Fulminant type 1 diabetes mellitus with anti‐programmed cell death‐1 therapy

Anti‐programmed cell death‐1 (PD‐1) antibodies are regarded as a risk factor for insulin‐dependent diabetes mellitus as a side‐effect. While a small number of cases have been reported, evidence remains limited. This is the first report of an Asian patient developing insulin‐dependent diabetes during anti‐PD‐1 therapy. A 55‐year‐old euglycemic woman receiving nivolumab for malignant melanoma showed abrupt onset of ketonuria, and elevated levels of plasma glucose (580 mg/dL) and hemoglobin A1c (7.0%). Over the next 2 weeks, serum C‐peptide levels fell below the limit of detection. Islet autoantibodies were negative, and the patient showed a human leukocyte antigen haplotype associated with type 1 diabetes. Anti‐PD‐1 therapy can cause rapid onset of insulin‐dependent diabetes, possibly because of inappropriate activation of T cells. Human leukocyte antigen haplotypes might be related to the onset of this disease. Physicians should be aware of this serious adverse event and carry out routine blood glucose testing during anti‐PD‐1 therapy.     

Simultaneous development of Graves’ disease and type 1 diabetes during anti‐programmed cell death‐1 therapy: A case report

We present the first case of simultaneous development of Graves’ disease and type 1 diabetes during anti‐programmed cell death 1 therapy. A 48‐year‐old man with parotid gland adenocarcinoma and lung metastasis had received five courses of nivolumab. Fourteen days after administration of the sixth course, his casual plasma glucose and hemoglobin A1c levels were 379 mg/dL and 7.2%, respectively. Furthermore, thyrotoxicosis was detected with a blood test. Serum total ketone body and thyroid‐stimulating hormone receptor antibody levels increased, and serum C‐peptide level decreased to 0.01 ng/mL thereafter. Thus, we concluded that he simultaneously developed anti‐programmed cell death 1 therapy‐associated type 1 diabetes and Graves’ disease. Among Japanese patients with autoimmune polyglandular syndrome type III, the frequency of human leukocyte antigen‐DRB1*04:05 is higher in those with both type 1 diabetes and Graves’ disease. Our case had human leukocyte antigen‐DRB1*04:05, which might be associated with the simultaneous development of the two diseases.     

Analysis of pancreatic volume in acute‐onset,slowly‐progressive and fulminant type 1 diabetes in a Japanese population

Aims/Introduction

A decrease in the size of the pancreas is observed in islet autoantibody‐positive non‐diabetic donors and acute‐onset type 1 diabetes irrespective of the diabetes duration. Little is known, however, about the relationship between the size of the pancreas and type 1 diabetes subtypes, including fulminant type 1 diabetes.

Materials and Methods

We examined the pancreatic volume (PV) in 44 adult patients with type 1 diabetes (16 acute‐onset type 1 diabetes, 18 slowly progressive type 1 diabetes and 10 fulminant type 1 diabetes) and 39 age‐ and body mass index‐matched non‐diabetic controls. PV was measured by computed tomography. The ability to secrete insulin was assessed by stimulated C‐peptide after intravenous glucagon administration.

Results

PV was significantly correlated with bodyweight in both control participants and type 1 diabetes patients. The PV index (PVI; PV/bodyweight) was decreased by 39% in type 1 diabetes compared with that in controls. PVI was significantly decreased in acute‐onset type 1 diabetes patients and slowly progressive type 1 diabetes patients (both P < 0.0001), but not in fulminant type 1 diabetes patients (P = 0.10), compared with control participants. In cases patients with recent‐onset type 1 diabetes (0–7 days post‐diagnosis), PVI was significantly decreased in acute‐onset type 1 diabetes patients (n = 8, P = 0.0005), but not in fulminant type 1 diabetes patients (n = 7, P = 0.44), compared with controls. PVI showed no correlations with the diabetes duration, C‐peptide levels, glycated hemoglobin, glutamic acid decarboxylase autoantibody levels, serum amylase or daily total insulin dose in type 1 diabetes subtypes.

