Prevalence and prognosis of fulminant type 1 diabetes mellitus in The Middle East: a comparative analysis in a 5-year nationwide cohort.

PURPOSE: To analyze the prevalence and progression of fulminant type 1 diabetes (FT1D) in Qatar. METHODS: This retrospective study analyzed consecutive index- diabetic ketoacidosis (DKA) admissions (2015-2020) among patients with new-onset T1D (NT1D) in Qatar. RESULTS: Of the 242 patients, 2.5% fulfilled the FT1D diagnostic criteria. FT1D patients were younger (median-age 4-years vs.15-years in classic-T1D). Gender distribution in FT1D was equal, whereas the classic-T1D group showed a female predominance at 57.6% (n = 136). FT1D patients had a mean C-peptide of 0.11 ± 0.09 ng/ml, compared to 0.53 ± 0.45 ng/ml in classic-T1D. FT1D patients had a median length of stay (LOS) of 1 day (1-2.2) and a DKA duration of 11.25 h (11-15). The median (length of stay) LOS and DKA duration in classic-T1D patients were 2.5 days (1-3.9) and 15.4 h (11-23), respectively. The FT1D subset primarily consisted of moderate (83.3%) and severe 916.7%) DKA, whereas classic T1D had 25.4% mild, 60.6% moderate, and 14% severe DKA cases. FT1D was associated with a higher median white cell count (22.3 × 103/uL) at admission compared to classic T1D (10.6 × 103/uL). ICU admission was needed for 66.6% of FT1D patients, compared to 38.1% of classic-T1D patients. None of the patients in the FT1D group had mortality, while two died in the classic-T1D group. CONCLUSION: This is the first study establishing the existence of FT1D in ME, which presented distinctively from classic-T1D, exhibiting earlier age onset and higher critical care requirements. However, the clinical outcomes in patients with FT1D seem similar to classic T1D.

Stevens-Johnson Syndrome/Toxic epidermal necrolysis complicated with fulminant type 1 diabetes mellitus: a case report and literature review.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but life-threatening skin lesion triggered by hypersensitive drug reaction. They are characterized by extensive epidermal necrosis and skin exfoliation. Fulminant type 1 diabetes mellitus (FT1DM) is featured by a rapid-onset of hyperglycemia with ketoacidosis due to severely destroyed ß-cell function. Fulminant type 1 diabetes mellitus as a sequela of SJS/TEN has rarely been reported. CASE PRESENTATION: We present a 73-year-old female patient who developed SJS/TEN skin allergic reaction after taking carbamazepine and phenytoin for 35 days. Then, hyperglycemia and diabetic ketoacidosis occurred 20 days after discontinuation of antiepileptic drugs. A very low serum C-peptide level (8.79 pmol/l) and a near-normal glycosylated hemoglobin level met the diagnostic criteria for fulminant T1DM. Intravenous immunoglobulin (IVIG) and insulin were promptly administered, and the patient recovered finally. CONCLUSIONS: This rare case indicates that monitoring blood glucose is necessary in SJS/TEN drug reaction, and comprehensive therapy with rehydration, insulin, antibiotics, and IVIG may improve the prognosis.

Snap diagnosis of fulminant type 1 diabetes by the normalized glucose/HbA1c ratio.

Elevated Fulminant Index (FI), [plasma glucose (PG)/glycosylated hemoglobin A1c (HbA1c)], was reportedly a sensitive index to differentiate fulminant type 1 diabetes (FT1D) from non-fulminant T1D (nFT1D). Aim of this study was to describe a better, but simpler index of FT1D. 49 and 52 patients with FT1D and nFT1D, respectively, were registered, and the discriminating ability of the rounded, normalized ratio, [PG (mmol/L) - 5.0]/[HbA1c (%) - 5.0], and the original ratio, [PG (mmol/L)]/[HbA1c (%)], was compared. Normalizing the ratio significantly raised its accuracy: area under the curve for receiver operating curve, AUROC (95%CI), 0.927 (0.858-0.964) and 0.851 (0.763-0.910), respectively, with and without the normalization (p < 0.01). Rounding of the figure into [PG (mmol/L) - 5.0]/[HbA1c (%) - 5.0] did not significantly sacrifice the discriminating ability of the index. Namely, the optimal cut point of rounded and normalized GAR, 10.0, showed 89.8% sensitivity. In conclusion, rounded, normalized (rn) GAR ≥10 (the rounded optimal cut-off) could be used for the snap diagnosis of FT1D.

