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Aim Several genetic loci related to lean mass have been identified in healthy individuals by genome-wide association studies; however, the contribution of these loci to body composition in type 2 diabetes remains to be investigated. Here, we aimed to clarify the genetic determinants of body composition in individuals with type 2 diabetes. Methods A total of 176 Japanese outpatients (70 women and 106 men) with type 2 diabetes were studied using a cross-sectional design. Body composition was measured using bioimpedance analysis with a commercially available device (InBody770). Single-nucleotide polymorphisms in IRS1 (rs2943656), HSD17B11 (rs9991501), VCAN (rs2287926), ADAMTSL3 (rs4842924) and FTO (rs9936385) were evaluated by genotyping. The contributions of single-nucleotide polymorphisms to body composition were examined, considering known clinical determinants. Results Sex, body composition and age were identified as clinical predictors. IRS1 rs2934656 was identified as an independent predictor of skeletal muscle mass (β = 0.11, P = 0.026), and ADAMTSL3 rs4842924 was an independent predictor of body fat mass (β = 0.15, P = 0.0095) and appendicular lean mass (β = -0.13, P = 0.017). Conclusions The findings clarified the contribution of genetic factors - IRS1 and ADAMTSL3 - to interindividual variation in body composition, independent of clinical factors, in type 2 diabetes patients. These data will contribute to the establishment of effective methods for the prediction, prevention, and intervention of sarcopenia and frailty in diabetes patients. Geriatr Gerontol Int 2021; ••: ••-••.

Diabetes mellitus is etiologically classified into type 1, type 2 and other types of diabetes. Despite distinct etiologies and pathogenesis of these subtypes, many studies have suggested the presence of shared susceptibilities and underlying mechanisms in β‐cell failure among different types of diabetes. Understanding these susceptibilities and mechanisms can help in the development of therapeutic strategies regardless of the diabetes subtype. In this review, we discuss recent evidence indicating the shared genetic susceptibilities and common molecular mechanisms between type 1, type 2 and other types of diabetes, and highlight the future prospects as well., Despite distinct etiologies and pathogenesis of type 1, type 2 and other types of diabetes, many studies have suggested the presence of shared susceptibilities and underlying mechanisms in β‐cell failure among different types of diabetes. Understanding these susceptibilities and mechanisms can help in the development of therapeutic strategies regardless of the diabetes subtype. In this review, we discuss recent evidence indicating the shared genetic susceptibilities and common molecular mechanisms between type 1, type 2 and other types of diabetes, and highlight the future prospects as well.

This trial was conducted to assess the long-term safety, efficacy, and benefit of early add-on of linagliptin to insulin in patients with type 2 diabetes mellitus (T2DM). This trial enrolled 246 subjects. The subjects were randomized to the linagliptin group or the control group and were observed for 156 weeks. After week 16, subjects in the control group were also allowed to add linagliptin to evaluate the benefit of early add-on of linagliptin to insulin. The primary end point was a change in HbA1c from baseline to week 16. Secondary end points included fasting plasma glucose, daily insulin dose, and frequency of adverse events. HbA1c and fasting plasma glucose levels significantly decreased from baseline to week 16 in the linagliptin group compared with the control group. The significant improvement in HbA1c continued until week 52. The daily insulin dose significantly decreased in the linagliptin group compared with the control group. The frequency of hypoglycemia and adverse events was comparable in both groups. Add-on of linagliptin to insulin was tolerated, improved glycemic control, and reduced the daily insulin dose. This study demonstrates the long-term safety, efficacy and benefit of early add-on of linagliptin to insulin in Japanese T2DM patients.

ContextThe rate of glucose metabolism changes drastically after partial pancreatectomy.ObjectiveThis work aims to analyze changes in patients’ glucose metabolism and endocrine and exocrine function before and after partial pancreatectomy relative to different resection types (Kindai Prospective Study on Metabolism and Endocrinology after Pancreatectomy: KIP-MEP study).MethodsA series of 278 consecutive patients with scheduled pancreatectomy were enrolled into our prospective study. Of them, 109 individuals without diabetes, who underwent partial pancreatectomy, were investigated. Data were compared between patients with pancreaticoduodenectomy (PD, n = 73) and those with distal pancreatectomy (DP, n = 36).ResultsBlood glucose levels during the 75-g oral glucose tolerance test (75gOGTT) significantly decreased after pancreatectomy in the PD group (area under the curve [AUC] –9.3%, P ConclusionsBlood glucose levels after the OGTT differed markedly between PD and DP populations. The observed differences between PD and DP suggest the importance of individualization in the management of metabolism and nutrition after partial pancreatectomy.

Since fulminant type 1 diabetes was reported as a distinct subtype of type 1 diabetes in 2000, the Committee on Type 1 diabetes, Japan Diabetes Society has continuously recruited patients and conducted genomic research to elucidate the genetic basis of fulminant type 1 diabetes. The contribution of the human leukocyte antigen complex (HLA) to genetic susceptibility to fulminant type 1 diabetes was compared with that of other subtypes in 2009. The alleles and haplotypes associated with fulminant type 1 diabetes were found to be different from acute-onset and slowly progressive type 1 diabetes. DRB1*15:01-DQB1*06:02, a protective haplotype against acute-onset type 1 diabetes, does not provide protection against fulminant type 1 diabetes and DRB1*08:02-DQB1*03:02, a susceptible haplotype to acute-onset type 1 diabetes, does not confer susceptibility to fulminant type 1 diabetes. Recently, the first genome-wide association study (GWAS) of fulminant type 1 diabetes was performed in Japanese individuals. A strong association was observed with multiple single nucleotide polymorphisms (SNPs) in the HLA region, and the strongest association was observed with rs9268853 in the class II DR region. In addition, 11 SNPs outside the HLA region showed some evidence of association with the disease. In particular, rs11170445 in CSAD/lnc-ITGB7-1 on chromosome 12q13.13 showed an association at a genome-wide significance level. Fine mapping revealed that rs3782151 in CSAD/lnc-ITGB7-1 showed the lowest P value. CSAD/lnc-ITGB7-1 was found to be strongly associated with susceptibility to fulminant, but not classical, autoimmune type 1 diabetes, implicating this locus in the distinct phenotype of fulminant type 1 diabetes.

Aims/Introduction A flash glucose monitoring (FGM) system has become available. To clarify the relationship between FGM and self‐monitoring blood glucose (SMBG) values, we compared the two values after simultaneous measurement in Japanese patients with type 1 diabetes, under daily life settings. Materials and Methods A total of 20 outpatients with type 1 diabetes were analyzed. When FGM and SMBG were carried out simultaneously (within ±3 min), the values were adopted and each FGM value was matched and compared with the corresponding SMBG value. In addition, we analyzed other cases of simultaneity defined as “within ±2 min,” “within ±1 min” and “at the exact same time.” Results The percentage of SMBG and FGM values in the clinically acceptable zone A + B in Clarke and consensus error grid analyses were 97.9 and 99.2%, respectively. Deming regression (x‐axis: FGM values, y‐axis: SMBG values) determined a slope of 0.9128 (95% confidence interval 0.9008–0.9247) and an intercept of +15.94 mg/dL (95% confidence interval 14.05–17.84). FGM values were lower than SMBG values in the lower glucose range, and higher in the higher glucose range. The shorter the time lag between measurements, the higher the rate of concordance between FGM and SMBG values. Conclusions The results of this study provided evidence on the reliability of FGM in Japanese patients with type 1 diabetes in home conditions. Based on the results, if an abnormal glucose value is detected by FGM, SBMG should then be used to confirm the result., Flash glucose monitoring values were lower than self‐monitoring blood glucose values in the lower glucose range, and higher in the higher glucose range. The shorter the time lag between measurements, the higher the rate of concordance between flash glucose monitoring and self‐monitoring blood glucose values.

