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Aims/hypothesis Pancreatic polypeptide (PP) cells, which secrete PP (encoded by the Ppy gene), are a minor population of pancreatic endocrine cells. Although it has been reported that the loss of beta cell identity might be associated with beta-to-PP cell-fate conversion, at present, little is known regarding the characteristics of Ppy-lineage cells. Methods We used Ppy-Cre driver mice and a PP-specific monoclonal antibody to investigate the association between Ppy-lineage cells and beta cells. The molecular profiles of endocrine cells were investigated by single-cell transcriptome analysis and the glucose responsiveness of beta cells was assessed by Ca2+ imaging. Diabetic conditions were experimentally induced in mice by either streptozotocin or diphtheria toxin. Results Ppy-lineage cells were found to contribute to the four major types of endocrine cells, including beta cells. Ppy-lineage beta cells are a minor subpopulation, accounting for 12–15% of total beta cells, and are mostly (81.2%) localised at the islet periphery. Unbiased single-cell analysis with a Ppy-lineage tracer demonstrated that beta cells are composed of seven clusters, which are categorised into two groups (i.e. Ppy-lineage and non-Ppy-lineage beta cells). These subpopulations of beta cells demonstrated distinct characteristics regarding their functionality and gene expression profiles. Ppy-lineage beta cells had a reduced glucose-stimulated Ca2+ signalling response and were increased in number in experimental diabetes models. Conclusions/interpretation Our results indicate that an unexpected degree of beta cell heterogeneity is defined by Ppy gene activation, providing valuable insight into the homeostatic regulation of pancreatic islets and future therapeutic strategies against diabetes. Data availability The single-cell RNA sequence (scRNA-seq) analysis datasets generated in this study have been deposited in the Gene Expression Omnibus (GEO) under the accession number GSE166164 (www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE166164). Graphical abstract

Aims/Introduction Thrombin exerts various pathophysiological functions by activating protease‐activated receptors (PARs). Recent data have shown that PARs influence the development of glomerular diseases including diabetic kidney disease (DKD) by regulating inflammation. Heparin cofactor II (HCII) specifically inactivates thrombin; thus, we hypothesized that low plasma HCII activity correlates with DKD development, as represented by albuminuria. Materials and Methods Plasma HCII activity and spot urine biomarkers, including albumin and liver‐type fatty acid‐binding protein (L‐FABP), were determined as the urine albumin‐to‐creatinine ratio (uACR) and the urine L‐FABP‐to‐creatinine ratio (uL‐FABPCR) in 310 Japanese patients with diabetes mellitus (176 males and 134 females). The relationships between plasma HCII activities and those DKD urine biomarkers were statistically evaluated. In addition, the relationship between plasma HCII activities and annual uACR changes was statistically evaluated for 201/310 patients (115 males and 86 females). Results The mean plasma HCII activity of all participants was 93.8 ± 17.7%. Multivariate‐regression analysis including confounding factors showed that plasma HCII activity independently contributed to the suppression of the uACR and log‐transformed uACR values (P = 0.036 and P = 0.006, respectively) but not uL‐FABPCR (P = 0.541). In addition, plasma HCII activity significantly and inversely correlated with annual uACR and log‐transformed uACR increments after adjusting for confounding factors (P = 0.001 and P = 0.014, respectively). Conclusions The plasma HCII activity was inversely and specifically associated with glomerular injury in patients with diabetes. The results suggest that HCII can serve as a novel predictive factor for early‐stage DKD development, as represented by albuminuria., Plasma HCⅡ activity is significantly and inversely associated with urinary albumin excretion but not liver‐type fatty acid‐binding protein in Japanese patients with diabetes.

Aims/Introduction The 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 Methods This 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. Results Among 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. Conclusions Sarcopenia 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., Sarcopenia was highly observed in type 1 diabetes patients compared with non‐diabetes and type 2 diabetes patients. In contrast, the prevalence of dynapenia was markedly higher in type 1 and type 2 diabetes patients compared with individuals without diabetes.

Aims/Introduction To investigate the basal insulin requirement in patients with type 1 diabetes who are on multiple daily injections (MDI) and to assess the patient characteristics that affect the percent of total daily basal insulin dose to the total daily insulin dose (%TBD/TDD). Materials and Methods The subjects of this study were 67 inpatients with type 1 diabetes who were served diabetic meals of 25–30 kcal/kg standard body weight during several weeks of hospitalization. The basal insulin requirement was adjusted to keep the blood glucose level from bedtime to before breakfast within a 30 mg/dL difference. The bolus insulin dose before the meal was adjusted to keep the blood glucose level below 140 and 200 mg/dL before and 2 h after each meal, respectively. The total daily insulin dose (TDD), the percent of total daily basal insulin dose (TBD) to TDD (%TBD/TDD), and clinical characteristics were collected. Results The median (Q1, Q3) of TDD was 33.0 (26.0, 49.0) units, and the %TBD/TDD was 24.1 ± 9.8%. The %TBD/TDD was positively correlated with the body mass index (BMI) and negatively correlated with the age at the onset and at the examination according to a univariate analysis. However, the %TBD/TDD was dependent on the BMI (β = 0.340, P = 0.004) and the age at examination (β = −0.288, P = 0.012) according to the multiple regression analysis. Conclusions The average %TBD/TDD in patients with type 1 diabetes on MDI was approximately 24% under inpatient conditions. The basal insulin requirement was dependent on the BMI and the age at examination.

