Amino acid polymorphisms in human histocompatibility leukocyte antigen class II and proinsulin epitope have impacts on type 1 diabetes mellitus induced by immune-checkpoint inhibitors.

Introduction: Immune-checkpoint inhibitors are effective in various advanced cancers. Type 1 diabetes mellitus induced by them (ICI-T1DM) is a serious complication requiring prompt insulin treatment, but the immunological mechanism behind it is unclear. Methods: We examined amino acid polymorphisms in human histocompatibility leukocyte antigen (HLA) molecules and investigated proinsulin epitope binding affinities to HLA molecules. Results and Discussion: Twelve patients with ICI-T1DM and 35 patients in a control group without ICI-T1DM were enrolled in the study. Allele and haplotype frequencies of HLA-DRB1*04:05, DQB1*04:01, and most importantly DPB1*05:01 were significantly increased in patients with ICI-T1DM. In addition, novel amino acid polymorphisms in HLA-DR (4 polymorphisms), in DQ (12 polymorphisms), and in DP molecules (9 polymorphisms) were identified. These amino acid polymorphisms might be associated with the development of ICI-T1DM. Moreover, novel human proinsulin epitope clusters in insulin A and B chains were discovered in silico and in vitro peptide binding assays to HLA-DP5. In conclusion, significant amino acid polymorphisms in HLA-class II molecules, and conformational alterations in the peptide-binding groove of the HLA-DP molecules were considered likely to influence the immunogenicity of proinsulin epitopes in ICI-T1DM. These amino acid polymorphisms and HLA-DP5 may be predictive genetic factors for ICI-T1DM.

Pheochromocytoma Multisystem Crisis Complicated by Severe Acute Pancreatitis.

A 43-year-old man developed headache, dizziness, abdominal pain, and vomiting. His blood pressure was 203/121 mmHg, heart rate 122 beats/min, body temperature 39.1°C, and respiratory rate 24/min. He had elevated levels of creatinine at 2.95 mg/dL and lipase at 1,364 U/L as well as an extremely low calcium level at 5.2 mg/dL. Hypertriglyceridemia and hyperglycemia were seen. Chest and abdominal computed tomography showed interstitial pneumonia, severe pancreatitis, and a right adrenal tumor. The patient also developed vertebral artery dissection and medullary infarction. After right adrenalectomy, the patient was diagnosed with pheochromocytoma multisystem crisis (PMC). Acute pancreatitis might augment numerous life-threatening manifestations of PMC.

Serum ketone body measurement in patients with diabetic ketoacidosis.

Background: Diabetic ketoacidosis (DKA) is a critical manifestation in patients with diabetes mellitus. DKA has been conventionally diagnosed by the presence of hyperglycemia (blood glucose levels > 250 mg/dl) and metabolic acidosis (blood gas bicarbonate [HCO3 -] < 18 mmol/l and pH in blood gas < 7.30). However, quantitative evaluation of serum ketone bodies has not been established. The current study investigates serum ketone body levels in patients suspected for DKA. Methods: We have retrospectively evaluated patients with hyperglycemia whose serum ketone body levels at the outpatient clinic and emergency department were measured simultaneously with blood gas analysis during 2011-2019. Clinical backgrounds, severity of diabetes, serum ketone bodies, and blood gas factors were analyzed. Results: Seventy-two patients were enrolled in the study, after the exclusion of patients who had ketosis due to factors other than diabetes. Serum ketone body levels were negatively correlated with the levels of blood HCO3 - and pH. By receiver-operating-characteristic curve analyses, optimal cut-off values for diagnosis of DKA were determined at 6.3 mmol/l of beta-hydroxybutyrate, 1.4 mmol/l of acetoacetate, and 8.0 mmol/l of total ketone body, respectively. Moreover, serum ketone bodies appeared to effectively differentiate between type 1 and type 2 diabetes mellitus. The cut-off values were higher than those in previous reports. Conclusions: Serum ketone body levels were thought to be useful in the diagnosis of DKA. Further investigations with increased numbers of patients are required to establish the appropriate application of serum ketone bodies in patients with DKA. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-022-00581-2.

Human Leukocyte Antigens and Biomarkers in Type 1 Diabetes Mellitus Induced by Immune-Checkpoint Inhibitors.