Isolated adrenocorticotropic hormone deficiency following immune checkpoint inhibitors treatment often occurs in polyglandular endocrinopathies.

BACKGROUND: With the increasing application of immune checkpoint inhibitors (ICI) in cancer therapy, the occurrence of isolated adrenocorticotropic hormone deficiency (IAD), as an adverse effect, is also on the rise. Nevertheless, there are only a few studies regarding IAD induced by ICI. This study aimed at investigating the characteristics of IAD induced by ICI and its relationship with other endocrine adverse events. METHODS: A retrospective study was conducted in the Endocrinology Department from January 2019 to August 2022 to investigate characteristics of patients with IAD. Clinical features, laboratory findings and treatment information were collected. All patients underwent a follow-up of 3-6-month. RESULTS: 28 patients with IAD were enrolled. All patients received treatment with anti-PD-1/ PD-L1. The median occurrence time of IAD was 24 (18-39) weeks after initiation of ICI treatment. Over half of the patients (53.5%) had an additional endocrinopathy, including primary hypothyroidism and fulminant type 1 diabetes mellitus (FT1DM), while other types of endocrinopathies were not identified. The interval between the occurrences of two gland damages was between 4 and 21 weeks or simultaneous. Primary hypothyroidism (46.4%) was more prevalent than FT1DM (7.1%). Fatigue and nausea were common symptoms, with a frequent occurrence of hyponatremia. All patients continued on oral glucocorticoids during follow-up. CONCLUSIONS: IAD induced by ICI could manifest independently, or more frequently in combination with hypothyroidism or FT1DM. This damage could happen at any point of ICI treatment. Given that IAD can be life-threatening, it is critical to evaluate pituitary function dynamically in patients undergoing immunotherapy.

Clinical characteristics of patients with early-onset diabetes mellitus: a single-center retrospective study.

BACKGROUND: The prevalence of diabetes mellitus (DM) is dramatically increasing around the world, and patients are getting younger with changes in living standards and lifestyle. This study summarized and analyzed the clinical characteristics of different types of newly diagnosed diabetes mellitus patients with an onset age between 18 and 40 years to provide clinical evidence for the early diagnosis and treatment of diabetes, reduce short-term and long-term complications and offer scientific and personalized management strategies. METHODS: A total of 655 patients newly diagnosed with early-onset diabetes mellitus in the Department of Endocrinology, the First Medical Center of PLA General Hospital from January 2012 to December 2022 were retrospectively enrolled in this study, with an onset age of 18-40 years. Their clinical data were collected and investigated. All patients were divided into two groups according to whether they presented with diabetic microangiopathy. Similarly, patients with early-onset type-2 diabetes were grouped in accordance with whether they had ketosis at the time of diagnosis. Binary logistic regression analysis was performed to analyze risk factors, and receiver-operating characteristic (ROC) analysis was used to explore the predictive value of significant risk factors. RESULTS: The findings were as follows: (1) Of 655 enrolled patients, 477 (72.8%) were male and 178 (27.1%) were female, with a mean age of onset of was 29.73 years ± 0.24 SD. (2) The prevalence of early-onset diabetes was gradually increasing. Type-2 diabetes was the most common type of early-onset diabetes (491, 75.0%). The ages of onset of early-onset type-1 diabetes, type-2 diabetes and LADA were mainly 18-24 years, 25-40 years and 33-40 years, respectively. (3) Initial clinical manifestations of early-onset diabetes were classic diabetes symptoms (361, 55.1%), followed by elevated blood glucose detected through medical examination (207, 31.6%). (4) Binary logistic regression analysis suggested that high serum uric acid (UA), a high urinary albumin-to-creatinine ratio (UACR) and diabetic peripheral neuropathy (DPN) were risk factors for microangiopathy in early-onset diabetes patients (P < 0.05). The area under the curve (AUC) on ROC analysis of the combination of UA, UACR and DPN was 0.848, 95% CI was 0.818 ~ 0.875, sensitivity was 73.8% and specificity was 85.9%, which had higher predictive value than those of UA, UACR and DPN separately. (5) Weight loss, high glycosylated hemoglobin (HbA1c) and young onset age were risk factors for ketosis in patients with early-onset type-2 diabetes (P < 0.05). CONCLUSION: (1) Men were more likely to have early-onset diabetes than women. (2) Early-onset diabetes patients with high serum uric acid levels, high UACRs and peripheral neuropathy were prone to microangiopathy. Comprehensive evaluation of these risk factors could have higher predictive value in the prediction, diagnosis and treatment of microvascular lesions. (3) Patients with weight loss at onset, high HbA1c and young onset age were more likely to develop ketosis. Attention should be given to the metabolic disorders of these patients.