We report the identification of a mutation in the solute carrier family 5 member 2 (SLC5A2) gene, which encodes sodium–glucose cotransporter 2, in a family with familial renal glucosuria. The proband was a 26‐year‐old Japanese man referred to the diabetes division with repeated glucosuria without hyperglycemia. His mother, uncle and grandfather also had a history of glucosuria. A heterozygous missense mutation (c.303T>A:p.N101K) in SLC5A2 was identified in the patient and his mother, but not in 200 chromosomes from 100 healthy and unrelated individuals, or in 3,408 Japanese individuals in the Tohoku Medical Megabank. Furthermore, bioinformatics software predicted that this lesion would be pathogenic. We infer that the mutation led to clinically relevant sodium–glucose cotransporter 2 dysfunction. The patient showed no symptoms of hypoglycemia, but continuous glucose monitoring confirmed asymptomatic hypoglycemia., We report the identification of a heterozygous missense mutation (c.303T>A:p.N101K) in the solute carrier family 5 member 2 gene, which encodes sodium-glucose cotransporter 2, in a family with familial renal glucosuria.

Mixed corticomedullary tumors (MCMTs) are rare and comprise medullary and cortical cells in a single adrenal tumor. The mechanisms underlying their development have not been fully elucidated. Here, we report a case of MCMT in a 42-year-old woman. Based on the preoperative clinical findings, the patient was diagnosed as having a pheochromocytoma with subclinical Cushing syndrome. Postoperative pathological diagnosis revealed that the tumor demonstrated morphologically distinct medullary and cortical components, which produced catecholamines and cortisol, respectively. Hybrid tumor cells producing both catecholamines and cortisol were not detected. Adrenocorticotropin (ACTH)-positive tumor cells were identified to be present in the pheochromocytoma. This ectopic production of ACTH can contribute to an autonomous cortisol production in a paracrine manner. In addition, micronodules producing aldosterone were detected in the adrenal tissue adjacent to the tumor. The simultaneous development of these 2 lesions may not be correlated with each other; however, this case confirms the importance of a detailed histopathological examination of the adrenal lesions harboring complicated hormonal abnormalities by providing pivotal and indispensable information on their pathogenesis and the possible interaction of the hormones produced in the adrenal gland.

Adrenocortical carcinoma (ACC) is a rare tumor, and some histological variants (oncocytic, myxoid, and sarcomatoid ACCs) have been reported in addition to the conventional ACC. Among these subtypes, oncocytic ACC is histologically characterized by the presence of abundant eosinophilic granular cytoplasm in the carcinoma cells owing to the accumulation of mitochondria, which generally yields high 18F-fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET). Herein, we report the case of a 21-year-old woman with oncocytic ACC with low FDG uptake on PET scan. Her circulating levels of androgens were high, and androgen-synthesis enzymes were detected in carcinoma cells. The patient also had hypocholesterolemia. However, glucose transporter 1 (GLUT1) was not detected in the tumor, which was considered to account for the low FDG uptake by the tumor. To the best of our knowledge, this is the first case of low FDG uptake by oncocytic ACC without GLUT1 expression. Additionally, since hypocholesterolemia was reported in 3 previous reports of androgen-producing tumors, a possible correlation between androgenicity in adrenal tumors and the development of hypocholesterolemia could be postulated; however, further investigations are needed for clarification. This case highlights important information regarding the diversity of ACC and its impact on hypocholesterolemia.

Aims/Introduction Hyperglycemia is a risk factor for sarcopenia when comparing individuals with and without diabetes. However, no studies have investigated whether the findings could be extrapolated to patients with diabetes with relatively higher glycemic levels. Here, we aimed to clarify whether glycemic control was associated with sarcopenia in patients with type 2 diabetes. Materials and Methods Study participants consisted of patients with type 2 diabetes (n = 746, the average age was 69.9 years) and an older general population (n = 2,067, the average age was 68.2 years). Sarcopenia was defined as weak grip strength or slow usual gait speed and low skeletal mass index. Results Among patients with type 2 diabetes, 52 were diagnosed as having sarcopenia. The frequency of sarcopenia increased linearly with glycated hemoglobin (HbA1c) level, particularly in lean individuals (HbA1c

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.

Type 1 diabetes (T1D) is classified into three subtypes: acute-onset, slowly progressive, and fulminant T1D, according to the heterogeneity of clinical course in Japan. Although several cross-sectional databases of T1D have been reported, prospective longitudinal databases to investigate clinical outcomes are lacking in our country. Therefore, we herein construct multi-center prospective longitudinal database of the three subtypes of T1D, accompanied with genetic information and biobanking, which is named Japanese Type 1 Diabetes Database Study (TIDE-J). Inclusion criteria of this study are as follows: (1) the duration of T1D was less than 5 years, (2) the patients had one or more islet-related autoantibodies and/or fasting serum C-peptide levels were less than 1.0 ng/mL, (3) the patients could clearly understand the study consent in writing. In the TIDE-J, clinical data, including glycemic control, endogenous insulin secretion, islet-related autoantibodies, diabetic complications, and treatment, are collected annually using electric data collection system, which is named REDCap. Furthermore, HLA genotypes of each participant were analyzed at entry and the blood samples were stored for assessing exploratory markers and further genetic analysis annually. The TIDE-J certainly helps in revealing distinct clinical course of each T1D subtype. Moreover, this database may help in identifying novel markers for diagnosing each subtype of T1D and predicting clinical outcomes (including pancreatic beta cell function and disease severity) in patients.

