This is a national register study in Sweden comparing the cumulative incidence of type 1 diabetes in two birth cohorts of 240 844 children 0-17 years old born 1992-1993, during the "epidemic", and 179 530 children born 1997-1998, after the "epidemic". Children diagnosed with type 1 diabetes were identified using three national registers. RESULTS: The cumulative incidence of type 1 diabetes by the age of 17 was statistically significantly higher in those born after the "epidemic" 0.77% than in those born during the "epidemic" 0.68% (p < 0.001). CONCLUSION: The incidence of type 1 diabetes is higher in those born after the epidemic compared to those born during the epidemic, which does not support the hypothesis that gluten introduction increases the incidence of T1D. Changes in gluten introduction did not halt the increased incidence of type 1 diabetes in Sweden.

Lack of association between month of birth and risk of developing type 1 diabetes in Brazil: a 40-year analysis.

OBJECTIVES: Seasonal environment at birth may influence diabetes incidence in later life. We sought evidence for this effect and analyzed the association between the month of birth and the risk of developing type 1 diabetes mellitus (T1DM). METHODS: This was a cohort study carried out with 814 patients diagnosed with T1DM in the region of Bauru - São Paulo State, Brazil, receiving medical care in a private Endocrinology clinic or in the public Brazilian National Health Care System, from 1981 to 2021. All live births that occurred in São Paulo State between 1974 and 2020 were classified by month of birth and were considered as the control group. RESULTS: We found no statistically significant difference (χ2=16.31, critical 19.68) between the month of birth and risk of developing T1DM, when comparing our patients with the background population of the region. There was no association between the month of birth, sex, age at diagnosis, duration of symptoms before diagnosis, self-reported color, and socioeconomic status. CONCLUSIONS: We found no association between month of birth and the risk of developing T1DM in this highly admixed South American population. Our data suggest that our population heterogeneity and geographic location may be important factors in the development of T1DM. Future prospective studies, evaluating environmental factors that may confer risk or protection to the disease, are warranted.

Fruit, berry, and vegetable consumption and the risk of islet autoimmunity and type 1 diabetes in children-the Type 1 Diabetes Prediction and Prevention birth cohort study.

BACKGROUND: Prospective studies investigating the association among fruit, berry, and vegetable consumption and the risk of islet autoimmunity (IA) and type 1 diabetes (T1D) are few. OBJECTIVES: In this cohort study, we explored whether the consumption of fruits, berries, and vegetables is associated with the IA and T1D development in genetically susceptible children. METHODS: Food consumption data in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) cohort study were available from 5674 children born between September 1996 and September 2004 in the Oulu and Tampere University Hospitals. Diet was assessed with 3-d food records at the age of 3 and 6 mo and annually from 1 to 6 y. The association between food consumption and the risk of IA and T1D was analyzed using joint models adjusted for energy intake, sex, human leukocyte antigen (HLA) genotype, and a family history of diabetes. RESULTS: During the 6-y follow-up, 247 children (4.4%) developed IA and 94 (1.7%) T1D. Furthermore, 64 of 505 children with at least 1 repeatedly positive autoantibody (12.7%) progressed from islet autoantibody positivity to T1D. The consumption of cruciferous vegetables was associated with decreased risk of IA [hazard ratio (HR): 0.83; 95% credible intervals (CI): 0.72, 0.95, per 1 g/MJ increase in consumption] and the consumption of berries with decreased risk of T1D (0.60; 0.47, 0.89). The consumption of banana was associated with increased risk of IA (1.08; 1.04, 1.12) and T1D (1.11; 1.01, 1.21). Only the association between banana and IA remain significant after multiple testing correction. CONCLUSIONS: In children genetically at risk for T1D, the consumption of cruciferous vegetables was associated with decreased risk of IA and consumption of berries with decreased risk of T1D. In addition, the consumption of banana was associated with increased risk of IA and T1D.

The Impact of Dietary Factors during Pregnancy on the Development of Islet Autoimmunity and Type 1 Diabetes: A Systematic Literature Review.