New-Onset Fulminant Type 1 Diabetes Following SARS-CoV-2 Protein Subunit Vaccine: A Case Report and Literature Review.

The ravages of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide have sped up the development of relevant vaccines, which is accompanied by public concerns over possible adverse effects. We report a rare case of a 39-year-old woman who suffered from severe hyperglycemia and ketoacidosis with normal hemoglobin A1c four days after SARS-CoV-2 protein subunit vaccine, which is consistent with the diagnosis of fulminant type 1 diabetes (FT1D). She received insulin therapy and recovered after 24 days from onset of the symptoms. This is the first case of new-onset FT1D after SARS-CoV-2 protein subunit vaccination and one of only six that developed after any form of SARS-CoV-2 vaccination. We hope to raise awareness of this potential adverse consequence and recommend careful monitoring after vaccination in patients even without a medical history of diabetes.

[Clinical Analysis of 17 Adult Patients With Fulminant Type 1 Diabetes Mellitus].

Objective: To explore the clinical characteristics of adult patients with fulminant type 1 diabetes mellitus (FT1DM), a specific subtype of type 1 diabetes mellitus (T1DM). Methods: We collected the clinical data of patients who were admitted to West China Hospital, Sichuan University in 2010-2019 for FT1DM and type 1 diabetes mellitus (T1DM) presenting with diabetic ketoacidosis (DKA) at the onset. In addition, all the FT1DM patients were followed up. Results: A total of 70 patients presenting with DKA at the onset of T1DM were admitted to and received treatment at West China Hospital in 2010-2019. Among them, 17 (24.3%) had FT1DM and 53 did not. The mean ages of the FT1DM patients and the non-FT1DM patients were (33.2±12.8) years and (27.5±11.2) years, and the mean body mass indices were (22.6±2.9) kg/m 2 and (19.2±2.9) kg/m 2, respectively. A total of 14 FT1DM cases had symptoms of upper respiratory tract infection or acute gastroenteritis before the onset of the disease and 4 cases were related to pregnancy. The median time from the onset of the disease to the first diagnosis of DKA of the FT1DM group (median [P 25-P 75]: 2 [1-4] days, P<0.001) was significantly shorter than that of the non-FT1DM group (median [P 25-P 75]: 30 [17-78] days). The mean maximum blood glucose levels at the time of the first visit to the doctor of the FT1DM patients ([39.9±11.4] mmol/L, P<0.001) were significantly higher than that of the non-FT1DM patients ([28.9±9.2] mmol/L), but the HbA1c (6.6%±0.6%, P<0.001) and glycosylated serum albumin (GA) (21.4%±3.0%, P=0.001) levels of the FT1DM patients were significantly lower than those of the non-FT1DM group (HbA1c: 12.8%±2.7%; GA: 44.8%±15.0%). The median serum amylase in the FT1DM group was significantly higher than that in the non-FT1DM group (101 [54-336] IU/L vs. 54 [42-166] IU/L, P=0.045) and the median serum lipase in the FT1DM group showed a trend of being higher than that in the T1DM group (81 [57-154] IU/L vs. 46 [28-195] IU/L, P=0.051). 8.7% of the non-FT1DM patients tested positive for anti-glutamic acid decarboxylase antibody (GAD-Ab), while the FT1DM patients all tested negative. At the time of discharge, the mean daily insulin dose of the FT1DM patients was (0.67±0.22) IU/kg, which was not significantly different from that of the non-FT1DM group ([0.74±0.29] IU/kg, P=0.349). After about 6.5 years of follow-up, the mean daily insulin dose of the FT1DM patients was (0.73±0.19) IU/kg, which was similar to the insulin dosage on discharge ( P=0.409). Conclusion: Compared with the non-FT1DM patients presenting with DKA at the onset, FT1DM patients have fewer typical diabetic symptoms, lower fasting C-peptide levels, higher serum amylase levels, and increased incidence of vomiting or other symptoms of gastrointestinal infections, and are more likely to be misdiagnosed. Therefore, it is very important for clinicians to correctly identify FT1DM as early as possible and administer early and long-term insulin replacement therapy.