International audience; Aims: To describe glycaemic control and diabetes management in adults with type 1 diabetes (T1DM), in a real-life global setting.Materials and methods: Study of Adults' GlycEmia (SAGE) was a multinational, multicentre, single visit, non-interventional, cross-sectional study in adult patients with T1DM. Data were collected at a single visit, analysed according to predefined age groups (26-44, 45-64, and ≥65 years), and reported across different regions. The primary endpoint was the proportion of participants achieving HbA1c

AIMS/INTRODUCTION: Type 1 diabetes is rare in the general Japanese population, but becoming more common in adults with increased longevity owing to advancements in treatment. We aimed to examine the current state of glycemic control and diabetes management using real-world data on Japanese adults with type 1 diabetes in different age groups. MATERIALS AND METHODS: This was a subanalysis of Japanese participants from a multinational, cross-sectional, observational study of adults with type 1 diabetes aged ≥ 26 years conducted in 2018 (Study of Adults’ Glycemia in T1DM). Glycemic control achievement rate and goal setting, incidence of hypoglycemia, and diabetes management of individuals aged 26‒44 years, 45‒64 years, and ≥ 65 years were summarized. RESULTS: The data on 528 participants were analyzed. The mean glycated hemoglobin (HbA1c) value was 7.8% (61.3 mmol/mol). Of the participants, 25.8% achieved an HbA1c level of

The targets for continuous glucose monitoring (CGM)-derived metrics were recently set; however, studies on CGM data over a long period with stable glycemic control are limited. We analyzed 194,279 CGM values obtained from 19 adult Japanese patients with type 1 diabetes. CGM data obtained during stable glycemic control over four months were analyzed. CGM-related metrics of different durations “within 120, 90, 60, 30, and 7 days” were calculated from baseline. Time in range (TIR; glucose 70–180 mg/dL), time above range (TAR; glucose ≥ 181 mg/dL), and average glucose levels, but not time below range (TBR; glucose ≤ 69 mg/dL), strongly correlated with glycated hemoglobin (HbA1c) values (P

Characterization of adrenocortical disorders is challenging because of varying origins, laterality, the presence or absence of hormone production, and unclarity about the benign or malignant nature of the lesion. Histopathological examination in conjunction with immunohistochemistry is generally considered mandatory in this characterization. We report a rare case of bilateral adrenocortical adenomas associated with unilateral adrenal endothelial cysts in a 65-year-old woman whose condition was not diagnosed before surgery. Detailed histological examination of the resected adrenal glands revealed hyperplasia in the zona glomerulosa. Despite hyperplasia, the patient had normal serum aldosterone levels and renin activity without clinical evidence of hypertension. The patient was treated with a sodium-glucose cotransporter protein 2 (SGLT2) inhibitor. This may have stimulated the renin-angiotensin-aldosterone system. To the best of our knowledge, this is the first case in which both relatively large bilateral adrenocortical adenomas and unilateral adrenal endothelial cysts were detected. This case also highlights the complexity and difficulty of preoperative diagnosis. Furthermore, this case reports the first detailed histopathological examination of adrenal lesions with SGLT2 treatment and the possibility of SGLT2 inhibitor treatment resulting in histological hyperplasia in the zona glomerulosa; however, it is difficult to prove a causative relationship between SGLT2 inhibitors and hyperplasia of the zona glomerulosa based on the data of this case. It can be confirmed only under limited conditions; therefore, further studies on adrenal gland histology employing SGLT2 inhibition are warranted.

Aims/Introduction Glucosuria is a representative symptom in diabetes patients with poor glycemic control and in those treated with sodium–glucose cotransporter 2 inhibitors. Renal threshold levels of glucose excretion are known to vary among individuals, but factors contributing to glucosuria are not well characterized. The present study aimed to clarify clinical and genetic determinants of glucosuria in individuals with diabetes mellitus. Materials and Methods The 24‐h urinary glucose excretion was measured in 135 hospitalized patients on admission, with continuous measurement for five consecutive days in 75 patients. Genetic and clinical factors contributing to glucosuria were studied. As a genetic factor, SLC5A2 polymorphism was genotyped. A total of 476 participants (266 participants with type 2 diabetes and 210 healthy controls) were additionally genotyped for the association study of SLC5A2 with type 2 diabetes. A meta‐analysis was carried out with the present study and previous association studies. Results Multiple regression analysis showed that the independent variables of average blood glucose (β = 0.41, P = 1.4 × 10−7), estimated glomerular filtration rate (β = 0.28, P = 6.0 × 10−5), sex (β = 0.28, P = 5.7 × 10−5) and SLC5A2 rs9934336 polymorphism (β = 0.17, P = 0.02) were significantly correlated with urinary glucose excretion. The frequency of the A allele of rs9934336 tended to be lower in participants with type 2 diabetes than in controls (odds ratio 0.78, 95% confidence interval 0.53–1.13, not significant), and meta‐analysis showed a significant association between the A allele and type 2 diabetes (summary odds ratio for minor allele [A] 0.86, 95% confidence interval 0.78–0.94, P, Clinical and genetic determinants of urinary glucose excretion were clarified in hospitalized diabetes patients by using data of 24‐h urine collection. Blood glucose, estimated glomerular filtration rate, sex and SLC5A2 polymorphism were independent determinants of glucosuria in diabetes mellitus patients.

Poor glycemic control is a risk factor for many diabetes-related complications, but global real-world data on diabetes management in adults with T1D is limited. SAGE was a multinational, observational, cross-sectional study to describe glycemic control of participants aged ≥26 years with T1D for ≥1 year. Of 3858 participants from 17 countries, 54.6% were female, with mean (standard deviation [SD]) age 47.4 (14.0) years, T1D duration 20.7 (12.6) years, and age at T1D onset 26.7 (14.4) years. Childhood-onset T1D was most common (48%) in the 26-44 years age group. Mean (SD) HbA1c was 7.95 (1.42) % (63.4 [15.6] mmol/mol), and similar across predefined age groups (Table). Only 20.9% of participants reached their individualized HbA1c target. Prevalence of microvascular complications was 36-63%, increasing with age and duration of diabetes. Incidence of diabetic ketoacidosis was similar in all age groups and consistent with previous reports. SAGE shows that the prevalence of microvascular complications remains high, affecting over half of the study population aged ≥65 years, and is more prevalent in those with a longer duration of diabetes. Disclosure E. Renard: Board Member; Self; Abbott, Insulet Corporation, Novo Nordisk A/S, Roche Diabetes Care. Consultant; Self; Air Liquide, Eli Lilly and Company, Sanofi. Research Support; Self; Dexcom, Inc., Tandem Diabetes Care. Z. Bosnyak: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. F. Lauand: Employee; Self; Sanofi. P. Pozzilli: Advisory Panel; Self; Abbott, AstraZeneca, Eli Lilly and Company. Research Support; Self; Medtronic, Sanofi. H. Ikegami: None. J. Kesavadev: Speaker’s Bureau; Self; Biocon, Novo Nordisk Inc., Sanofi-Aventis. A.G. Vianna: Board Member; Self; Abbott, Medtronic, Novo Nordisk A/S. Research Support; Self; Sanofi. Speaker’s Bureau; Self; Lilly Diabetes. Funding Sanofi

Most people with T1D do not achieve HbA1c targets, but this may vary with patient- and disease-related factors. SAGE was a multinational, cross-sectional study using data from medical records and interviews of eligible people with T1D for ≥1 year, aged ≥26 years (N=3858). The relationship between each group of selected factors (sociodemographics, diabetes complications and comorbidities, T1D treatment, structure and process of medical care) and HbA1c target achievement (both general [HbA1c Overall, 24.3% of people achieved HbA1c HbA1c target achievement remains a challenge but SAGE identified factors that appear to be associated with HbA1c target achievement, offering opportunities for intervention. Disclosure J. Seufert: Research Support; Self; Sanofi. Speaker’s Bureau; Self; Sanofi. H. Ikegami: None. S. Brette: Other Relationship; Self; Sanofi. V. Pilorget: Employee; Self; Sanofi. F. Lauand: Employee; Self; Sanofi. E.G. Wilmot: Advisory Panel; Self; Abbott, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Medtronic. Speaker’s Bureau; Self; Abbott, Eli Lilly and Company, Insulet Corporation, Novo Nordisk Inc., Sanofi. E. Renard: Board Member; Self; Abbott, Insulet Corporation, Novo Nordisk A/S, Roche Diabetes Care. Consultant; Self; Air Liquide, Eli Lilly and Company, Sanofi. Research Support; Self; Dexcom, Inc., Tandem Diabetes Care. J.J. Gagliardino: None.