Conclusions

The present results show that patients with acute‐onset type 1 diabetes and slowly progressive type 1 diabetes have small pancreases irrespective of the diabetes duration or C‐peptide levels. In contrast to earlier findings on acute‐onset type 1 diabetes, we found no reduction of PVI at the onset of fulminant type 1 diabetes.     

Transition of blood glucose level in a patient with pregnancy-associated fulminant type 1 diabetes mellitus

We report on the transition in blood glucose levels before and after the onset of fulminant type 1 diabetes mellitus in a perinatal woman. In week 38 of pregnancy, before which the patient had normal glucose tolerance, idiopathic acute pancreatitis was diagnosed. Five days thereafter, she became hypoglycemic, so we closely monitored her blood glucose levels. A total of 13 days later, she was hyperglycemic with a blood glucose level >16.0 mmol/L and glycated hemoglobin of 6.4%. Her fasting serum C-peptide reactivity level was 3.6 ng/mL on the 5th day, and 0.2 ng/mL on the 18th day. Multiple insulin injection therapy was administered since the 18th day; after that, ketoacidosis did not occur. The patient was diagnosed with fulminant type 1 diabetes mellitus based on hyperglycemia without high glycated hemoglobin levels and sudden onset insulin-dependent diabetes. Monitoring glucose levels in the case of idiopathic acute pancreatitis during pregnancy and prompt initiation of insulin therapy are important.     

Maturity‐onset diabetes of the young type 5 uncovered during pregnancy with a long‐term diagnosis of type 1 diabetes

We report a case of missed diagnosis of maturity‐onset diabetes of the young type 5 uncovered during pregnancy with a previous diagnosis of type 1 diabetes. Maturity‐onset diabetes of the young type 5 cannot be excluded in early‐onset diabetes with positive islet‐related autoantibodies and type 1 diabetes‐prone human leukocyte antigen subtypes. Abdominal ultrasound should be used in all patients with pre‐gestational diabetes, and maturity‐onset diabetes of the young type 5 should be considered when renal abnormality is presented.     

Pathogenesis of fulminant type 1 diabetes: Genes,viruses and the immune mechanism,and usefulness of patient‐derived induced pluripotent stem cells for future research

We reviewed fulminant type 1 diabetes, a recently established subtype of type 1 diabetes, from the aspects of genes, viruses, immune mechanism and usefulness of patient‐derived induced pluripotent stem cells (iPSCs). In an analysis of the pancreas of patients with fulminant type 1 diabetes, viral antigens and viral receptors were expressed in β‐cells, as well as macrophages and T lymphocytes surrounding the β‐cells. These findings suggest that the β‐cells of patients with fulminant type 1 diabetes are destroyed during an immune response against viral infection of the pancreas. Recently, fulminant type 1 diabetes was induced by treatment with anti‐programmed cell death 1 antibodies, suggesting that immune regulatory mechanisms are also involved in the onset of this disease. We generated iPSCs from patients with fulminant type 1 diabetes for the first time. We also successfully differentiated patient‐derived iPSCs into insulin‐producing cells in vitro, and produced a disease model. The proportion of cytokine‐induced apoptotic cells among insulin‐positive cells was higher in the iPSCs from patients with fulminant type 1 diabetes than in iPSCs from healthy control participants. We carried out ribonucleic acid sequencing in insulin‐producing cells differentiated from patient‐derived iPSCs, and are now attempting to identify new biomarkers for the disease.     

Aggravation of diabetes,and incompletely deficient insulin secretion in a case with type 1 diabetes‐resistant human leukocyte antigen DRB1*15:02 treated with nivolumab