Background: With limited real-world insulin glargine 300 U/mL (Gla-300) data among Japanese patients with type 1 diabetes mellitus (T1DM) available, the authors describe its effectiveness and safety in Japanese T1DM patients switching to Gla-300. Research design and methods: X-STAR was a 12-month prospective, observational, post-marketing study in Japanese patients with diabetes mellitus from 2015 to 2018: insulin-experienced T1DM patients initiating Gla-300 were analyzed. Results: Of 774 patients, mean (±standard deviation) HbA1c (%) and fasting plasma glucose (mg/dL) decreased from 8.27 ± 1.55 to 8.15 ± 1.35 (by −0.12 ± 1.30 [p = 0.013]) and 167.9 ± 92.6 to 153.9 ± 70.9 (by −13.9 ± 103.8 [p = 0.067]) from baseline to month 12, respectively. A total of 16.3% achieved HbA1c

With limited real-world insulin glargine 300 unit/mL (Gla-300) data available, we assessed the effectiveness and safety of Gla-300 in the Japanese type 2 diabetes mellitus (T2DM) population.X-STAR was a prospective, observational, 12-month post-marketing study of Gla-300 from 2015 to 2018. T2DM patients received Gla-300 as the first insulin (insulin-naïve) or after treatment with another type of insulin (insulin-experienced).We identified 1,227 insulin-naïve and 3,394 insulin-experienced patients. Insulin-naïve group increased the Gla-300 starting dose by 2.80 U/day during 12 months (7.49 to 10.29 U/day). Mean HbA1c reduced by 1.99% (9.82 to 7.83%), and 28.4% showed HbA1c 7.0%. Insulin-experienced group had a baseline insulin dose of 14.86 U/day, which increased by 0.73 U/day. Mean HbA1c reduced by 0.18% (7.99 to 7.81%), and 24.6% showed HbA1c 7.0%. Adverse drug reactions occurred in 3.42% (insulin-naïve) and 4.45% (insulin-experienced); symptomatic hypoglycemia (2.93% and 3.86%, respectively) was the most common in both groups.Gla-300, in clinical practice, provides an effective and safe therapy as HbA1c was reduced/maintained in insulin-naïve/experienced Japanese T2DM patients without new safety signal. This study provides insights into the current Japanese clinical practices where insulin use is delayed and conservative despite relatively low HbA1c achievement.

Severe hypoglycaemia (SH) remains a challenge to people with type 1 diabetes (T1DM), and new‐generation basal insulins may improve patient outcomes. This post hoc meta‐analysis explored the risk of SH with insulin glargine 300 U/mL (Gla‐300) versus glargine 100 U/mL (Gla‐100) in a pooled population with T1DM from three randomized, multicentre, 6‐month similarly designed phase 3 trials: EDITION 4, EDITION JP 1 and EDITION JUNIOR. Endpoints included incidence and time to first occurrence of SH. Among 629 and 626 participants randomized to Gla‐300 and Gla‐100, respectively, glycated haemoglobin reductions were similar. Fewer participants experienced ≥1 SH event with Gla‐300 (6.2%) than with Gla‐100 (9.3%). From baseline to month 6, the risk of a first SH event was lower with Gla‐300: hazard ratio 0.65 [95% confidence interval (CI) 0.44–0.98; stratified log‐rank test P = 0.038]. SH event rates were numerically lower with Gla‐300 versus Gla‐100 from baseline to month 6 [relative risk (RR) 0.80 (95% CI 0.49–1.29); P = 0.356] and baseline to week 8 [RR 0.73 (95% CI 0.37–1.44); P = 0.369]. Thus, Gla‐300 demonstrated similar glycaemic control with lower risk of SH versus Gla‐100, particularly during the titration period.

Aim: To compare nasal glucagon (NG) with intramuscular glucagon (IMG) for the treatment of insulin‐induced hypoglycaemia in Japanese patients with type 1 (T1DM) or type 2 diabetes mellitus (T2DM). Materials and methods: This phase 3, randomized, open‐label, two‐treatment, two‐period crossover non‐inferiority study enrolled Japanese adults with T1DM or T2DM on insulin therapy, with glycated haemoglobin levels ≤86 mmol/mol (≤10%). After ≥8 hours of fasting, hypoglycaemia was induced with human regular insulin (intravenous infusion). Patients received NG 3 mg or IMG 1 mg approximately 5 minutes after insulin termination. The primary endpoint was the proportion of patients achieving treatment success [plasma glucose (PG) increase to ≥3.9 mmol/L (≥70 mg/dL) or ≥1.1 mmol/L (≥20 mg/dL) increase from the PG nadir within 30 minutes of receiving glucagon]. Non‐inferiority was declared if the upper limit of the two‐sided 95% confidence interval (CI) of the mean difference in the percentage of patients achieving treatment success (IMG minus NG) was 2 patients were rhinalgia, increased blood pressure, nausea, ear pain and vomiting in the NG group, and nausea and vomiting in the IMG group. Conclusion: Nasal glucagon was non‐inferior to IMG for successful treatment of insulin‐induced hypoglycaemia in Japanese patients with T1DM/T2DM, supporting use of NG as a rescue treatment for severe hypoglycaemia.

Background: Continuous subcutaneous insulin infusion (CSII) is associated with improved glycemic control, a reduced incidence of hypoglycemia, and improved quality of life (QOL). To date, however, ...

Fibroblast growth factor (FGF) 23 is a bone-derived hormone regulating serum inorganic phosphate (Pi) concentration. FGF23 is also involved in the development of chronic kidney disease (CKD)-mineral and bone disorder. Serum FGF23 concentration begins to increase early in the progression of CKD and can be remarkably high in hemodialysis patients with end-stage renal disease. It has been reported that high FGF23 concentration is a risk factor for cardiac dysfunction, atherosclerosis, infection or systemic inflammation in CKD patients. FGF23 was also shown to induce cardiac hypertrophy directly acting on cardiomyocytes. However, it is still controversial whether high FGF23 is causing cardiac dysfunction, atherosclerosis, infection or systemic inflammation in CKD patients. In the current study, we investigated whether FGF23 concentration is associated with cardiac dysfunction, atherosclerosis, infection or systemic inflammation in Japanese hemodialysis patients. We recruited 119 hemodialysis patients and examined the association between serum FGF23 concentration and several parameters concerning mineral metabolism, cardiac dysfunction, atherosclerosis, infection, and systemic inflammation. Serum FGF23 concentration was independently associated with serum calcium and Pi concentration (β = 0.276, p