Fulminant Type 1 Diabetes Mellitus Developed about Half a Year after Discontinuation of Immune Checkpoint Inhibitor Combination Therapy with Nivolumab and Ipilimumab: A Case Report.

The cytotoxic T-lymphocyte antigen-4 and programmed cell death 1 pathways are novel therapeutic targets in immune checkpoint inhibitor (ICI) therapy for cancer. However, they may cause endocrine-related adverse events, including hypophysitis, autoimmune thyroiditis and type 1 diabetes mellitus (DM). Moreover, delayed immune-related adverse events (irAEs) after discontinuation of ICI therapy have been reported. Here we report a 60-year-old female patient with advanced renal cell carcinoma with brain metastasis who was treated with nivolumab, ipilimumab and prednisolone. At the 3rd course of combination therapy, the administration was discontinued due to the onset of colitis and the dosage of prednisolone was increased. About half a year after discontinuation, she was admitted to the hospital with general malaise, hyperglycemia (330 mg/dL) and diabetic ketoacidosis. Glycated hemoglobin level was 6.5%. Islet-related autoantibodies were negative. The glucagon tolerance test showed complete depletion of insulin. Therefore, we diagnosed fulminant type 1 DM and treated with multiple daily injections of insulin. The onset of type 1 DM was rapid in many cases treated with combination therapy of ICIs. The present case is a rare case in which fulminant type 1 DM developed about half a year after discontinuation of nivolumab and ipilimumab. The literature shows two cases of type 1 DM occurring 4 months after discontinuation of ICI therapy by nivolumab or atezolizumab. The present case indicates that regular monitoring is mandatory for fulminant type 1 DM and other delayed irAEs after discontinuation of ICI therapy even under the low-dose prednisolone treatment.

[A case of fulminant type 1 diabetes mellitus in an elderly patient who developed cardiopulmonary arrest from diabetic ketoacidosis and whose imaging course was monitored].

A 71-year-old man with a history of hypertension and nephrosclerosis visited a primary care doctor for a regular visit. After a few days of vomiting and diarrhea, gastroenteritis was suspected and he was prescribed medication for these symptoms by his previous doctor. The next morning, he visited our hospital complaining of malaise and abdominal distention.The patient's blood glucose level was 1,385 mg/dL, his arterial blood pH was 6.885 (followed by an elevated serum ketone level), and hyperkinesis from diabetic ketoacidosis (DKA) was observed. The patient had experienced cardiopulmonary arrest, likely due to ventricular fibrillation. After cardiopulmonary resuscitation, the patient was admitted to hospital and treated for DKA. The urinary and serum C-peptide levels were below the limit of sensitivity, and anti-glutamic acid decarboxylase antibody and anti-insulinoma-associated antigen-2 antibody were not detected in the serum. These findings were consistent with a diagnosis of fulminant type 1 diabetes mellitus. We herein report a rare case of resuscitation in an elderly patient with fulminant-onset type 1 diabetes mellitus. We carefully observed the imaging history of the patient with great interest.