BACKGROUND: Type 1 diabetes mellitus induced by immune-checkpoint inhibitors (ICI-T1DM) is a rare critical entity. However, the etiology of ICI-T1DM remains unclear. METHODS: In order to elucidate risk factors for ICI-T1DM, we evaluated the clinical course and immunological status of patients with ICI-T1DM who had been diagnosed during 2016 to 2021. RESULTS: Seven of 871 (0.8%, six men and one woman) patients developed ICI-T1DM. We revealed that the allele frequencies of human leukocyte antigen (HLA)-DPA1*02:02 and DPB1*05:01 were significantly higher in the patients with ICI-T1DM In comparison to the controls who received ICI (11/14 vs. 10/26, P=0.022; 11/14 vs. 7/26, P=0.0027, respectively). HLA-DRB1*04:05, which has been found to be a T1DM susceptibility allele in Asians, was also observed as a high-risk allele for ICI-T1DM. The significance of the HLA-DPB1*05:01 and DRB1*04:05 alleles was confirmed by an analysis of four additional patients. The absolute/relative neutrophil count, neutrophils-lymphocyte ratio, and neutrophil-eosinophil ratio increased, and the absolute lymphocyte count and absolute/relative eosinophil count decreased at the onset as compared with 6 weeks before. In two patients, alterations in cytokines and chemokines were found at the onset. CONCLUSION: Novel high-risk HLA alleles and haplotypes were identified in ICI-T1DM, and peripheral blood factors may be utilized as biomarkers.

Beneficial effects of sodium glucose cotransporter 2 inhibitors on left ventricular mass in patients with diabetes mellitus.

BACKGROUND: Sodium glucose cotransporter 2 inhibitor (SGLT2i) has recently been suggested to reduce the risk of cardiovascular events. Left ventricular hypertrophy (LVH) is associated with cardiovascular events. Diabetic macroangiopathy is a crucial complication in patients with diabetes mellitus (DM). This study examined the effect of SGLT2i on LVH in patients with type 2 DM (T2DM). METHODS: The retrospective cohort study was conducted in consecutive outpatients with T2DM from 2010 to 2020. Left ventricular mass index (LVMI) was used as an indicator of LVH based on echocardiography. The minimum follow-up period was 1 year. After propensity score-matching for clinical profiles, patients who underwent annual echocardiography twice for a routine checkup and took SGLT2i were defined to the SGLT2i group, whereas patients without SGLT2 inhibitors were defined to the non-SGLT2 group. SGLT2i was administered after baseline echocardiography followed by a second examination. RESULTS: LVMI levels in the SGLT2i group (n = 169) significantly decreased from baseline compared with those in the non-SGLT2i group (n = 169), % changes in LVMI2.7(g/m2.7 ) in median (interquartile ranges [IQR]) were - 7.7 (-18.7, 2.5) vs -3.6 (-14.3, 5.8), respectively, P = 0.017). In a subgroup analysis, LVMI levels in the patients who had LVH in the SGLT2i group more significantly decreased than those without LVH, % changes in LVMI2.7(g/m2.7 ) in median (IQR) were -13.5 (-22.1, -2.4) vs -2.8 (-12.6, 9.8), respectively, P < 0.001). CONCLUSIONS: SGLT2i treatment was shown to improve LVH in patients with T2DM and may play a pivotal role in the future treatment of diabetic cardiovascular complications.

A case of postpartum thyroiditis following SARS-CoV-2 infection.

Postpartum thyroiditis (PPT) is characterized by mild thyrotoxicosis occurring within one year of parturition commonly followed by transient hypothyroidism. Having genetic background of autoimmune thyroid disorders is a risk factor for it because the immune reactivation during postpartum period is a trigger for PPT. Pandemic of COVID-19: caused by SARS-CoV-2 infection is a global health problem, and occurrence of Graves' disease and Hashimoto's thyroiditis after the viral infection have been reported but occurrence of PPT with COVID-19 has never been reported. A 29-year-old woman developed general fatigue four and a half months after parturition, and was diagnosed as having PPT: one month before, she had COVID-19. Hereafter, we define the date of delivery as Day 0 to make timeline clear. SARS-CoV-2 infection was diagnosed by PCR on Day 103, its disappearance from the upper airway confirmed on Day 124, and the thyroiditis diagnosed on Day 136. She had been euthyroid on Day 0 and 95, but thyrotoxic on Day 136. Serum thyroglobulin (Tg) concentration was normal in the presence of anti-Tg antibody, other thyroid-related autoantibodies were negative, and by ultrasonography, the thyroid gland was normal in size and no evidence of increased vascularity. Thyroid function returned to normal by Day 172 without any specific drug therapy. In conclusion, although a clear causal relationship could not be found, we documented the world's first case of PPT developed following COVID-19.

Autoimmune polyglandular syndrome III in a patient with idiopathic portal hypertension.

A 42-year-old woman with a history of idiopathic portal hypertension (IPH) developed type 1A diabetes and was found to have chronic thyroiditis. The concurrence of IPH and type 1A diabetes has been previously reported in only one case. This is the second known case, and our patient was classified as having autoimmune polyglandular syndrome (APS) III. The patient's HLA DR and DQ alleles were determined to be susceptible to autoimmune thyroid diseases but resistant to type 1A diabetes.