To establish widespread cell therapy for type 1 diabetes mellitus, we aimed to develop an effective protocol for generating insulin-producing cells (IPCs) from adipose-derived stem cells (ADSCs). We established a 3D culture using a human recombinant peptide (RCP) petaloid μ-piece with xeno-antigen free reagents. Briefly, we employed our two-step protocol to differentiate ADSCs in 96-well dishes and cultured cells in xeno-antigen free reagents with 0.1 mg/mL RCP μ-piece for 7 days (step 1), followed by addition of histone deacetylase inhibitor for 14 days (step 2). Generated IPCs were strongly stained with dithizone, anti-insulin antibody at day 21, and microstructures resembling insulin secretory granules were detected by electron microscopy. Glucose stimulation index (maximum value, 4.9) and MAFA mRNA expression were significantly higher in 3D cultured cells compared with conventionally cultured cells (P P in vitro and in vivo.

Sarcopenia as a progressive and generalized skeletal muscle disorder that is associated with an increased likelihood of adverse outcomes, including falls, fractures, physical disability, and mortality. On the other hand, an age-related decline in muscle strength prior to the reduction of muscle mass, is proposed to be "dynapenia". Sarcopenia and dynapenia has recently been recognized as a diabetic complications in type 2 diabetes. We firstly indicated that sarcopenia was frequently observed in 16.6% of patients with type 1 diabetes aged even over 40 years. Additionally, we recently reported that the prevalence rate of dynapenia was higher than sarcopenia in patients with type 2 diabetes. Chronic hyperglycemia also accelerates accumulation of advanced glycation end products (AGEs), which causes diabetic vascular complications through oxidative stress and chronic inflammation. We also demonstrated that skin autofluorescence (AF) as a marker of AGEs, was the independent determinant for skeletal muscle mass and strength in patients with type 2 diabetes and muscle strength in type 1 diabetes. Therefore, the early diagnosis of muscle weakness is essential for patients with diabetes and sustained good glycemic control with exercise and dietary intervention might be beneficial to prevent the progression of muscle weakness in these patients.

Aims/Introduction Advanced glycation end‐products (AGEs), which are a major cause of diabetic vascular complications, accumulate in various tissues under chronic hyperglycemic conditions, as well as with aging in patients with diabetes. The loss of muscle mass and strength, so‐called sarcopenia and dynapenia, has recently been recognized as a diabetic complication. However, the influence of accumulated AGEs on muscle mass and strength remains unclear. The present study aimed to evaluate the association of sarcopenia and dynapenia with accumulated AGEs in patients with type 2 diabetes. Materials and Methods We recruited 166 patients with type 2 diabetes aged ≥30 years (mean age 63.2 ± 12.3 years; body mass index 26.3 ± 4.9 kg/m2; glycated hemoglobin 7.1 ± 1.1%). Skin autofluorescence as a marker of AGEs, limb skeletal muscle mass index, grip strength, knee extension strength and gait speed were assessed. Results Sarcopenia and dynapenia were observed in 7.2 and 13.9% of participants, respectively. Skin autofluorescence was significantly higher in patients with sarcopenia and dynapenia. Skin autofluorescence was the independent determinant for skeletal muscle mass index, grip strength, knee extension strength, sarcopenia and dynapenia. Conclusions Accumulated AGEs could contribute to reduced muscle mass and strength, leading to sarcopenia and dynapenia in patients with type 2 diabetes.

Pancreatic polypeptide (PP) is a 36-amino acid peptide encoded by the Ppy gene, which is produced by a small population of cells located in the periphery of the islets of Langerhans. Owing to the high amino acid sequence similarity among neuropeptide Y family members, antibodies against PP that are currently available are not convincingly specific to PP. Here we report the development of mouse monoclonal antibodies that specifically bind to PP. We generated Ppy knockout (Ppy-KO) mice in which the Ppy-coding region was replaced by Cre recombinase. The Ppy-KO mice were immunized with mouse PP peptide, and stable hybridoma cell lines producing anti-PP antibodies were isolated. Firstly, positive clones were selected in an enzyme-linked immunosorbent assay for reactivity with PP coupled to bovine serum albumin. During the screening, hybridoma clones producing antibodies that cross-react to the peptide YY (PYY) were excluded. In the second screening, hybridoma clones in which their culture media produce no signal in Ppy-KO islets but detect specific cells in the peripheral region of wild-type islets, were selected. Further studies demonstrated that the selected monoclonal antibody (23-2D3) specifically recognizes PP-producing cells, not only in mouse, but also in human and rat islets. The monoclonal antibodies with high binding specificity for PP developed in this study will be fundamental for future studies towards elucidating the expression profiles and the physiological roles of PP.

Pancreas transplantation (PTx) has been performed worldwide for patients with type 1 diabetes accompanied with end-stage renal disease or uncontrollable glycemic fluctuation. Nevertheless, risk factors of posttransplant glucose intolerance, which is responsible for progress of diabetic complications, remains unclear, especially in cases without pancreatic graft function loss. Therefore, this study was conducted to search for predictive factors of future glucose tolerance in PTx recipients without pancreatic graft function loss. Subjects were selected from among 41 Japanese patients with type 1 diabetes who received PTx between 2000 and 2016 in Osaka University Hospital, and 24 subjects free from rejections and thromboses were analyzed. Several examinations to evaluate insulin secretion and insulin sensitivity within 6 months after transplantation (initial examination) were performed. Glucose tolerance was evaluated by 120-minute post-load plasma glucose level during 75-g oral glucose tolerance tests (OGTT), referred to as PGOGTT120, at the initial examination and between 1 year and 2 years posttransplantation (maintenance period). The initial examination factors that were correlated with PGOGTT120 in the maintenance period were PGOGTT120 [r = 0.52 (p = 0.01)], insulinogenic index [r = -0.65 (p < 0.01)], and the ratio of incremental area under the curve of insulin to that of plasma glucose (iAUCR) calculated from data of OGTT [r = -0.65 (p < 0.01)]. Insulinogenic index [β = -0.28 (p = 0.02)] and iAUCR [β = -0.29 (p = 0.02)] were still significantly correlated with PGOGTT120 in the maintenance period after adjustment for PGOGTT120 at the initial examination. In conclusion, insulinogenic index and iAUCR from OGTT performed in the early posttransplantation period were predictive factors of future glucose intolerance.