Fulminant type 1 diabetes: A comprehensive review of an autoimmune condition.

Fulminant type 1 diabetes (FT1D) is a subset of type 1 diabetes characterized by extremely rapid pancreatic ß-cell destruction with aggressive progression of hyperglycaemia and ketoacidosis. It was initially classified as idiopathic type 1 diabetes due to the absence of autoimmune markers. However, subsequent studies provide evidences supporting the involvement of autoimmunity in rapid ß-cell loss in FT1D pathogenesis, which are crucial for FT1D being an autoimmune disease. This article highlights the role of immunological aspects in FT1D according to the autoimmune-associated genetic background, viral infection, innate immunity, adaptive immunity, and pancreas histology.

A rare case of fulminant type 1 diabetes mellitus accompanied by both acute pancreatitis and myocarditis - case report.

BACKGROUND: Fulminant type 1 diabetes mellitus (FT1D) is a newly established subtype of type 1 diabetes. Its etiology has not been fully elucidated. Several cases with FT1D have exhibited pancreatitis or myocarditis. CASE PRESENTATION: We report a 31-year-old Japanese woman who showed upper abdominal pain and was admitted to a local hospital. She was initially diagnosed with acute pancreatitis based on serum amylase elevation and swelling of the pancreas on computed tomography. Four days after admission, she developed diabetic ketoacidosis and was transferred to our hospital. Her symptoms and laboratory findings met the FT1D criteria. On the 3rd hospital day, electrocardiography (ECG) showed ST-segment elevation, and serum cardiac enzymes were markedly elevated. Because she exhibited late gadolinium enhancement in the apical wall on contrast-enhanced cardiac magnetic resonance imaging, she was diagnosed as acute myocarditis. Abnormal ECG findings and elevations of biomarkers associated with myocarditis showed improvement on the next day. CONCLUSIONS: This is the first case of FT1D accompanied by both pancreatitis and myocarditis and suggests that the pathophysiology of FT1D is related to the common etiology of acute pancreatitis and myocarditis.

Nivolumab-induced type 1 diabetes mellitus as an immune-related adverse event.

BACKGROUND: Immune checkpoint inhibitors are medications that activate anti-tumor responses by disrupting the inhibitory signaling to T cells. Nivolumab is an immune checkpoint inhibitor that selectively blocks the programmed cell death-1 (PD-1). Anti-PD-1 agents can breach immunologic tolerance. Fulminant diabetes is an immune endocrinopathy that results from a violent immune attack leading to complete destruction of pancreatic beta cells. We present a rare case of fulminant diabetes precipitated by anti-PD-1 immunotherapy. CASE: A 49-year-old male with a body mass index of 26.4 kg/m2, a history of Dandy-Walker syndrome and epilepsy, and no personal or family history of diabetes underwent left radical nephrectomy and retroperitoneal lymph node dissection for stage IV metastatic renal cell carcinoma (metastases to lungs). He received first-line sunitinib treatment for three months. He developed new hepatic metastasis, and a second-line treatment with nivolumab 3 mg/kg every two weeks was introduced. At 10 months of nivolumab, before the 22nd infusion, the patient suddenly complained of severe asthenia, somnolence, weight loss, polydipsia, and polyuria. Laboratory tests revealed potassium 4.2 mmol/L, sodium 138 mmol/L, bicarbonate 17.8 mmol/L, blood glucose 801 mg/dL, and arterial blood pH 7.27. He was diagnosed with diabetic ketoacidosis. Hemoglobin A1C was 10.9%. C-peptide was so low as 0.24. Glutamic acid decarboxylase autoantibodies, insulin autoantibodies and islet cell antibodies were all negative. CONCLUSION: Anti-PD-1 immunotherapy is effective in the treatment of cancers. These agents can precipitate autoimmune disorders. As the use of anti-PD-1 agents is expected to rise, physicians should be educated about the potential side effects.