T1D is a chronic disease impacting patients’ lives and psychosocial health; we explored how this may vary by age and region. SAGE was a multinational, cross-sectional observational study using data from medical records and interviews of participants (N=3858) aged ≥26 years with T1D for ≥1 year. Results from PROs questionnaires (Hypoglycemia Fear Survey [HFS-II], Problem Areas in Diabetes [PAID], Insulin Treatment Satisfaction Questionnaire [ITSQ], Audit of Diabetes-Dependent Quality of Life [ADDQoL]) were analyzed by region (Asia [A], Eastern Europe [EE], Western Europe [WE], Latin America [LA], Middle East [ME]) and age group (26- HFS-II scores showed fear of hypoglycemia was lowest in A for all age groups (Table). HFS-II scores increased with age in EE and decreased with age in LA. PAID scores showed highest levels of emotional distress in ME for all age groups. ITSQ scores showed treatment satisfaction increased with age in WE, LA and ME, and was more stable in EE and A. ADDQoL total scores showed a small negative impact of T1D on quality of life, with the highest and lowest impact in EE and ME, respectively, across all ages. PROs scores indicated relatively low levels of diabetes-related impact and high treatment satisfaction. Age and regional differences may reflect variations in T1D control and management, as well as cultural and healthcare-system-related factors. Disclosure L. Berard: Consultant; Self; Abbott, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Becton, Dickinson and Company, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Montméd, Novo Nordisk Inc., Sanofi. Speaker’s Bureau; Self; Boehringer Ingelheim (Canada) Ltd. F. Ampudia Blasco: None. S. Brette: Other Relationship; Self; Sanofi. D. Bruttomesso: Consultant; Self; Abbott, Eli Lilly and Company, Movi, Novo Nordisk, Roche Diagnostics, Sanofi. K.L. Close: Other Relationship; Self; Abbott, Air Liquide, American Diabetes Association, AstraZeneca, Dexcom, Inc., Janssen Pharmaceuticals, Inc., JDRF, Leona M. and Harry B. Helmsley Charitable Trust, Lilly Diabetes, Merck & Co., Inc. H. Ikegami: None. D. Jurišic-Eržen: None. F. Lauand: Employee; Self; Sanofi. A.L. Peters: Advisory Panel; Self; Abbott, Bigfoot Biomedical, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MannKind Corporation, Medscape, Novo Nordisk Inc., Sanofi US. Consultant; Self; Livongo Health. Research Support; Self; Dexcom, Inc., vTv Therapeutics. Other Relationship; Self; Livongo Health, Mellitus Health, Omada Health, Stability Healthcare, Whole Biome Inc. V. Pilorget: Employee; Self; Sanofi. R. Balamurugan: None. E. Renard: Board Member; Self; Abbott, Insulet Corporation, Novo Nordisk A/S, Roche Diabetes Care. Consultant; Self; Air Liquide, Eli Lilly and Company, Sanofi. Research Support; Self; Dexcom, Inc., Tandem Diabetes Care. E.G. Wilmot: Advisory Panel; Self; Abbott, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Medtronic. Speaker’s Bureau; Self; Abbott, Eli Lilly and Company, Insulet Corporation, Novo Nordisk Inc., Sanofi. A. Roborel de Climens: Employee; Self; Sanofi. Funding Sanofi

Introduction. Streptozotocin- (STZ-) induced diabetes is under polygenic control, and the genetic loci for STZ susceptibility are mapped to chromosome (Chr) 11 in Nagoya-Shibata-Yasuda (NSY) mice. In addition to Chr11, other genes on different chromosomes may contribute to STZ susceptibility in NSY mice. The aim of this study was to determine whether NSY-Chr14 contributes to STZ susceptibility and contains the STZ-susceptible region. Materials and Methods. A consomic C3H-14NSY strain (R0: homozygous for NSY-derived whole Chr14 on the control C3H background), two congenic strains (R1: the region retained proximal and middle segments of NSY-Chr14 and R2: the region retained a proximal segment of NSY-Chr14), and parental NSY and C3H mice were intraperitoneally injected with a single injection of STZ at a dose of 175 mg/kg body weight at 12 weeks of age. Blood glucose levels and body weights were measured at days 0, 1, 2, 4, 5, 7, 8, and 14 after STZ injection. At day 14 after STZ injection, pancreata were dissected and fixed. Results. After STZ injection, blood glucose levels were significantly higher in R0 mice than in C3H mice. However, blood glucose levels in R0 mice were not as severely affected as those in NSY mice. In R1 and R2 mice, blood glucose levels were similar to those in C3H mice and were significantly lower than those in R0 mice. Body weights were decreased in NSY and R0 mice; however, this change was not observed in R1, R2, and C3H mice. Although islet tissues in all strains exhibited degeneration and cellular infiltration, histological changes in NSY and R0 mice were more severe than those in R1, R2, and C3H mice. Conclusions. These data demonstrated that NSY-Chr14 was a STZ-susceptible chromosome and that STZ susceptibility was mapped to the distal segment of NSY-Chr14.

Diabetes mellitus is a multifactorial disease caused by a complex interaction of environmental and genetic factors. Some diabetes mellitus cases, however, are caused by a limited number of mutant genes. Chromosome 13q deletion syndrome, an extremely rare genetic disorder, is caused by structural and functional monosomy of the 13q chromosomal region. We report the case of a 38-year-old Japanese man with Chr13q deletion (a mosaic pattern with heterozygous ring Chr13q) who developed diabetes mellitus. Early-onset diabetes mellitus developed in this patient because of insulin resistance and a lack of adequate insulin secretion. Microarray analysis identified a 4.8-Mb deletion of distal Chr13q, leading to a copy number loss of 40 genes. Among those genes, the insulin receptor substrate 2 gene (IRS2) was the most likely causative candidate for the development of diabetes mellitus in this patient, based on the model of IRS2 knockout mice, which have abnormal glucose and insulin homeostasis closely resembling the human diabetes phenotype. These data provide important information regarding the contribution of a microdeletion of Chr13q, including in IRS2, to the pathogenesis of diabetes mellitus in humans.