Our previous study revealed that sarcopenia was frequently observed in subjects with type 1 diabetes mellitus (T1DM). However, the factors associated with sarcopenia that are related to T1DM have not yet been clarified. Insulin-like growth factor-1 (IGF-1) has been shown to play a role in skeletal muscle growth, differentiation, and regeneration. The present study, therefore, investigated the association between the serum IGF-1 level and sarcopenia and low skeletal muscle mass in subjects with T1DM.This cross-sectional study enrolled subjects with T1DM (n = 168) and without diabetes (n = 59) who had had their clinical data on serum IGF-1 collected in the iDIAMOND study.The z-score of serum IGF-1 was significantly lower in the subjects with T1DM than that in those without diabetes (p 0.001). Among subjects with T1DM, the z-score of serum IGF-1 was significantly lower in sarcopenic subjects than in non-sarcopenic subjects. The multivariable logistic regression analysis showed that the serum IGF-1 z-score was an independent determinant of sarcopenia and a low skeletal muscle mass index, but not low grip strength nor slow gait speed in subjects with T1DM.A low serum IGF-1 level is correlated with sarcopenia and low skeletal muscle mass in subjects with T1DM.

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

Aims Since diabetes-associated kidney complication changes from diabetic nephropathy to diabetic kidney disease (DKD), more suitable biomarkers than urinary albumin are required. It has been hypothesized that urinary adiponectin (u-ADPN) is associated with the progression of DKD. We therefore evaluated the effectiveness of u-ADPN in predicting the decline of the renal function in patients with diabetes prior to end-stage renal disease. Methods An ultrasensitive immune complex transfer enzyme immunoassay (ICT-EIA) was used to measure total and high molecular weight (HMW) adiponectin separately. We evaluated the relationships between the creatinine-adjusted urinary total-ADPN and HMW-ADPN, albumin (UACR) and liver-type fatty acid binding protein (L-FABP) at baseline and the 2-year change of the estimated glomerular filtration rate (ΔeGFR). Results This 2-year prospective observational study included 201 patients with diabetes. These patients were divided into three groups according to their ΔeGFR: ≤−10 mL/min/1.73m2, >−10 and ≤0 mL/min/1.73m2, and >0 mL/min/1.73m2. Jonckheere-Terpstra test showed that lower ΔeGFR was associated with higher u-HMW-ADPN (p = 0.045). In logistic regression analysis, u-HMW-ADPN was associated with ΔeGFR after adjusted age, sex, and basal eGFR. Conclusion Urinary HMW-ADPN could predict a declining renal function in patients with diabetes.

Background: Information about factors related to better adherence to continuous glucose monitoring (CGM) sensor adherence is quite limited. Materials and Methods: Forty-six participants with type 1 diabetes using continuous subcutaneous insulin infusion (CSII) without CGM were recruited. The participants’ characteristics and diabetes-related quality of life (QOL) were evaluated at baseline and one year after starting to use CGM. Participants wearing the sensor for ≥60% of the time were considered as adherent. Results: The mean age of the 46 participants was 44.1 ± 15.0 years old and the mean glycohemoglobin (HbA1c) was 7.7 ± 1.0%; 60.9% of the participants were classified as adherent. The duration of using CSII was longer in the adherent group, and the degree of diabetic retinopathy was significantly different. There were no significant differences in age, frequency of self-monitoring of blood glucose, or Hypoglycemia Fear Survey (HFS-B for behavior, HFS-W for worry) score at baseline between the adherent and nonadherent groups. The Problem Areas in Diabetes (PAID) score at baseline was significantly higher and the total CSII-QOL score at baseline was significantly lower in the adherent group. The usage of dual-wave bolus was significantly increased in the adherent group (34.6%-61.5%, P = .016), but not in the nonadherent group (33.3%-33.3%, P > .999). The HbA1c level showed a significant improvement in the adherent group (7.8%-7.3%, P Conclusions: Higher adherence to CGM sensors may be associated with a heavier emotional burden of diabetes and a worse QOL in relation to CSII at baseline.