AIMS AND HYPOTHESIS: The incidence of type 1 diabetes mellitus in children is considerably increasing in western countries. Thus, identification of the environmental determinants involved could ultimately lead to disease prevention. Here, we aimed to systematically review (PROSPERO ID: CRD42022362522) the current evidence of the association between maternal dietary factors during gestation and the risk of developing type 1 diabetes and/or islet autoimmunity (IA) in murine and human offspring. METHODS: In accordance with PRISMA guidelines, the present systematic review searched PubMed and Scopus (n = 343) for different combinations of MeSH terms, such as type 1 diabetes, diet, islet autoimmunity, prenatal, nutrient, gluten, gliadin, vitamin, milk, and fibers. RESULTS: We found that the most investigated dietary factors in the present literature were gluten, dietary advanced glycosylated end products (dAGEs), vitamin D, fatty acids, and iron. The results concerning prenatal exposure to a gluten-free environment showed a consistently protective effect on the development of IA. Prenatal exposures to vitamin D and certain fatty acids appeared to protect against the development of IA, whereas in utero iron and fat exposures correlated with increased risks of IA. CONCLUSION: We conclude that a definite association is not established for most factors investigated as the literature represents a heterogeneous pool of data, although fetal exposures to some maternal dietary components, such as gluten, show consistent associations with increased risks of IA. We suggest that human prospective dietary intervention studies in both cohort and clinical settings are crucial to better evaluate critical and protective prenatal exposures from the maternal diet during pregnancy.

SARS-CoV-2 Infection and Development of Islet Autoimmunity in Early Childhood.

Importance: The incidence of diabetes in childhood has increased during the COVID-19 pandemic. Elucidating whether SARS-CoV-2 infection is associated with islet autoimmunity, which precedes type 1 diabetes onset, is relevant to disease etiology and future childhood diabetes trends. Objective: To determine whether there is a temporal relationship between SARS-CoV-2 infection and the development of islet autoimmunity in early childhood. Design, Setting, and Participants: Between February 2018 and March 2021, the Primary Oral Insulin Trial, a European multicenter study, enrolled 1050 infants (517 girls) aged 4 to 7 months with a more than 10% genetically defined risk of type 1 diabetes. Children were followed up through September 2022. Exposure: SARS-CoV-2 infection identified by SARS-CoV-2 antibody development in follow-up visits conducted at 2- to 6-month intervals until age 2 years from April 2018 through June 2022. Main Outcomes and Measures: The development of multiple (≥2) islet autoantibodies in follow-up in consecutive samples or single islet antibodies and type 1 diabetes. Antibody incidence rates and risk of developing islet autoantibodies were analyzed. Results: Consent was obtained for 885 (441 girls) children who were included in follow-up antibody measurements from age 6 months. SARS-CoV-2 antibodies developed in 170 children at a median age of 18 months (range, 6-25 months). Islet autoantibodies developed in 60 children. Six of these children tested positive for islet autoantibodies at the same time as they tested positive for SARS-CoV-2 antibodies and 6 at the visit after having tested positive for SARS-CoV-2 antibodies. The sex-, age-, and country-adjusted hazard ratio for developing islet autoantibodies when the children tested positive for SARS-CoV-2 antibodies was 3.5 (95% CI, 1.6-7.7; P = .002). The incidence rate of islet autoantibodies was 3.5 (95% CI, 2.2-5.1) per 100 person-years in children without SARS-CoV-2 antibodies and 7.8 (95% CI, 5.3-19.0) per 100 person-years in children with SARS-CoV-2 antibodies (P = .02). Islet autoantibody risk in children with SARS-CoV-2 antibodies was associated with younger age (<18 months) of SARS-CoV-2 antibody development (HR, 5.3; 95% CI, 1.5-18.3; P = .009). Conclusion and relevance: In young children with high genetic risk of type 1 diabetes, SARS-CoV-2 infection was temporally associated with the development of islet autoantibodies.

Is socio-economic status associated with risk of childhood type 1 diabetes? Literature review.

AIMS: Studies of social inequality and risk of developing type 1 diabetes are inconsistent. The present review aimed to comprehensively review relevant literature and describe what has been reported on socio-economic status or parental occupation and risk of type 1 diabetes in children. METHODS: We searched for publications between 1 January 1970 and 30 November 2021. We focused on the most recent and/or informative publication in cases of multiple publications from the same data source and referred to these as primary studies. RESULTS: Our search identified 69 publications with relevant data. We identified eight primary cohort studies with individual-level data, which we considered the highest quality of evidence. Furthermore, we identified 13 primary case-control studies and 14 semi-ecological studies with area-level socio-economic status variables which provided a weaker quality of evidence. Four of eight primary cohort studies contained data on maternal education, showing non-linear associations with type 1 diabetes that were not consistent across studies. There was no consistent pattern on the association of parental occupation and childhood-onset type 1 diabetes. CONCLUSIONS: There is a need for more high-quality studies, but the existing literature does not suggest a major and consistent role of socio-economic status in the risk of type 1 diabetes.

Prospective External Validation of an Algorithm Predicting Hourly Basal Insulin Infusion Rates from Characteristics of Patients with Type 1 Diabetes Treated with Insulin Pumps.