Fulminant Type 1 Diabetes with Diversity in Peripheral Blood Lymphocytes: A Case Report.

A 29-year-old woman was admitted to our hospital for treatment of fulminant type 1 diabetes (FT1D) with diabetic ketoacidosis. The phenotype of peripheral blood lymphocytes was analyzed using an 8-color flow cytometer. An analysis of the CD4-positive T cells showed a tendency for higher proportions of effector and central memory T cells and a normal proportion of regulatory T (Treg) cells, compared to healthy control. An analysis of B cell differentiation showed higher proportions of switched memory B cells and plasmablasts. The differences in lymphocyte phenotypes between our case and previously reported cases suggest a diversity of FT1D pathology.

Clinical characteristics of fulminant Type 1 diabetes mellitus. / 暴发1åž‹ç³–å°¿ç— çš„ä¸´åºŠç‰¹å¾.

OBJECTIVES: To compare the differences in clinical characteristics between Type 1 diabetes mellitus (T1DM) and fulminant Type 1 diabetes mellitus (FT1DM), and to reduce the missed diagnosis, misdiagnosis, and mistreatment of FT1DM by medical staff. METHODS: A total of 101 hospitalized patients with T1DM (including 8 cases of FT1DM) were enrolled in this study from Changsha Central Hospital between June 2012 and December 2018. Clinical characteristics of the 8 FT1DM patients were collected and compared with all T1DM patients. RESULTS: All FT1DM patients were adult with the average age of (30.25±5.28) years old, accompanied by severe diabetic ketoacidosis (DKA) occurred within 1 week after onset. Moreover, pancreatic beta cells in these patients were destroyed and the islet-related antibodies were negative, while the serum pancreatic enzyme levels were increased. Compared with classic T1DM patients, the plasma glucose levels in FT1DM patients were much higher [(41.89±12.54) mmol/L vs (22.57±9.74) mmol/L], but glycosylated hemoglobin (HbA1c) and fasting C peptide levels were significantly lower [(6.08±0.41)% vs (10.87±2.46%)%, P<0.05] and [(0.02±0.00) nmol/L vs (0.03±0.06) nmol/L, P<0.05]. CONCLUSIONS: The onset time of FT1DM patients is very urgent via driving DKA. These patients have higher blood glucose concentration than classic T1DM patients, accompanied by electrolyte disturbances, impaired renal function, partially impaired liver function, as well as gastrointestinal symptoms and elevated trypsin. Most FTDM patients are adolescents and adults with no gender difference, especially pregnant women who are at high risk. Lifelong insulin dependence in FT1DM patients should be paid more attention in clinical treatment.

Fulminant type 1 diabetes: The clinical and continuous glucose monitoring characteristics in Chinese patients.