Aims/Introduction Patients with a total pancreatectomy and type 1 diabetes are similar in regard to absolute insulin deficiency, but different in regard to glucagon, providing a unique opportunity to study the contribution of glucagon to glucose metabolism in an insulin‐dependent state. The aim of the present study was to investigate the contribution of glucagon to glucose homeostasis in complete insulin deficiency in vivo. Methods A total of 38 individuals with a complete lack of endogenous insulin (fasting C‐peptide

Aims Differences in the efficacy and safety of anti-diabetic drugs among different ethnic groups are well documented. Metformin is widely used in the treatment of type 2 diabetes in Western countries, but high doses of metformin have been approved only recently for clinical use in Japan. The aim of this study was to investigate the effects of dosage and dosing frequency on the efficacy and safety of high-dose metformin in Japanese patients. Methods A total of 71 Japanese patients with type 2 diabetes were prospectively studied for the effects of dosage and dosing frequency on the efficacy and safety of metformin during hospitalization. Dose effects were studied in 27 patients treated with 0, 500, 1000, 1500 and 2250 mg/day of metformin. The effect of dosing frequency was compared in 56 patients with 1500 mg/day of metformin administered either twice or three times per day. Results Significant dose-dependent improvement in daily profiles of blood glucose was observed with metformin dosages up to 1500 mg/day, with a trend towards further improvement observed at 2250 mg/day. The efficacy of 1500 mg of metformin was comparable when the drug was administered either two or three times per day. The most frequently reported side effects were gastrointestinal symptoms, which were not affected by the dosage or dosing frequency of metformin. Conclusions These results indicate that the efficacy of high-dose metformin is dose-dependent in Japanese patients. The efficacy and safety of metformin were similar when the drug was administered either two or three times per day. This article is protected by copyright. All rights reserved.

Our previous observations clarified that Graves' disease (GD) is the most frequent autoimmune disease in patients with alopecia areata (AA), and 42.7% of patients with AA were positive for thyrotropin receptor antibody (TRAb). A class II HLA haplotype DRB1∗15:01-DQB1∗06:02 was suggested to contribute to autoimmunity against the thyroid gland in AA. To further clarify the genetic factors contributing to organ specificity in autoimmune diseases, we studied the contribution of non-HLA genes to organ specificity in GD and AA. A high frequency of AA (13.4%) was observed in patients with GD, indicating strong phenotypic association between GD and AA. CTLA4 and TSHR were significantly associated with GD (Pc=0.007 and Pc

Ken Sugimoto, Hiroshi Ikegami, Yasunori Takata, Tomohiro Katsuya, Masahiro Fukuda, Hiroshi Akasaka, Yasuharu Tabara, Haruhiko Osawa, Yoshihisa Hiromine, Hiromi Rakugi, Glycemic Control and Insulin Improve Muscle Mass and Gait Speed in Type 2 Diabetes: The MUSCLES-DM Study, Journal of the American Medical Directors Association, 2020, https://doi.org/10.1016/j.jamda.2020.11.003., Objectives: Type 2 diabetes is a risk factor for sarcopenia. Evidence on the prevention of sarcopenia using blood glucose–lowering therapy is limited. We aimed to examine the relationship between changes in glycemic control and sarcopenia and the effect of antidiabetic agents against sarcopenia in patients with type 2 diabetes. Design: We conducted an observational longitudinal study. Setting and Participants: In total, 588 Japanese patients with diabetes of an ongoing multicenter study completed 1-year follow-up measurements for sarcopenia and clinical data. Methods: The data set of the Multicenter Study for Clarifying Evidence for Sarcopenia in patients with Diabetes Mellitus (the MUSCLES-DM study) was analyzed. Results: During the follow-up period, the frequency of sarcopenia marginally increased, and the means of skeletal muscle mass index (SMI), handgrip strength, and gait speed did not show any changes. However, on dividing into 5 groups depending on the degree of changes in glycated hemoglobin (HbA1c) value, the patients with a decrease of ≥1% in HbA1c exhibited a significant increase in SMI. Our analysis revealed similar results for gait speed but not handgrip strength. Using the multiple linear regression model, we identified that a ≥1% decrease in HbA1c value was an independent determinant of the changes in SMI and gait speed. We also determined that insulin use at baseline was an independent factor for the changes in SMI. Conclusions and Implications: Correction of poor glycemic control and use of insulin were significantly associated with the increase in skeletal muscle mass or gait speed in Japanese patients with type 2 diabetes. The current finding increases our understanding of the importance of glycemic control for the prevention of cardiovascular diseases and sarcopenia.

Type 1 diabetes is caused by destruction of insulin-producing beta cells of the pancreas. The etiology of type 1 diabetes is immune-mediated by either an organ-specific autoimmune mechanism in autoimmune type 1 diabetes or a still unknown but probably immune-mediated mechanism in fulminant type 1 diabetes. Immunomodulation is therefore expected to accelerate or inhibit type 1 diabetes. Recent progress in anti-cancer therapy by immune-checkpoint blockade, such as anti-PD-1 and anti-CTLA4 monoclonal antibodies, has markedly improved the prognosis of patients with advanced cancers. These drugs activate anti-tumor immunity by blocking inhibitory signals of T lymphocytes. Activation of immunological pathways, however, is expected to accelerate immune-mediated diseases. In fact, the development of autoimmune-thyroid diseases and type 1 diabetes, including fulminant type 1 diabetes, has been reported in patients treated with immune checkpoint blockers. The development of fulminant type 1 diabetes is a major concern because of its abrupt onset and very rapid progression, leading to death unless proper treatment is initiated immediately after diagnosis. In this review, the development of type 1 diabetes with immune-checkpoint therapy and its etiological background are discussed.

ObjectiveGlomerular filtration rate (GFR) decreases without or prior to the development of albuminuria in many patients with diabetes. Therefore, albuminuria and/or a low GFR in patients with diabetes is referred to as diabetic kidney disease (DKD). A certain proportion of patients with diabetes show a rapid progressive decline in renal function in a unidirectional manner and are termed early decliners. This study aimed to elucidate the prevalence of DKD and early decliners and clarify their risk factors.Research design and methodsThis combination cross-sectional and cohort study included 2385 patients with diabetes from 15 hospitals. We defined DKD as a urinary albumin to creatinine ratio (ACR) ≥30 mg/gCr and/or estimated glomerular filtration rate (eGFR) ResultsOf our cohort, 52% had DKD. Above all, 12% with a low eGFR but no albuminuria had no traditional risk factors, such as elevated glycated hemoglobin, elevated blood pressure, or diabetic retinopathy in contrast to patients with albuminuria but normal eGFR. Additionally, 14% of our patients were early decliners. Older age, higher basal eGFR, higher ACR, and higher systolic blood pressure were significantly associated with early decliners.ConclusionsThe prevalence of DKD in this cohort was larger than ever reported. By testing eGFR yearly and identifying risk factors in the early phase of diabetes, we can identify patients at high risk of developing end-stage renal disease.

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.

