Characteristics and clinical course of type 1 diabetes mellitus related to anti-programmed cell death-1 therapy.

AIMS: We conducted a national survey to clarify the characteristics and clinical course of type 1 diabetes related to anti-programmed cell death-1 therapy. METHODS: We analyzed the detailed data of 22 patients that were collected using a Japan Diabetes Society survey and a literature database search. RESULTS: Among the 22 patients, 11 (50.0%) met the criteria for fulminant type 1 diabetes and 11 (50.0%) met the criteria for acute-onset type 1 diabetes. The average patient age was 63 years. The mean duration between the date of the first anti-PD-1 antibody injection and development of type 1 diabetes was 155 days and ranged from 13 to 504 days. Flu-like symptoms, abdominal symptoms, and drowsiness were observed in 27.8, 31.6, and 16.7% patients, respectively. Mean ± standard deviation or median (first quartile-third quartile) glucose levels, HbA1c levels, urinary C-peptide immunoreactivity levels, and fasting serum C-peptide immunoreactivity levels were 617 ± 248 mg/dl, 8.1 ± 1.3%, 4.1 (1.4-9.4) µg/day, and 0.46 (0.20-0.70) ng/ml, respectively. Seventeen of 20 patients (85.0%) developed ketosis, and 7 of 18 patients (38.9%) developed diabetic ketoacidosis. Ten of 19 patients (52.6%) showed at least one elevated pancreatic enzyme level at the onset and two of seven patients showed this elevation before diabetes onset. Only one of 21 patients was anti-glutamic acid decarboxylase antibody positive. CONCLUSIONS: Anti-programmed cell death-1 antibody-related type 1 diabetes varies from typical fulminant type 1 diabetes to acute-onset type 1 diabetes. However, diabetic ketoacidosis was frequently observed at the onset of diabetes. An appropriate diagnosis and treatment should be provided to avoid life-threatening metabolic alterations.

Insulin-producing cells derived from 'induced pluripotent stem cells' of patients with fulminant type 1 diabetes: Vulnerability to cytokine insults and increased expression of apoptosis-related genes.

AIMS/INTRODUCTION: The present study was carried out to generate induced pluripotent stem cells (iPSCs) from patients with fulminant type 1 diabetes, and evaluate the cytokine-induced apoptotic reactions of ß-like insulin-producing cells differentiated from the iPSCs. MATERIALS AND METHODS: iPSCs were generated from fibroblasts of patients with fulminant type 1 diabetes by inducing six reprogramming factors. Insulin-producing cells were differentiated from the iPSCs in vitro. The proportion of cleaved caspase-3-positive or terminal deoxynucleotidyl transferase 2'-deoxyuridine, 5'-triphosphate nick end labeling-positive cells among insulin (INS)-positive cells derived from fulminant type 1 diabetes iPSC and control human iPSC lines was evaluated under treatment with tumor necrosis factor-α, interleukin-1ß and interferon-γ. Ribonucleic acid sequencing was carried out to compare gene expressions in INS-positive cells derived from fulminant type 1 diabetes iPSC and control human iPSC lines. RESULTS: Two iPSC clones were established from each of three patients with fulminant type 1 diabetes. The differentiation of insulin-producing cells from fulminant type 1 diabetes iPSC was confirmed by immunofluorescence analysis and KCl-induced C-peptide secretion. After treatment with pro-inflammatory cytokines, these INS-positive cells showed higher expression of cleaved caspase-3 than those derived from control human iPSCs. Altered expression levels of several apoptosis-related genes were observed in INS-positive cells derived from the fulminant type 1 diabetes iPSCs by ribonucleic acid sequencing. CONCLUSIONS: We generated iPSCs from patients with fulminant type 1 diabetes and differentiated them into insulin-producing cells. This in vitro disease model can be used to elucidate the disease mechanisms of fulminant type 1 diabetes.

Risk factors for sudden death and cardiac arrest at the onset of fulminant type 1 diabetes mellitus.