Background: Nasal glucagon (NG), a ready-to-use drug-device combination for treatment of severe hypoglycemia, contains 3 mg glucagon dry powder that is absorbed passively through nasal mucosa. We examined the efficacy and safety of NG compared to 1 mg injectable glucagon (IG) in reversing insulin-induced hypoglycemia in a global population of adults with T1D or T2D. Notably, this is the first analysis including pooled T2D data. Methods: Post-hoc analyses used data from 3 randomized, cross-over studies. Treatment success was defined as an increase in BG to ≥70 mg/dL or an increase of ≥20 mg/dL from nadir BG within 30 min of receiving glucagon. Tolerability was assessed using treatment-emergent adverse events and a symptom questionnaire. Results: In the T1D+T2D pooled analysis, 99.5% (213/214) of NG and 100% (214/214) of IG patients achieved treatment success in a mean time (preparation time excluded) of 13 and 11 min, respectively. All NG T2D patients (N=41) achieved treatment success. NG and IG induced similar BG changes (Figure). NG and IG had similar incidences of nausea and vomiting, with NG having a higher rate of side effects related to nasal administration [headache (13% NG, 7% IG), nasal discomfort (4% NG, 1% IG), etc.]. Separate T1D and T2D analyses showed similar results as T1D+T2D. Conclusion: NG was efficacious and well-tolerated in reversing insulin-induced hypoglycemia in adults with T1D or T2D. Disclosure E.R. Seaquist: Advisory Panel; Self; MannKind Corporation, Zucara Therapeutics Inc. Other Relationship; Self; American Board of Internal Medicine, Endocrine Society, International Hypoglycemia Study Group. K. Khunti: Advisory Panel; Self; Amgen, AstraZeneca, Bayer AG, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Menarini Group, Merck Sharp & Dohme Corp., Napp Pharmaceuticals, Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi-Aventis, Servier. Board Member; Self; AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. Consultant; Self; Amgen, AstraZeneca, Bayer AG, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Menarini Group, Merck Sharp & Dohme Corp., Napp Pharmaceuticals, Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi-Aventis, Servier. Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis, Servier. Speaker’s Bureau; Self; Amgen, AstraZeneca, Bayer AG, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Menarini Group, Merck Sharp & Dohme Corp., Napp Pharmaceuticals, Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi-Aventis, Servier. M.X. Zhang: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. Q. Wang: Employee; Self; Eli Lilly and Company. Y. Takita: Employee; Self; Eli Lilly Japan K.K. C.J. Child: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. Y. Nagai: Employee; Self; Eli Lilly Japan K.K. Stock/Shareholder; Self; Eli Lilly and Company. Y. Yan: Employee; Self; Eli Lilly and Company. M. Matsuhisa: Research Support; Self; Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Novo Nordisk Inc., Sanofi, Sysmex Corporation. Speaker’s Bureau; Self; Astellas Pharma Inc., Eli Lilly Japan K.K., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Sanofi K.K., Takeda Pharmaceutical Company Limited. Funding Eli Lilly and Company

Supplemental material, Murata_T_PARCS_study_Supplementary_File_rev2 for Predictive Factors of the Adherence to Real-Time Continuous Glucose Monitoring Sensors: A Prospective Observational Study (PARCS STUDY) by Takashi Murata, Akio Kuroda, Munehide Matsuhisa, Masao Toyoda, Moritsugu Kimura, Yushi Hirota, Ken Kato, Hideaki Sawaki, Atsuhito Tone, Satoshi Kawashima, Akira Okada, Tomokazu Watanabe, Shinsuke Nirengi, Akiko Suganuma and Naoki Sakane in Journal of Diabetes Science and Technology

Introduction It is unclear whether adding basal insulin or enhancing incretin signaling with a glucagon-like peptide-1 receptor agonist (GLP-1RA) is more effective as an up-titration strategy after dipeptidyl peptidase-4 inhibitor (DPP-4i)-based oral antidiabetic drug (OAD) therapy. GLP-1RAs can be injected without dose adjustment, unlike basal insulin. Our objective was to examine the efficacy of changing patients inadequately controlled with oral DPP-4i-based OAD therapy to injectable GLP-1RA and discontinuing the DPP4i versus adding basal insulin glargine (IGlar) with the continuation of the oral DPP4i. Methods Sixty patients with type 2 diabetes (T2DM) and glycated hemoglobin (HbA1c) between 7.0% and 10.0% on DPP-4i-based OAD therapy were randomized to either adding IGlar and remaining on the DPP-4i or liraglutide and discontinuing the DPP-4i for 24 weeks. Patients in the IGlar group started with 0.1 unit/kg and were titrated according to the algorithm. In the liraglutide group, the DPP-4i was replaced with liraglutide 0.9 mg/day, the maximum dose in Japan. We evaluated HbA1c, glycated albumin (GA), and anthropometrics. Results HbA1c was significantly lower at week 24 (− 1.0 ± 0.9% in the IGlar group and − 0.6 ± 0.8% in the liraglutide group), but the difference between groups was not significant. Changes in GA were similar (− 2.9 ± 3.2% vs. − 2.6 ± 3.2%) in both groups. Body weight (BW) was significantly lower only in the liraglutide group (+ 0.5 ± 2.6 kg vs. − 2.2 ± 2.0 kg). The rate of minor hypoglycemic episodes was similar for both groups. Conclusion For poorly controlled T2DM on DPP-4i-based OAD therapy, switching to single-dose liraglutide to enhance incretin signaling is as effective as dose-titrated basal IGlar, but significant BW reduction was only seen in the liraglutide group. These results suggest that enhancing incretin signaling with a single-dose injectable GLP-1 RA might be an alternative to dose-titrated basal insulin therapy in patients with T2DM poorly controlled with DPP-4i-based OAD therapy. These findings should be confirmed in a longer and larger trial. Trial Registration Trial Registry (UMIN-CTR) as UMIN000012224. Electronic supplementary material The online version of this article (10.1007/s13300-018-0486-1) contains supplementary material, which is available to authorized users.

Fibroblast growth factor (FGF) 23 produced by the bone is the principal hormone to regulate serum phosphate level. Serum FGF23 needs to be tightly regulated to maintain serum phosphate in a narrow range. Thus, we hypothesized that the bone has some phosphate-sensing mechanism to regulate the production of FGF23. Previously we showed that extracellular phosphate induces the phosphorylation of FGF receptor 1 (FGFR1) and FGFR1 signaling regulates the expression of Galnt3, whose product works to increase FGF23 production in vitro. In this study, we show the significance of FGFR1 in the regulated FGF23 production and serum phosphate level in vivo. We generated late-osteoblast/osteocyte-specific Fgfr1-knockout mice (Fgfr1fl/fl; OcnCre/+) by crossing the Ocn-Cre and the floxed Fgfr1 mouse lines. We evaluated serum phosphate and FGF23 levels, the expression of Galnt3 in the bone, the body weight and life span. A selective ablation of Fgfr1 aborted the increase of serum active full-length FGF23 and the enhanced expression of Galnt3 in the bone by a high phosphate diet. These mice showed more pronounced hyperphosphatemia compared with control mice. In addition, these mice fed with a control diet showed body weight loss after 23 weeks of age and shorter life span. These results reveal a novel significance of FGFR1 signaling in the phosphate metabolism and normal life span.