Multiple autoimmune diseases, such as autoimmunity against the thyroid gland and pancreatic islets, are often observed in a single patient. Although alopecia areata (AA) is one of the most frequent organ-specific autoimmune diseases, the association of AA with other autoimmune diseases and the genetic basis of the association remain to be analyzed.The aim of this study was to clarify the similarities and differences in HLA and clinical characteristics of thyroid and islet autoimmunity in patients with AA.A total of 126 patients with AA were newly recruited. Anti-islet and antithyroid autoantibodies were tested, and genotypes of HLA genes were determined.Among the autoimmune diseases associated with AA, autoimmune thyroid disease was most frequent (10.0%), followed by vitiligo (2.7%) and rheumatoid arthritis (0.9%) but not type 1 diabetes (0.0%). The prevalence of thyroid-related autoantibodies in patients with AA was significantly higher than that in controls (TSH receptor antibody [TRAb]: 42.7% vs 1.2%, P = 1.6 × 10(-46); thyroid peroxidase antibody: 29.1% vs 11.6%; P = 1.7 × 10(-6)), whereas the prevalence of islet-related autoantibodies was comparable between patients with AA and control subjects. The frequency of DRB1*15:01-DQB1*06:02, a protective haplotype for type 1 diabetes, was significantly higher in TRAb-positive (12.8%, P = .0028, corrected P value [Pc] = .02) but not TRAb-negative (7.1%, not significant) patients with AA than in control subjects (4.5%). The frequency of DRB1*04:05-DQB1*04:01, a susceptible haplotype for type 1 diabetes, was significantly lower in patients with AA (TRAb-positive: 8.5%; TRAb-negative: 11.9%) than in those with type 1 diabetes (29.5%, Pc.0003 and Pc.0008, respectively).AA was associated with thyroid autoimmunity but not islet autoimmunity, which correlated with class II HLA haplotypes susceptible or resistant to each autoimmune disease.

Abrupt disease onset and severe metabolic disorders are main characteristics of fulminant type 1 diabetes. Diffusion-weighted magnetic resonance imaging (DWI) is an imaging technique that reflects restricted diffusion in organs and can detect mononuclear cell infiltration into the pancreas at the onset of the disease. Fourteen patients with fulminant type 1 diabetes who underwent abdominal magnetic resonance imaging were recruited for the measurement of apparent diffusion coefficient (ADC) values of the pancreas that were compared with those of 21 non-diabetic controls. The ADC values of all parts of the pancreas were significantly lower in fulminant type 1 diabetes than in controls (head, 1.424 ± 0.382 × 10(−3) vs. 1.675 ± 0.227 × 10(−3) mm(2)/s; body, 1.399 ± 0.317 × 10(−3) vs. 1.667 ± 0.170 × 10(−3) mm(2)/s; tail, 1.336 ± 0.247 × 10(−3) vs. 1.561 ± 0.191 × 10(−3) mm(2)/s; mean, 1.386 ± 0.309 × 10(−3) vs. 1.634 ± 0.175 × 10(−3) mm(2)/s) (p

Summary Background Limited evidence suggests that multifactorial interventions for control of glucose, blood pressure, and lipids reduce macrovascular complications and mortality in patients with type 2 diabetes. However, safe and effective treatment targets for these risk factors have not been determined for such interventions. Methods In this multicentre, open-label, randomised, parallel-group trial, undertaken at 81 clinical sites in Japan, we randomly assigned (1:1) patients with type 2 diabetes aged 45–69 years with hypertension, dyslipidaemia, or both, and an HbA 1c of 6·9% (52·0 mmol/mol) or higher, to receive conventional therapy for glucose, blood pressure, and lipid control (targets: HbA 1c 1c 1c , and history of cardiovascular disease. Neither patients nor investigators were masked to group assignment. The primary outcome was occurrence of any of a composite of myocardial infarction, stroke, revascularisation (coronary artery bypass surgery, percutaneous transluminal coronary angioplasty, carotid endarterectomy, percutaneous transluminal cerebral angioplasty, and carotid artery stenting), and all-cause mortality. The primary analysis was done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00300976. Findings Between June 16, 2006, and March 31, 2009, 2542 eligible patients were randomly assigned to intensive therapy or conventional therapy (1271 in each group) and followed up for a median of 8·5 years (IQR 7·3–9·0). Two patients in the intensive therapy group were found to be ineligible after randomisation and were excluded from the analyses. During the intervention period, mean HbA 1c , systolic blood pressure, diastolic blood pressure, and LDL cholesterol concentrations were significantly lower in the intensive therapy group than in the conventional therapy group (6·8% [51·0 mmol/mol] vs 7·2% [55·2 mmol/mol]; 123 mm Hg vs 129 mm Hg; 71 mm Hg vs 74 mm Hg; and 85 mg/dL vs 104 mg/dL, respectively; all p vs 283 [22%] in the conventional therapy group, p vs 129 [10%], p=0·0001), the frequencies of major adverse events did not differ between groups. Interpretation Our results do not fully support the efficacy of further intensified multifactorial intervention compared with current standard care for the prevention of a composite of coronary events, cerebrovascular events, and all-cause mortality. Nevertheless, our findings suggest a potential benefit of an intensified intervention for the prevention of cerebrovascular events in patients with type 2 diabetes. Funding Ministry of Health, Labour and Welfare of Japan, Asahi Kasei Pharma, Astellas Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Kissei Pharmaceutical, Kowa Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, MSD, Novartis Pharma, Novo Nordisk, Ono Pharmaceutical, Pfizer, Sanwa Kagaku Kenkyusho, Shionogi, Sumitomo Dainippon Pharma, Taisho Toyama Pharmaceutical, and Takeda.

Background We report a rare case of a juxta-adrenal schwannoma that could not be discriminated from an adrenal tumor before surgical resection and was complicated by bilateral hyperaldosteronism. To the best of our knowledge, this is first case in which both a juxta-adrenal schwannoma and hyperaldosteronism co-existed. Case presentation A 69-year-old male treated for hypertension was found to have a left supra-renal mass (5.8 × 5.2 cm) by abdominal computed tomography. His laboratory data showed that his plasma aldosterone concentration (PAC) was within the normal range, but his plasma renin activity (PRA) was reduced, resulting in an increased aldosterone/renin ratio (ARR). Load tests of captopril or furosemide in the standing position demonstrated autonomous aldosterone secretion and renin suppression. Adrenal venous sampling (AVS) with ACTH stimulation indicated bilateral hypersecretion of aldosterone. A left supra-renal tumor was resected because of the possibility of malignancy and was found to be a benign schwannoma arising from the juxta-adrenal region together with an adrenal gland. The dissected left adrenal gland was morphologically hyperplastic in the zona glomerulosa, but was immunohistochemically negative for CYP11B2 (aldosterone synthase). Multiple CYP11B2-positive adrenocortical micronodules were detected in the adrenal gland, indicating micronodular hyperplasia. Although bilateral aldosteronism was indicated by AVS before the operation, the PRA, PAC and ARR values were within their respective reference ranges after resection of the unilateral tumor, suggesting that the slight increase in hormone secretion from the remaining right-sided lesion could not be detected after resection. Conclusion A clinical and morphologic diagnosis of juxta-adrenal schwannoma is difficult, particularly in a case of hyperaldosteronism, as shown in this case. These data suggest the complexity and difficulty diagnosing adrenal incidentaloma.