AIMS: The onset of fulminant type 1 diabetes mellitus is sometimes accompanied by sudden death or cardiac arrest. The aim of this study was to determine the risk factors for the development of these conditions at the onset of fulminant type 1 diabetes mellitus. METHODS: We conducted a search of the literature on fulminant type 1 diabetes and sudden death or cardiac arrest published up to 2012 in PubMed and Ichushi (a Japanese article database), and a questionnaire survey was administered to the authors of the articles and to diabetes specialists affiliated to the Japan Diabetes Society. We analyzed the clinical data at disease onset of 17 patients with fulminant type 1 diabetes mellitus who experienced sudden death or cardiac arrest, and those of 257 patients who did not develop these conditions. RESULTS: Patients with sudden death or cardiac arrest were younger, had a higher rate of impaired consciousness, more severe acidosis, hyperglycemia, hyponatremia, hyperkalemia, and hypochloremia, a higher serum blood urea nitrogen level, a higher serum creatinine level, and a higher plasma osmolality level than the other patients. In multiple logistic regression analyses, plasma glucose level was positively associated with sudden death or cardiac arrest. Receiver operating characteristic curve analyses showed that patients with a plasma glucose level over 1000 mg/dl (55.5 mmol/l) were at a high risk of cardiac arrest. CONCLUSIONS: Severe metabolic derangement, especially a high plasma glucose level, is associated with sudden death or cardiac arrest at the onset of fulminant type 1 diabetes mellitus.

Examination of a Viral Infection Mimetic Model in Human iPS Cell-Derived Insulin-Producing Cells and the Anti-Apoptotic Effect of GLP-1 Analogue.

AIMS: Viral infection is associated with pancreatic beta cell destruction in fulminant type 1 diabetes mellitus. The aim of this study was to investigate the acceleration and protective mechanisms of beta cell destruction by establishing a model of viral infection in pancreatic beta cells. METHODS: Polyinosinic:polycytidylic acid was transfected into MIN6 cells and insulin-producing cells differentiated from human induced pluripotent stem cells via small molecule applications. Gene expression was analyzed by real-time PCR, and apoptosis was evaluated by caspase-3 activity and TUNEL staining. The anti-apoptotic effect of Exendin-4 was also evaluated. RESULTS: Polyinosinic:polycytidylic acid transfection led to elevated expression of the genes encoding IFNα, IFNß, CXCL10, Fas, viral receptors, and IFN-inducible antiviral effectors in MIN6 cells. Exendin-4 treatment suppressed the elevated gene expression levels and reduced polyinosinic:polycytidylic acid-induced apoptosis both in MIN6 cells and in insulin-producing cells from human induced pluripotent stem cells. Glucagon-like peptide-1 receptor, protein kinase A, and phosphatidylinositol-3 kinase inhibitors counteracted the anti-apoptotic effect of Exendin-4. CONCLUSIONS: Polyinosinic:polycytidylic acid transfection can mimic viral infection, and Exendin-4 exerted an anti-apoptotic effect both in MIN6 and insulin-producing cells from human induced pluripotent stem cells.

Relationship between serum cystatin C and serum adiponectin level in type 2 diabetic patients.

BACKGROUND: To investigate the relationship between serum levels of cystatin C and adiponectin in patients with type 2 diabetes. METHODS: We examined serum cystatin C and adiponectin levels in 234 patients with type 2 diabetes who visited our hospital. RESULTS: The serum level of cystatin C was positively correlated with age (P < 0.001), duration of diabetes (P = 0.013), serum creatinine (P < 0.001), uric acid (P < 0.001), and adiponectin (p = 0.001), while it was inversely correlated with estimated glomerular filtration rate (P < 0.001). Serum adiponectin was significantly higher in patients with high serum cystatin C levels than in those with normal cystatin C levels (8.3 ± 4.7 and 6.2 ± 3.2 µg/mL, respectively; P < 0.001). Adiponectin was also significantly higher in male patients with high cystatin C levels, but not in females. In multiple regression analysis, serum adiponectin was also independently and significantly correlated to age, diastolic blood pressure, high-density lipoprotein cholesterol, triglyceride and serum cystatin C. CONCLUSIONS: Serum adiponectin level was correlated with serum cystatin C level on simple and multiple regression analyses in patients with type 2 diabetes. Although circulating adiponectin is increased in advanced kidney disease, it might be biologically inactive due to binding to cystatin C and thus not display an anti-arteriosclerotic effect.

Long-term efficacy of trilostane for Cushing's syndrome due to adrenocorticotropin-independent bilateral macronodular adrenocortical hyperplasia.

A 66-year-old man with Cushing's syndrome due to adrenocorticotropin-independent bilateral macronodular adrenocortical hyperplasia (AIMAH) was treated for 7 years with trilostane, a 3ß-hydroxysteroid dehydrogenase inhibitor. Administration of trilostane reduced the serum cortisol level to around the upper limit of normal for 7 years, and symptoms of excessive glucocorticoid production (such as moon face and obesity) were gradually improved. On the other hand, the size of both adrenal glands gradually increased despite treatment with trilostane. Though trilostane therapy could not prevent adrenal growth, it did suppress cortisol secretion over the long term, so it might be a reasonable option for AIMAH in addition to adrenalectomy.