BACKGROUND: We previously published an algorithm predicting 24 h basal insulin infusion profiles in insulin pump-treated subjects with type 1 diabetes profiles from six subject characteristics. This algorithm was to be externally validated in an independent environment and patient population. METHODS: Thirty-two patients with pump-treated type diabetes were switched to their individually algorithm-derived basal insulin infusion profile, and the appropriateness of fasting glycemic control was scrutinized by means of a supervised 24 h fast. Primary endpoint was appropriate fasting glycemic control according to pre-defined criteria in at least 80% of the cohort. RESULTS: In 24 out of 32 patients switching to the algorithm-derived basal insulin infusion rate and undergoing a 24-h fasting period, appropriate glycemic control was achieved (=75%, lower than the pre-defined threshold of 80%), two patients discontinued the fast due to hyperglycemia, and six finished the fasting period, however, with inappropriate fasting glycemic control (entirely due to hyperglycemic episodes). There were no obvious differences in baseline characteristics between those with appropriate vs. inappropriate fasting glycemic control on the basal insulin infusion rate provided by the algorithm. CONCLUSION: In conclusion, when testing fasting glycemic control with an algorithm-derived individual basal insulin infusion profile during a 24 h fasting period in a cohort unrelated in terms of the hospital environment and catchment area, the success rate was lower than a pre-defined threshold for concluding utility of this algorithm. Therefore, applying this algorithm in order to initiate or optimize basal insulin infusion profiles in type 1 diabetes cannot be generally recommended.

Early and sustained increase in time in range 1 year after initiation of hybrid close loop therapy via telemedicine in type 1 diabetes patients.

BACKGROUND AND AIMS: Evidence supports the efficacy and safety of the Hybrid Close loop (HCL) system in patients with type 1 diabetes (T1D). However, limited data are available on the long-term outcomes of patients on HCL with telemedicine follow-up. METHODS: A prospective observational cohort study including T1D patients, who were upgrading to HCL system. Virtual training and follow-up were done through telemedicine. CGM data were analyzed to compare the baseline time in range (TIR), time below range (TBR), glycemic variability and auto mode (AM), with measurements performed at 3, 6 and 12 months. RESULTS: 134 patients were included with baseline A1c 7.6% ± 1.1. 40.5% had a severe hypoglycemia event in the last year. Baseline TIR, measured two weeks after starting AM was 78.6 ± 9.94%. No changes were evident at three (Mean difference - 0.15;CI-2.47,2.17;p = 0.96), six (MD-1.09;CI-3.42,1.24;p = 0.12) and 12 months (MD-1.30;CI-3.64,1.04;p = 0.08). No significant changes were found in TBR or glycemic variability throughout the follow-up. Use of AM was 85.6 ± 17.5% and percentage of use of sensor was 88.75 ± 9.5% at 12 months. No severe hypoglycemic (SH) events were reported. CONCLUSIONS: HCL systems allow to improve TIR, TBR and glycemic variability safely, early and sustained up to 1 year of follow-up in patients with T1D and high risk of hypoglycemia followed through telemedicine.

Protocol for a nested case-control study design for omics investigations in the Environmental Determinants of Islet Autoimmunity cohort.

Background: The Environmental Determinants of Islet Autoimmunity (ENDIA) pregnancy-birth cohort investigates the developmental origins of type 1 diabetes (T1D), with recruitment between 2013 and 2019. ENDIA is the first study in the world with comprehensive data and biospecimen collection during pregnancy, at birth and through childhood from at-risk children who have a first-degree relative with T1D. Environmental exposures are thought to drive the progression to clinical T1D, with pancreatic islet autoimmunity (IA) developing in genetically susceptible individuals. The exposures and key molecular mechanisms driving this progression are unknown. Persistent IA is the primary outcome of ENDIA; defined as a positive antibody for at least one of IAA, GAD, ZnT8 or IA2 on two consecutive occasions and signifies high risk of clinical T1D.Method: A nested case-control (NCC) study design with 54 cases and 161 matched controls aims to investigate associations between persistent IA and longitudinal omics exposures in ENDIA. The NCC study will analyse samples obtained from ENDIA children who have either developed persistent IA or progressed to clinical T1D (cases) and matched control children at risk of developing persistent IA. Control children were matched on sex and age, with all four autoantibodies absent within a defined window of the case's onset date. Cases seroconverted at a median of 1.37 years (IQR 0.95, 2.56). Longitudinal omics data generated from approximately 16,000 samples of different biospecimen types, will enable evaluation of changes from pregnancy through childhood.Conclusions: This paper describes the ENDIA NCC study, omics platform design considerations and planned univariate and multivariate analyses for its longitudinal data. Methodologies for multivariate omics analysis with longitudinal data are discovery-focused and data driven. There is currently no single multivariate method tailored specifically for the longitudinal omics data that the ENDIA NCC study will generate and therefore omics analysis results will require either cross validation or independent validation.KEY MESSAGESThe ENDIA nested case-control study will utilize longitudinal omics data on approximately 16,000 samples from 190 unique children at risk of type 1 diabetes (T1D), including 54 who have developed islet autoimmunity (IA), followed during pregnancy, at birth and during early childhood, enabling the developmental origins of T1D to be explored.