Background and objective Detection of chronic obstructive pulmonary disease (COPD) is crucial in the management of COPD. The aim of this study was to establish the utility of a community-based lung cancer screening for detecting COPD. Methods In Japan, community-based lung cancer screening for residents who are 40 years or older using chest radiography is well established. A screening system in Chiba City, Japan, was used to detect COPD. The criteria to consider COPD at screening included age of 60 years or older, a smoking history and chronic respiratory symptoms. Participants fulfilling these criteria were referred for diagnostic evaluation consisting of pulmonary function testing (PFT) and chest computed tomography (CT). Results Of 89 100 Chiba City residents who underwent lung cancer screening, 72 653 residents were 60 years or older. Among them, 878 (1.0%) were identified with suspected COPD and referred for further evaluation. Of those identified, a total of 567 residents (64.6%, 567/878) underwent further evaluations, and 161 (28.4%) were reported to have COPD, with 38.5% of them requiring COPD treatment. To verify the diagnoses from the secondary evaluation centres, PFT and CT data were collected from 228 study participants, and 24.9% were diagnosed with COPD. CT findings classified according to the Goddard classification revealed that 20.1% of these participants had moderate to severe emphysema. Conclusions COPD screening added to a community-based lung cancer screening programme may be effective in the detection of patients with COPD.

Type 1 diabetes is a disease characterized by destruction of pancreatic β-cells, which leads to absolute deficiency of insulin secretion. Depending on the manner of onset and progression, it is classified as fulminant, acute-onset or slowly progressive type 1 diabetes. Here, we propose the diagnostic criteria for acute-onset type 1 diabetes mellitus. Among the patients who develop ketosis or diabetic ketoacidosis within 3 months after the onset of hyperglycemic symptoms and require insulin treatment continuously after the diagnosis of diabetes, those with anti-islet autoantibodies are diagnosed with 'acute-onset type 1 diabetes mellitus (autoimmune)'. In contrast, those whose endogenous insulin secretion is exhausted (fasting serum C-peptide immunoreactivity, Journal of Diabetes Investigation, 5(1), pp.115-118; 2014

The pathogenesis of type 1 diabetes is different from that of type 2 diabetes, and anti-glutamic acid decarboxylase antibody (GADA) helps to diagnose autoimmune type 1 diabetes. Some studies reported that GADA seroconversion occurs during the clinical course of type 2 diabetes, leading to development of "type 1 on type 2 diabetes". To clarify the clinical characteristics and triggers of GADA seroconversion, we performed a nationwide questionnaire survey for clinical cases identified by literature search, and obtained information on 38 cases (24 with insulin therapy and 14 without it). The diabetes duration up to determination of GADA seroconversion was significantly longer in the group with insulin therapy than that without it. This finding was particularly noted in insulin-treated non-obese patients with lower serum C-peptide levels. In these patients, insulin therapy could have masked sudden increases in plasma glucose and HbA1c levels, possibly leading to delayed determination of GADA seroconversion. In non-obese patients without insulin therapy, an abrupt rise in the plasma glucose and HbA1c levels was observed at immediately before the determination, a finding which may help to predict GADA seroconversion. From the results of the present survey, we could not determine apparent triggers of GADA seroconversion. Thus, physicians may need to consider the possibility of concurrent type 1 diabetes during the therapeutic course of type 2 diabetes; GADA measurement should be considered when non-obese type 2 diabetic patients not receiving insulin therapy experience unexpected abrupt hyperglycemia and when those receiving insulin therapy show low serum C-peptide levels.

We have revised a part of the diagnostic criteria for fulminant type 1 diabetes. The new criteria were set both to express the essence of this disease of rapid increase of patients' blood glucose and to be highly sensitive to reduce the misdiagnosis. After analyzing the data of 382 patients with newly‐diagnosed fulminant type 1 diabetes, we adopted the glycated hemoglobin (HbA1c) level of 8.7% (National Glycohemoglobin Standardization Program [NGSP] value). The new criterion indicates 100% of sensitivity and the best value by receiver operating characteristic curve analysis. In addition, we added a comment that ‘This value (HbA1c

The present study is the first national investigation of intestinal parasites in private-household cats in Japan. A total of 942 faecal samples were collected from private-household cats. Giardia species was assessed using an enzyme-linked immunosorbent assay kit and other intestinal parasites were identified microscopically. The overall prevalence of intestinal parasites was 10.1%; two protozoan parasites ( Giardia species and Cystoisospora species) and five helminths ( Toxocara cati, Toxascaris leonina, Ancylostoma tubaeforme, Taenia species and Spirometra erinacei) were detected. The total prevalence of intestinal parasite infection was significantly higher in cats aged ≤6 months old than in cats older than 6 months because of a significantly higher prevalence of Cystoisospora species and T cati. The total infection prevalence was higher among outdoor cats as a result of the significantly higher prevalence of T cati and S erinacei. Sex and faecal condition were not related to intestinal parasite infections. Regional differences were observed in Cystoisospora species and A tubaeforme.

Nivolumab is a monoclonal antibody directed against PD1 (programmed cell death 1) that can improve survival in patients with metastatic melanoma. Such immune checkpoint inhibitors have been known to induce type 1 diabetes mellitus (T1D) [1, 2].A 54-year-old woman reported enlarging black nodules on her left sole, which had been present for seven months (figure 1A). CT imaging revealed swollen lymph nodes in the left inguinal and pelvic regions (figure 1B). After clinical diagnosis of malignant melanoma [...]

Type 1 diabetes is etiologically a multifactorial disease caused by a complex interaction of genetic and environmental factors, with the former consisting of multiple susceptibility genes. Identification of genes conferring susceptibility to type 1 diabetes would clarify etiological pathways in the development and progression of type 1 diabetes, leading to the establishment of effective methods for prevention and intervention of the disease. Among multiple susceptibility genes, HLA and INS are particularly important because of their contribution to tissue specificity in the autoimmune process. DRB1*04:05-DQB1*04:01 is associated with autoimmune type 1 diabetes, idiopathic fulminant type 1 diabetes and anti-islet autoimmunity in autoimmune thyroid diseases, suggesting that this haplotype is associated with beta-cell specificity in autoimmune diseases. Genes involved in the expression of insulin in the thymus contribute to beta-cell-specific autoimmune mechanisms in type 1 diabetes. These genes and pathways are important targets for tissue-specific prevention and intervention of type 1 diabetes. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00176.x, 2011).

OBJECTIVE Interferon therapy can trigger induction of several autoimmune diseases, including type 1 diabetes. To assess the clinical, immunologic, and genetic characteristics of type 1 diabetes induced by interferon therapy, we conducted a nationwide cross-sectional survey. RESEARCH DESIGN AND METHODS Clinical characteristics, anti-islet autoantibodies, and HLA-DR typing were examined in 91 patients for whom type 1 diabetes developed during or shortly after interferon therapy. RESULTS Median age at the onset of type 1 diabetes was 56 (interquartile range 48–63) years and mean ± SD BMI was 20.8 ± 2.7 kg/m2. The time period from the initiation of interferon therapy to type 1 diabetes onset in patients receiving pegylated interferon and ribavirin was significantly shorter than that in patients with nonpegylated interferon single therapy (P < 0.05). Anti-islet autoantibodies were detected in 94.5% of patients at diabetes onset. Type 1 diabetes susceptibility HLA-DRs in the Japanese population, DR4 and DR9, were also associated with interferon treatment–related type 1 diabetes. Furthermore, the prevalence of HLA-DR13 was significantly higher in interferon treatment–related type 1 diabetes than in healthy control subjects (odds ratio 3.80 [95% CI 2.20–7.55]; P < 0.0001) and classical type 1 diabetes (2.15 [1.17–3.93]; P < 0.05). CONCLUSIONS Anti-islet autoantibodies should be investigated before and during interferon therapy to identify subjects at high risk of type 1 diabetes. Stronger antiviral treatment may induce earlier development of type 1 diabetes. Furthermore, patients who develop interferon-induced type 1 diabetes are genetically susceptible.