Aims / Introduction We investigated the safety of the batteries and power units used in insulin pumps in Japan. Materials and Methods A self-administered questionnaire was sent to the 201 members of the Association for Innovative Diabetes Treatment in Japan (ASINDTJ). Results Fifty-six members responded, and among the 1,499 active devices, 66 had episodes of trouble related to the batteries and power units. The ratio of reported troubles to the number of insulin pumps was significantly higher in insulin pumps with CGM sensor compared to insulin pumps without CGM sensor (Odds ratio 2.82, P < 0.05). The cause and the consequences varied. The brands of the batteries varied; alkaline batteries purchased at drug stores and other shops accounted for 19.7%. Termination of battery life within 72 hours of usage was reported most frequently (50.0%), suspension of the insulin pump (21.2%) and leakage of the battery fluid (4.5%) followed. Fifty-three point two percent of the reported insulin pumps needed to be replaced, and 37.1% of them recovered after replacement of the battery. Conclusions As trouble related to the batteries and power units of insulin pumps was frequent, practical guidance should be provided to respective patients regarding the usage of reliable batteries, and to be well prepared for unexpected insulin pump failure. This article is protected by copyright. All rights reserved.

Background: Glucose values of continuous glucose monitoring (CGM) have time delays compared with plasma glucose (PG) values. The artificial pancreas (STG-55, Nikkiso, Japan) (AP), which measures venous blood glucose directly, also has a time delay because of the long tubing lines from sampling vessel to the glucose sensor. We investigate accuracy and time delay of CGM and AP in comparison with PG values during 2-step glucose clamp study. Methods: Seven patients with type 2 diabetes and 2 healthy volunteers were included in this study. CGM (Enlite sensor, Medtronic, Northridge, CA, USA) was attached on the day before the experiment. Hyperglycemic (200 mg/dL) clamp was performed for 90 minutes, followed by euglycemic (100 mg/dL) hyperinsulinemic (100 μU/mL) clamp for 90-120 minutes using AP. CGM sensor glucose was calibrated just before and after the clamp study. AP and CGM values were compared with PG values. Results: AP values were significantly lower than PG values at 5, 30 minute during hyperglycemic clamp. In comparison, CGM value at 0 minute was significantly higher, and its following values were almost significantly lower than PG values. The time delay of AP and CGM values to reach maximum glucose levels were 5.0 ± 22.3 (NS) and 28.6 ± 32.5 ( P < .05) min, respectively. Mean absolute rate difference of CGM was significantly higher than AP (24.0 ± 7.6 vs 15.3 ± 4.6, P < .05) during glucose rising period (0-45 min); however, there were no significant differences during other periods. Conclusions: Both CGM and AP failed to follow plasma glucose values during nonphysiologically rapid glucose rising, but indicated accurate values during physiological glucose change.

Acromegaly is caused by excessive growth hormone secretion, usually from pituitary adenomas. Somoatostatin analogues are widely used as primary or adjunctive therapy in the management of acromegaly. In this report, we present a case with remarkable shrinkage of a tumor after relatively short-term octreotide long-acting release (LAR) administration. During the 30-month follow-up after starting octreotide LAR, there was no recurrence of acromegaly with remarkable shrinkage of the tumor on pituitary magnetic resonance imaging. A literature review of the predictors for tumor shrinkage after the administration of somatostatin analogues in patients with acromegaly is also discussed in relation to this case.

Aim: Accumulation level of fluorescent advanced glycation end products (AGEs) in the skin can be measured non-invasively as skin autofluorescence (skin AF) by autofluorescence reader. The aim of this study was to assess possible associations between skin AF and diabetic complications, especially early-stage atherosclerosis, in Japanese type 1 diabetic patients. Methods: Skin AF was measured by AGE reader® in 105 Japanese type 1 diabetic patients (34 men and 71 women, aged 37.4 ± 12.4 years (± SD)) and 23 age-matched healthy non-diabetic subjects. Ultrasonic carotid intima-media thickness (IMT), ankle-brachial index (ABI), and brachial ankle pulse wave velocity (baPWV) were evaluated as indices of early-stage diabetic macroangiopathy. Urinary albumin-to-creatinine ratio (UACR), the coefficient of variation of R-R intervals (CVR-R), and presence of retinopathy were also evaluated. Results: Skin AF values were significantly higher in type 1 diabetic patients than in healthy controls (2.07 ± 0.50 (mean ± SD) and 1.90 ± 0.26, respectively, p = 0.024). Skin AF was associated with carotid IMT (r = 0.446, p

Aims : To compare assessment of the oral health conditions and behaviors of in-patients with diabetes using a clinical version of the Diabetes Oral Health Assessment Tool (C-DiOHAT©) with dental examinations. Methods : A cross-sectional design was used. A nurse assessed 60 in-patients using the C-DiOHAT© (a formatted questionnaire to assess four factors of patients' oral health conditions and behaviors : oral health conditions, oral hygiene behaviors, sharing health information among patients and dental/medical professionals, and perception and knowledge of oral health) while a dentist examined their oral health conditions. Results : "Use of supplementary tools (e.g., interdental brush, dental floss)" in the item of C-DiOHAT© was significantly associated with dental examination of "the number of present teeth" and "no recommendation of further dental visit". "Symptoms of gingival swelling" in the item of C-DiOHAT© was also significantly associated with "recommendation of dental visit". "Knowledge of a relationship between periodontal disease and systemic disease including diabetes" was significantly associated with Community Periodontal Index. Conclusions : These results suggest that nurses should prioritize these assessment items to most quickly acquire useful information about patients' oral health. It is important to encourage nurses to be interested in patients' oral health by such small pile of clue. J. Med. Invest. 66 : 328-336 August, 2019.