The purpose of the current study was to investigate the clinical characteristics of fulminant type 1 diabetes mellitus (FT1DM) in Chinese patients and to further determine their glycaemic profiles through continuous glucose monitoring (CGM). Thirty subjects who were diagnosed with FT1DM according to the 2012 JDS criteria were enrolled. Clinical characteristics were compared to those reported in Japanese FT1DM. All subjects received retrospective CGM for 3 days after being converted to subcutaneous insulin injection therapy. Chinese FT1DM patients presented with a shorter duration of symptoms (2.84 ± 2.42 days vs 4.4 ± 3.1 days, P < 0.01), worse islet function (fasting C-peptide, 0.09 ± 0.11 ng/mL vs 0.30 ± 0.21 ng/mL; 2-hour C-peptide, 0.13 ± 0.14 ng/mL vs 0.30 ± 0.30 ng/mL, both P < 0.01), lower prevalence of flu-like symptoms (46.7% vs 71.4%, P < 0.05), and a significantly higher GADA positive rate (23.3% vs 5.1%, P < 0.01) when compared with Japanese patients. The CGM results showed that the mean time in range (TIR) of FT1DM patients was 49.8 ± 22.1%, while mean amplitude of glycaemic excursion (MAGE) and standard deviations of sensor glucose (SDSG) were 7.58 ± 3.59 mmol/L and 3.19 ± 1.22 mmol/L, respectively, with nearly 1/3 participants coefficient of variation (CV) > 36% (all are male), suggesting a large glucose fluctuation. The female patients were further divided into pregnancy-related FT1DM (PF) and non-PF (NPF) subgroups (both n = 5), and we found that PF patients had a significantly higher TIR than NPF patients (77.0 ± 16.1% vs 41.0 ± 22.4%, P < 0.05). There were heterogeneities in the clinical characteristics of FT1DM patients, and the CGM results indicated a very low TIR and large glucose fluctuation which needs careful attention.

Clinical characteristics of anti-glutamic acid decarboxylase antibody-positive fulminant type 1 diabetes.

This research aimed to examine the relationship between anti-glutamic acid decarboxylase antibody (GADA) titers and clinical parameters at onset and to clarify the association between clinical severity and GADA titers in GADA-positive fulminant type 1 diabetes. This cross-sectional observational study included 20 cases with GADA-positive fulminant type 1 diabetes (4 cases from our hospital and 16 from cases reported in the literature). The association between GADA titers and clinical parameters [age, sex, body weight, body mass index, period from appearance of any prodromal symptoms to diagnosis, period from development of hyperglycemic symptoms to diagnosis, GADA titer, HbA1c level, blood pH and HCO3- level, serum levels of ketone bodies and pancreatic exocrine enzymes] were analyzed. Spearman's rank correlation coefficient (rs) was used for the correlation analysis. The results showed that there was a significant inverse correlation between GADA titers and the "period from appearance of any prodromal symptoms to diagnosis" (rs = -0.559, p < 0.05). Moreover, GADA titers were inversely correlated with blood pH and HCO3- level (rs = -0.576, p < 0.05, rs = -0.578, p < 0.05, respectively), and positively correlated with serum levels of total ketone bodies, acetoacetate, and 3-hydroxybutyrate (rs = 0.661, p < 0.05; rs = 0.700, p < 0.05; and rs = 0.782, p < 0.01, respectively). These findings suggest that higher GADA titers may be linked to more severe clinical severity of GADA-positive fulminant type 1 diabetes at onset. This association may be attributed to possible pre-existence of autoimmunity-related ß-cell damage before the onset of fulminant type 1 diabetes.

Fulminant type 1 diabetes associated with Isolated ACTH deficiency induced by anti-programmed cell death 1 antibody-insight into the pathogenesis of autoimmune endocrinopathy.

Therapeutic blocking antibodies against programmed death 1 (PD1) and cytotoxic T-lymphocyte antigen 4 (CTLA4) are applied for advanced cancer therapy, but induce a wide range of immune-related adverse events. In our recent case of a 52-year-old female doctor suffering from breast cancer having metastasized to the lung and liver, it was decided to use nivolumab to prevent the disease progressing after excisional surgeries and multiple chemotherapies. One month after completing the nivolumab course, fatigue, hypoglycemia and hypotension developed and isolated ACTH deficiency (IAD) was diagnosed. A further month later, under steroid supplementation, hyperglycemia emerged alongside thirst and polydipsia, prompting a diagnosis of fulminant type 1 diabetes (FT1D). Her susceptibility to type 1 diabetes was examined by HLA haplotype and CTLA4 gene polymorphism analyses. Polymorphisms CT60G>A and +49G>A in CTLA4 both generated a GG genotype. Our patient manifested one of the rarest combinations of autoimmune disease induced by nivolumab. Whereas the HLA haplotype was unsusceptible to autoimmune type 1 diabetes, polymorphisms of CTLA4, the antibody of which frequently causes hypophysitis, were susceptible to FT1D. Peripheral modulation of activated T cells, mainly by PD-1 antibodies, induced FT1D associated with IAD in patients with CTLA4 polymorphism. This case reveals hints of the T-cell etiology in T1D and evidence of CTLA4 involvement in IAD.