Aims/Introduction: Fulminant type 1 diabetes is a subtype of type 1 diabetes characterized by a remarkably abrupt onset of insulin‐deficient hyperglycemia within a few days. The aim of the present study was to clarify characteristic class II HLA genotypes in a large number of patients with fulminant type 1 diabetes to date. Materials and Methods: We analyzed the HLA‐DRB1 and DQB1 genotypes, and their haplotypes in 207 patients with fulminant type 1 diabetes and 325 control subjects in the Japanese population. Results: The frequencies of the DRB1*04:05‐DQB1*04:01 and DRB1*09:01‐DQB1*03:03 haplotypes were significantly higher, and those of the DRB1*01:01‐DQB1*05:01, DRB1*15:02‐DQB1*06:01 and DRB1*08:03‐DQB1*06:01 haplotypes were significantly lower in patients with fulminant type 1 diabetes than in the control subjects. Combination analysis showed that the frequencies of homozygotes with DRB1*04:05‐DQB1*04:01 [odds ratio (OR) 7.0] and DRB1*09:01‐DQB1*03:03 (OR 9.5) were significantly higher in patients with fulminant type 1 diabetes. Within a limited portion of patients with fulminant type 1 diabetes with antibodies to glutamic acid decarboxylase (GADab; n = 25), the frequency of DRB1*09:01‐DQB1*03:03, but not DRB1*04:05‐DQB1*04:01, was significantly higher than in control subjects (44.0% vs 13.7%; Pc

In contrast to the large number of studies on autoimmunity against the thyroid gland in patients with type 1 diabetes mellitus, little is known about the anti-islet autoimmune status in patients with autoimmune thyroid diseases (AITDs). We therefore studied the anti-islet autoimmune status in patients with AITD and the clinical and genetic characteristics of AITD patients with anti-islet autoimmunity. The positivity and titer of glutamic acid decarboxylase antibody (GAD Ab) were studied in 866 Japanese patients with AITD (546 with Graves disease and 320 with Hashimoto thyroiditis), 221 patients with thyroid disease of nonautoimmune origin, and 282 control subjects. The clinical characteristics and genotypes of HLA-DRB1, DQB1, and CTLA4 were compared between AITD patients with and without GAD Ab. The prevalence of GAD Ab was significantly higher in AITD patients than in control subjects (5.8% vs 2.1%, P = .01), particularly in Graves disease (7.1% vs 2.1%, P = .0019). The prevalence of diabetes mellitus was significantly higher in AITD patients with GAD Ab than in those without (40.0% vs 10.1%, P < .0001), particularly in those with a high titer of GAD Ab (high vs low titer: 64% vs 16%, P = .001) and also in those positive for insulinoma-associated antigen 2 (IA-2) Ab (IA-2 positive vs negative: 75.0% vs 31.3%, P = .016). The AITD patients with GAD Ab were characterized by younger age at onset of diabetes, lower body mass index, higher hemoglobin A(1c) level, and higher frequency of insulin therapy than those without GAD Ab. The frequency of the DRB1*0405-DQB1*0401 haplotype was significantly higher in AITD patients with GAD Ab than in those without GAD Ab and control subjects. A single nucleotide polymorphism (rs3087243) of CTLA4 was significantly associated with AITD, but not with positivity of GAD Ab. These results indicate that patients with AITD, and in particular Graves disease, are prone to develop β-cell autoimmunity and insulin-requiring diabetes, particularly those with a high titer of GAD Ab and/or positive for both GAD and IA-2 Ab. Glutamic acid decarboxylase Ab positivity in AITD patients was associated with HLA, conferring susceptibility to type 1 diabetes mellitus.

Aim: The maximum dosage of metformin allowed for clinical use in Japan is much less than half that in Western countries, making it difficult to apply the results of clinical trials in Western countries to Japanese patients. In particular, the efficacy and safety of metformin in elderly patients are largely unknown. Methods: Among 1508 patients who were newly prescribed metformin at our hospital from 2000–2006, patients with sufficient clinical data were retrospectively studied for the safety (n = 1132) and efficacy (n = 568) of the drug. Of 568 patients in whom the efficacy of metformin was analyzed, 180 patients (31.7%) were elderly, aged 65 years or over. Results: Metformin was effective for the treatment of type 2 diabetes in Japanese patients, with significant improvement in HbA1c level at all time-points after 1 month, with the largest decrease by approximately 0.9% in patients treated with 750 mg/day and approximately 0.7% in those treated with 500 mg/day, at 4 months. Metformin improved glycemic control in elderly patients as well as non-elderly patients. The efficacy was independent of age, sex, degree of obesity and concomitant use of other drugs. No significant difference was observed in elevated lactic acid levels between elderly and non-elderly patients. No case of lactic acidosis was observed. Conclusions: These results suggest that the efficacy of metformin in Japanese elderly patients with type 2 diabetes is not different from that in non-elderly patients, and that its safety might be linked to specific and well-documented contraindications rather than age itself. Geriatr Gerontol Int 2011; 11: 55–62.

Recent genome-wide association studies have identified several novel type 1 diabetes (T1D) loci in white populations.In line with recent findings, we conducted a replication study of two loci on chromosome 12p13 and 16p13 and assessed their potential associations with thyroid autoimmunity in a Japanese population.Two single-nucleotide polymorphisms (SNPs), rs2292399 in ERBB3 on 12q13 and rs2903692 in CLEC16A (or KIAA0350) on 16p13, were analyzed in Japanese subjects consisting of 735 T1D patients, 330 patients with autoimmune thyroid disease (AITD), and 621 control subjects.According to a case-control study and logistic regression adjusting for sex and age, we observed that these SNPs in ERBB3 and CLEC16A were both significantly associated with T1D, with the risk alleles being consistent with those in white populations [adjusting odds ratio by multiplicative model: 1.37 (1.13-1.67), P = 0.001; and 1.28 (1.02-1.60), P = 0.030, respectively]. In both SNPs, the association was suggested to be stronger in T1D complicated with AITD (Graves' disease, Hashimoto's thyroiditis, or thyroid autoantibodies). Furthermore, a joint analysis, with the INS and CTLA4 SNPs, revealed that CTLA4 rs3087243, ERBB3 rs2292399, and CLEC16A rs2903692, but not INS rs689, were significant risk factors for the cooccurrence of AITD in Japanese T1D.We confirmed two loci on 12q13 and 16p13 that were identified by the independent genome-wide association studies in white populations, thus suggesting that these loci contribute to T1D susceptibility across different ethnic groups. In addition, these loci may also be associated with the cooccurrence of thyroid autoimmunity in T1D.