Low maternal education increases the risk of Type 1 Diabetes, but not other autoimmune diseases: a mediating role of childhood BMI and exposure to serious life events.

The objective of this paper was to investigate if socioeconomic status (SES), measured by maternal education and household income, influenced the risk of developing autoimmune disease (Type 1 Diabetes, Celiac disease, Juvenile Idiopathic Arthritis, Crohn's disease, Ulcerative colitis, and autoimmune thyroid disease), or age at diagnosis, and to analyse pathways between SES and autoimmune disease. We used data from the All Babies in Southeast Sweden (ABIS) study, a population-based prospective birth cohort, which included children born 1997-1999. Diagnoses of autoimmune disease was collected from the Swedish National Patient Register Dec 2020. In 16,365 individuals, low maternal education, but not household income, was associated with increased risk of Type 1 Diabetes; middle education RR 1.54, 95% CI 1.06, 2.23; P 0.02, low education RR 1.81, 95% CI 1.04, 3.18; P 0.04. Maternal education and household income was not associated with any other autoimmune disease and did not influence the age at diagnosis. Part of the increased risk of Type 1 Diabetes by lower maternal education was mediated by the indirect pathway of higher BMI and higher risk of Serious Life Events (SLE) at 5 years of age. The risk of developing Type 1 Diabetes associated to low maternal education might be reduced by decreasing BMI and SLE during childhood.

Changes in the Global Epidemiology of Type 1 Diabetes in an Evolving Landscape of Environmental Factors: Causes, Challenges, and Opportunities.

The worldwide incidence of type 1 diabetes mellitus (T1DM) has increased in recent decades. The reasons behind this phenomenon are not yet fully understood. Early life infections, prenatal and perinatal factors, and diet composition have been associated with the triggering of autoimmunity and the risk of presentation of T1DM. However, the rapid increase in new cases of the disease raises the hypothesis that lifestyle factors, which have traditionally been associated with type 2 diabetes, such as obesity and unhealthy eating patterns could also play a role in the genesis of autoimmune diabetes. This article aims to highlight the changing epidemiology of T1DM and the importance of properly recognizing the environmental factors behind it, as well as the connections with the pathogenesis of the disorder and the need to prevent or delay T1DM and its long-term complications.

COVID-19 as a Trigger for Type 1 Diabetes.

Type 1 diabetes (T1D) is usually caused by immune-mediated destruction of islet ß cells, and genetic and environmental factors are thought to trigger autoimmunity. Convincing evidence indicates that viruses are associated with T1D development and progression. During the COVID-19 pandemic, cases of hyperglycemia, diabetic ketoacidosis, and new diabetes increased, suggesting that SARS-CoV-2 may be a trigger for or unmask T1D. Possible mechanisms of ß-cell damage include virus-triggered cell death, immune-mediated loss of pancreatic ß cells, and damage to ß cells because of infection of surrounding cells. This article examines the potential pathways by which SARS-CoV-2 affects islet ß cells in these 3 aspects. Specifically, we emphasize that T1D can be triggered by SARS-CoV-2 through several autoimmune mechanisms, including epitope spread, molecular mimicry, and bystander activation. Given that the development of T1D is often a chronic, long-term process, it is difficult to currently draw firm conclusions as to whether SARS-CoV-2 causes T1D. This area needs to be focused on in terms of the long-term outcomes. More in-depth and comprehensive studies with larger cohorts of patients and long-term clinical follow-ups are required.

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.

Stress and Diabetes Mellitus: Pathogenetic Mechanisms and Clinical Outcome.

Evidence suggests that psychological and physical stress are relevant triggering factors for the onset of type 1 diabetes (T1D) and type 2 diabetes (T2D). The underlying mechanisms involve a complex neuroendocrine structure, involving the central nervous system and the periphery. Psychological stress leads to an increase of serum glucocorticoid concentrations and catecholamines release increasing the insulin need and the insulin resistance. According to the ß-cell stress hypothesis, also causes of increased insulin demand, such as rapid growth, overweight, puberty, low physical activity, trauma, infections, and glucose overload, are potentially relevant factors in development of T1D. It has also been demonstrated that chronic stress and obesity form a vicious circle which leads to a definitive metabolic failure, increasing the risk of developing T2D. In this review, we will provide the most recent data concerning the role of stress in the outcomes of T1D and T2D, with a focus on the role of physical and psychological stress on the onset of T1D.

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.