Sudden, Sharp Turn in an AIDS Patient's Course Following the Onset of Fulminant Type 1 Diabetes.

A previously healthy 40-year-old Japanese male was urgently admitted with a 2-month history of dysphagia, 30-kg weight loss, and fever. Human immunodeficiency virus (HIV) antibodies and cytomegalovirus antigenemia were positive. Pneumocystis pneumonia and cytomegalovirus pneumonia were suspected. The patient was diagnosed with acquired immune deficiency syndrome (AIDS). Cytomegalovirus antigenemia became negative 20 days after the positive result. On hospital day 41, he experienced cardiopulmonary arrest. The clinical diagnosis was fulminant type 1 diabetes mellitus. He later developed hypoglycemia and was diagnosed with adrenal insufficiency accompanied by septic shock. He died of multiple organ failure 29 h post-admission to our ICU.

Fulminant onset of insulin-dependent diabetes with positive anti-GAD antibody titers during treatment with nivolumab in a patient with NSCLC.

Programmed cell death-1 (PD-1) and programmed cell death-ligand-1 (PD-L1) inhibitors have been highlighted in the field of cancer treatment. The interaction between PD-1 and PD-L1 is thought to play an important role in the regulation of the self-immune tolerance mechanism, so blocking these molecules may cause serious immune-related adverse events (IrAE), including fulminant insulin-dependent (type 1) diabetes. Here, we describe a patient with fulminant type 1 diabetes induced by nivolumab, an anti-PD-1 antibody. The patient, a 78-year-old man, was being treated with nivolumab as a third-line treatment for squamous cell carcinoma of the lung. After three cycles, he experienced an abrupt flare-up of the blood glucose within half a day. His blood glucose further increased without clinical symptoms until his hospital visit. Laboratory data showed the complete exhaustion of intrinsic insulin and the elevation of serum antibody titer to glutamic acid decarboxylase (GAD). Although the patient was previously diagnosed with non-insulin-dependent (type 2) diabetes, his disease activity had been well controlled with oral medication and low-dose insulin therapy until just before the flare-up. Because of the laboratory findings and the extremely rapid onset of hyperglycemia, a diagnosis of fulminant, rather than the rapid onset, type 1 diabetes related to nivolumab therapy was strongly suspected. Our case study indicates that fulminant hyperglycemia can occur extremely rapidly. The blood glucose of patients receiving PD-1 antibody therapy should be closely monitored.

Recent findings on fulminant type 1 diabetes.

Fulminant type 1 diabetes (fT1D) is a new subtype of type 1 diabetes proposed by Imagawa in 2000. It is a clinical syndrome characterized by a markedly rapid and almost complete destruction of pancreatic ß cells. Metabolic derangement is more severe in this subtype than in autoimmune type 1 diabetes. The incidence of fT1D is associated with HLA DRB1*04:05DQB1*04:01; both innate and acquired immune disorders might contribute to the development of fT1D. The presence of specific innate immune responses to enterovirus infection connected with enhanced adaptive immune pathways responsible for aggressive ß cell toxicity in fT1D. The process of ß cell destruction is extremely rapid in fT1D, and the insulin secretary capacity rarely recovers after the onset. The serum glycated albumin to glycated haemoglobin ratio is significantly higher in fT1D; a cut-off value of 3.2 for serum glycated albumin to glycated haemoglobin ratio yielded 97% sensitivity and 98% specificity for differentiating fT1D from type 2 diabetes. Fulminant type 1 diabetes is associated with pregnancy. This article also updates the diagnostic criteria for fT1D by the Japanese Diabetes Association in 2012.