Anti‐programmed cell death‐1 (PD‐1) antibody therapy induces various adverse effects, especially in the endocrine system. Several cases of acute‐onset insulin‐dependent diabetes after anti‐PD‐1 antibody therapy have been reported. Many of these cases have a susceptible human leukocyte antigen (HLA) genotype for type 1 diabetes, possibly suggesting that HLA might be involved in the onset of diabetes with anti‐PD‐1 therapy. We describe an atypical case of hyperglycemia after anti‐PD‐1 antibody administration. A 68‐year‐old Japanese man with pancreatic diabetes and steroid diabetes was given nivolumab three times for chemoresistant adenocarcinoma of the lung. On day 5 after the third infusion of nivolumab, he had hyperglycemia (blood glucose 330 mg/dL and hemoglobin A1c 8.0%) without ketosis and with incompletely deficient insulin secretion. The patient had both type 1 diabetes susceptible (HLA‐A*24:02 and ‐DRB1*09:01) and resistant (HLA‐DRB1*15:02) HLA genotypes. These HLA genotypes differ from those previously reported in anti‐PD‐1 antibody‐induced diabetes, and might have influenced the preservation of insulin secretion after nivolumab administration in the present case.     

Prognostic significance of programmed cell death‐1‐positive cells in follicular lymphoma patients may alter in the rituximab era

Programmed cell death‐1 (PD‐1) is involved in one of the inhibitory pathways of the B7‐cluster of differentiation (CD) 28 family; this pathway is known to be involved in the attenuation of T‐cell responses and promotion of T‐cell tolerance. PD‐1 is known to negatively regulate T‐cell receptor‐mediated proliferation and cytokine production, lead to alternation in the tumor microenvironment. Although several studies have shown that high levels of PD‐1‐positive cells in follicular lymphoma (FL) patients influence their prognosis, those studies included patients treated without rituximab, and the prognostic impact of PD‐1 positivity in the rituximab era (R‐era) has not yet been elucidated. We retrospectively studied 82 patients with FL uniformly treated with standard R‐CHOP therapy at six institutions between 2001 and 2009 (median follow‐up for survivors: 55 months). We also collected and examined biopsy specimens for diagnosis with respect to PD‐1 positivity. The PD‐1 positivity was significantly higher in male patients and patients with high beta‐2 microglobulin (B2M ≥ 3.0) (P = 0.03 and 0.003, respectively). Three‐year progression free survival (PFS) and overall survival (OS) were 60% and 86%, respectively. By univariate analysis, elevated LDH (P = 0.07) worsened PFS. Male gender (P = 0.03), high FLIPI score (P = 0.05), and high B2M levels (P = 0.08) worsened OS. Multivariate analysis detected no significant prognostic factors, including PD‐1 positivity. However, in male subgroup, high levels of PD‐1‐positive cells were found to be a prognostic factor for PFS. Addition of rituximab might have altered the prognostic impact of PD‐1‐positive cells.     

暴发性1型糖尿病1例病例报道暨文献复习

暴发性1型糖尿病以急骤起病,代谢紊乱严重,胰酶升高而胰腺超声检查无异常为特点.属于特发性1型糖尿病,患者自身抗体多为阴性,推测病因可能与病毒感染和自身免疫有关.     

Onset of fulminant type 1 diabetes mellitus following hypophysitis after discontinuation of combined immunotherapy. A case report

Diabetes is a rare, but potentially life‐threatening, adverse event of immune checkpoint inhibitors that requires prompt recognition and treatment. It usually occurs in the first 3 months of treatment and is typically related to programmed cell death‐1 antibodies, alone or in combined therapy. It has rarely been described developing after immunotherapy cessation. We present a 51‐year‐old man with metastatic melanoma, who developed acute‐onset diabetes 52 days after combined immunotherapy cessation with nivolumab and ipilimumab, and 25.6 months after receiving the first dose. He presented with acute hyperglycemic symptoms, ketosis, complete insulin depletion and negative autoimmunity, fulfilling the criteria of fulminant type 1 diabetes. The patient had previously developed hypophysitis with isolated adrenocorticotropic hormone deficiency during immunotherapy. We describe a case of late‐onset fulminant type 1 diabetes developing after immunotherapy cessation. Patient education and active follow up after immunotherapy discontinuation are crucial to warrant a timely intervention.     