Continuous subcutaneous insulin infusion (CSII) is associated with improved glycemic control, reduced incidence of hypoglycemia and improved quality of life (QoL). To date, however, there is no QoL scale specific to CSII. The objective of this study was to develop and validate a scale to measure CSII-QoL for patients with type 1 diabetes (T1D).A total of 50 T1D patients aged ≥15 years who used CSII (28% males; age 47.6±17.0 years, mean±SD; duration of diabetes 14.7±9.7 years; duration of CSII use 6.1±3.3 years; HbA1c 7.4±0.8%) took part in the CSII-QoL study. Twenty-eight potential CSII-QoL items were developed in a combined approach consisting of semi-structured patient interviews, expert input and literature research. The resulting CSII-QoL was tested for factor analysis, validity, reliability and influence factors. The final 25-item questionnaire was found to have a three-domain structure (“convenience,” “social restriction,” and “psychological problems”), high internal consistency (Cronbach’s alpha = 0.851), and substantial test-retest reliability (intraclass correlation coefficient = 0.69). The CSII-QoL score correlated positively with basal insulin ratio, but not with age, sex, HbA1c, or total daily insulin dose. The CSII-QoL score correlated negatively with the Problem Areas in Diabetes (PAID) score. The CSII-QoL is the first CSII-related QoL scale for patients with T1D. This short, validated and reliable instrument can potentially be useful in future clinical studies and in routine clinical patient care. (UMIN-CTR: UMIN000031595). Disclosure M. Toyoda: Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Kyowa Hakko Kirin Co., Ltd., Medtronic Japan Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. A. Tone: Speaker's Bureau; Self; Lilly Diabetes, Medtronic Japan Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Sanofi, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. K. Kato: None. M. Kimura: None. S. Kawashima: Speaker's Bureau; Self; Novo Nordisk Inc., Sumitomo Dainippon Pharma Co., Ltd. H. Sawaki: None. Y. Hirota: Speaker's Bureau; Self; Abbott, Astellas Pharma Inc., AstraZeneca, Daiichi Sankyo Company, Limited, Eli Lilly and Company, Medtronic Japan Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. A. Okada: None. A. Kuroda: Speaker's Bureau; Self; Eli Lilly and Company, Novo Nordisk Inc., Sanofi. M. Matsuhisa: Advisory Panel; Self; Eli Lilly and Company. Board Member; Self; Daiichi Sankyo Company, Limited. Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Mitsubishi Tanabe Pharma Corporation. Speaker's Bureau; Self; Astellas Pharma Inc., Eli Lilly and Company, Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Sanofi, Takeda Pharmaceutical Company Limited. T. Watanabe: None. A. Suganuma: None. T. Murata: Research Support; Self; Kowa Company, Ltd. Speaker's Bureau; Self; Kowa Pharmaceutical Co. Ltd., Novo Nordisk Pharma Ltd., Sanofi K.K. N. Sakane: Board Member; Spouse/Partner; Kao Corporation.

Background/Objective: Currently available glucagon products for rescue treatment of severe hypoglycemia require cumbersome multistep reconstitution and injection procedures in an emergency situation. Nasal glucagon (NG) is a nasally administered, single-use, drug-device combination containing 3 mg glucagon dry powder. We aimed to evaluate noninferiority of NG to intramuscular glucagon (IMG) for treatment of insulin-induced hypoglycemia in patients with type 1 and type 2 diabetes (T1D/T2D) (NCT03421379). Methods: This was a randomized, two-period, crossover trial with NG and IMG. Hypoglycemia was induced by an intravenous insulin infusion; insulin was stopped once plasma glucose (PG) reached Results: Of the 68 evaluable patients (T1D 32, T2D 36) who received both NG and IMG, all patients achieved treatment success with a mean time of 12.0 min (NG) and 11.0 min (IMG). Noninferiority of NG to IMG was demonstrated. PG responses were similar between T1D and T2D. During the treatment period 26 treatment-emergent AEs (TEAEs) occurred with NG and 13 with IMG. Most TEAEs were mild in severity and none was severe. TEAEs with an incidence ≥5% were rhinalgia (NG 8.5%, IMG 0%), nausea (NG 5.6%, IMG 11.4%), and blood pressure increase (NG 5.6%, IMG 0%). With NG, very common (≥10%) symptoms from NNSQ were watery eyes and nasal congestion. Conclusion: NG was noninferior compared to IMG for the treatment of insulin-induced hypoglycemia in Japanese patients with T1D/T2D supporting the use of NG as a rescue treatment for severe hypoglycemia. Disclosure M. Matsuhisa: Advisory Panel; Self; Eli Lilly and Company. Board Member; Self; Daiichi Sankyo Company, Limited. Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Mitsubishi Tanabe Pharma Corporation. Speaker's Bureau; Self; Astellas Pharma Inc., Eli Lilly and Company, Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Sanofi, Takeda Pharmaceutical Company Limited. Y. Takita: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. R. Nasu: None. K. Ohwaki: Employee; Self; Eli Lilly and Company. H. Nagashima: None.