High prevalence and clinical impact of dynapenia and sarcopenia in Japanese patients with type 1 and type 2 diabetes: Findings from the Impact of Diabetes Mellitus on Dynapenia study

Aims/IntroductionThe present study aimed to clarify the prevalence and clinical characteristics of sarcopenia and dynapenia, which are muscle weakness with and without low muscle mass, respectively, in Japanese patients with type 1 diabetes mellitus and type 2 diabetes mellitus.Materials and MethodsThis cross‐sectional study enrolled 1,328 participants with type 1 diabetes (n = 177), type 2 diabetes (n = 645) and without diabetes (n = 506). Sarcopenia was defined as a low grip strength and slow gait speed with low skeletal muscle mass index, whereas dynapenia was defined as low strengths of grip and knee extension with a normal skeletal muscle mass index. Participants without sarcopenia and dynapenia were defined as robust.ResultsAmong participants aged ≥65 years, sarcopenia and dynapenia were observed in 12.2% and 0.5% of individuals without diabetes, 42.9% and 11.4% of type 1 diabetes patients, and 20.9% and 13.9% of type 2 diabetes patients. In both type 1 diabetes and type 2 diabetes patients, sarcopenic patients were significantly older and thinner, and showed a significantly higher rate of diabetic neuropathy than robust patients. In patients with type 1 diabetes and type 2 diabetes, dynapenic patients were older, and showed a higher rate of diabetic neuropathy and lower estimated glomerular filtration rate than robust patients. Patients complicated with sarcopenia and dynapenia showed a significantly lower physical quality of life and higher rate of incidental falls than robust patients.ConclusionsSarcopenia and dynapenia were more frequent in patients with type 1 diabetes and type 2 diabetes than in individuals without diabetes, which might contribute to their impaired quality of life and incidental falls.     

Bodyweight threshold for sudden onset of ketosis might exist in ketosis‐prone type 2 diabetes patients

Ketosis‐prone type 2 diabetes is recognized as atypical diabetes. These patients are often male, characterized by obesity, sudden onset of ketosis and a transient decrease in insulin secretion capacity that can be recovered with temporal insulin therapy. Here, we report a male patient with ketosis‐prone type 2 diabetes who was followed up for 8 years. During the follow‐up period, his bodyweight fluctuated and he experienced four episodes of critical ketosis recurrence in association with bodyweight gain. He discontinued insulin therapy after each ketosis episode within the first 4 years, but thereafter, he had to continue insulin therapy because of decreased insulin secretion capacity. Interestingly, his peak bodyweight just before the repeated ketosis episode gradually decreased, and the insulin secretion capacity after the recovery from repeated ketosis decreased in parallel with his peak bodyweight. This long‐term clinical course might be a clue to understand the pathophysiology of ketosis‐prone type 2 diabetes.     

Different role of zinc transporter 8 between type 1 diabetes mellitus and type 2 diabetes mellitus

Diabetes can be simply classified into type 1 diabetes mellitus and type 2 diabetes mellitus. Zinc transporter 8 (ZnT8), a novel islet autoantigen, is specifically expressed in insulin‐containing secretory granules of β‐cells. Genetic studies show that the genotypes of SLC30A8 can determine either protective or diabetogenic response depending on environmental and lifestyle factors. The ZnT8 protein expression, as well as zinc content in β‐cells, was decreased in diabetic mice. Thus, ZnT8 might participate in insulin biosynthesis and release, and subsequently involved deteriorated β‐cell function through direct or indirect mechanisms in type 1 diabetes mellitus and type 2 diabetes mellitus. From a clinical feature standpoint, the prevalence of ZnT8A is gradiently increased in type 2 diabetes mellitus, latent autoimmune diabetes in adults and type 1 diabetes mellitus. The frequency and epitopes of ZnT8‐specific T cells and cytokine release by ZnT8‐specific T cells are also different in diabetic patients and healthy controls. Additionally, the response to ZnT8 administration is also different in type 1 diabetes mellitus and type 2 diabetes mellitus. In the present review, we summarize the literature about clinical aspects of ZnT8 in the pathogenesis of diabetes, and suggest that ZnT8 might play a different role between type 1 diabetes mellitus and type 2 diabetes mellitus.