Background: Vascular complication of type 1 diabetes is associated with multiple factors. However, biomarkers which directly reflect vascular complication have not been elucidated. We have developed a method to detect unmethylated status of pancreatic β cell specific CpG sequences of insulin gene from cell-free DNA (cfDNA) in the circulation. Transmembrane protein ROBO4 is highly expressed in vascular endothelial cells, and it has been reported that the CpG sites in the promoter region are specifically unmethylated. Aim: To develop a novel PCR method to specifically detect unmethylated CpG sites of ROBO4 gene promoter region in serum cfDNA and to evaluate this method in the supernatant of vascular endothelial cell culture and serum of patients with type 1 diabetes. Material and Methods: After bisulfite conversion of cfDNA extracted from human umbilical vein endothelial cells (HUVEC) and patient serum, unmethylated ROBO4 gene was detected by the dual Amplifications Refractory Mutation Systems PCR, which amplifies only if 4 CpG sites (-185, -144, -118 and -103bp of transcription start sites of ROBO4) are all unmetylated. These methods were applied to 83 patients with type 1 diabetes (duration 16.1±13.9 years) and clinical characteristics were compared. Results: In HUVEC culture supernatant under constant and intermittent high glucose condition, the detection of ROBO4 gene copy number increased depending on the number of dead cells and cfDNA concentration. A positive correlation (p Conclusion: Novel PCR method for ROBO4 could detect vascular endothelial cell injury and atherosclerosis quantitatively in patients with type 1 diabetes. Disclosure A. Kuroda: Speaker's Bureau; Self; Eli Lilly and Company, Novo Nordisk Inc., Sanofi. M.Y. Yamada: None. Y. Takashi: None. M. Ohishi: None. H. Mori: None. M. Ishizu: None. R. Suzuki: None. O. Yinhua: None. Y. Tominaga: None. M. Matsuhisa: Advisory Panel; Self; Eli Lilly and Company. Board Member; Self; Daiichi Sankyo Company, Limited. Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Mitsubishi Tanabe Pharma Corporation. Speaker's Bureau; Self; Astellas Pharma Inc., Eli Lilly and Company, Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Sanofi, Takeda Pharmaceutical Company Limited. Funding Japan Society for the Promotion of Science

Background Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes.Methods We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18-85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR) 25-75 mL/min per 1.73 m(2) of body surface area, and a urine albumin-to-creatinine ratio (UACR) of 300-5000 mg/g who had received maximum labelled or tolerated renin-angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0.75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders) were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0.75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for >= 30 days) or end-stage kidney disease (eGFR = 90 days, chronic dialysis for >= 90 days, kidney transplantation, or death from kidney failure) in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials. gov, number NCT01858532.Findings Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325) or placebo group (n=1323). Median follow-up was 2.2 years (IQR 1.4-2.9). 79 (6.0%) of 1325 patients in the atrasentan group and 105 (7.9%) of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR] 0.65 [95% CI 0.49-0.88]; p=0.0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3.5%) of 1325 patients in the atrasentan group and 34 (2.6%) of 1323 patients in the placebo group (HR 1.33 [95% CI 0.85-2.07]; p=0.208). 58 (4.4%) patients in the atrasentan group and 52 (3.9%) in the placebo group died (HR 1.09 [95% CI 0.75-1.59]; p=0.65).Interpretation Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

Aims: This study investigated the hypoglycemia risk in people with type 2 diabetes (T2D) who initiated or switched to insulin glargine 300 U/mL (Gla-300) by stratifying them by age and renal function. Methods: We examined data from 4621 people with T2D (1227 insulin-naïve and 3394 insulin-experienced) of the X-STAR study, a prospective, observational, 12-month study conducted from December 2015 to August 2018 in Japan. Participants were stratified by age (

Accumulation of advanced glycation end‐products (AGEs) is thought to contribute to muscle weakness in a diabetic animal model. Skin autofluorescence is a proposed marker for accumulation of AGEs in the skin. We aimed to investigate the relationship between AGEs accumulation, sarcopenia and muscle function of Japanese patients with type 1 diabetes. A total of 36 patients with type 1 diabetes participated in the present cross‐sectional study. Sarcopenia parameters (skeletal muscle mass index and knee extension strength) were compared with subcutaneous AGEs accumulation using skin autofluorescence. The prevalence of sarcopenia and impaired knee extension strength was 16.6% (men 0.0%, women 22.2%) and 47.2% (men 22.2%, women 55.6%), respectively. Knee extension strength was negatively correlated with skin autofluorescence (r² = 0.14, P < 0.05), but not with skeletal muscle mass index. In conclusion, the AGEs accumulation might be one of the reasons of impaired lower limb muscle function in Japanese patients with type 1 diabetes.

Soluble insulin receptor (sIR), the ectodomain of the insulin receptor (IR), has been detected in human plasma and its concentration paralleled that of blood glucose. We have previously developed an in vitro model using HepG2 liver-derived cells, which mimics changes in sIR levels in plasma from diabetic patients and shows that calcium-dependent proteases cleave IR extracellularly (a process known as shedding). The present study aimed to reveal the mechanisms of IR cleavage. Using the in vitro model, we investigated the molecular mechanisms of IR cleavage, which is accelerated by high-glucose treatment. We also analysed the relationship between IR cleavage and cellular insulin resistance, and the correlation between plasma sIR levels and insulin sensitivity, which was assessed by the euglycaemic–hyperinsulinaemic clamp technique. Here, we determined that calpain 2, which is secreted into the extracellular space associated with exosomes, directly cleaved the ectodomain of the IRβ subunit (IRβ), which in turn promoted intramembrane cleavage of IRβ by γ-secretase. IR cleavage impaired insulin signalling and the inhibition of IR cleavage (by knockdown of calpain 2 and γ-secretase), restored IR substrate-1 and Akt, independent of IR. Furthermore, the glucose-lowering drug, metformin, prevented IR cleavage accompanied by inhibition of calpain 2 release in exosomes, and re-established insulin signalling. In patients with type 2 diabetes, plasma sIR levels inversely correlated with insulin sensitivity. Sequential cleavage of IR by calpain 2 and γ-secretase may contribute to insulin signalling in cells and its inhibition may be partly responsible for the glucose-lowering effects of metformin. Thus, IR cleavage may offer a new mechanism for the aetiology of insulin resistance.

Aims Currently, inhibition of dipeptidyl peptidase-4 (DPP-4) is widely used in the treatment of type 2 diabetes. Application of this strategy is awaited as a new therapeutic approach for type 1 diabetes, but the scientific basis is still lacking. This report describes the evaluation of serum DPP-4 activity in type 1 diabetes compared with control subjects, and assessment of relationships between DPP-4 activity and diabetic complication markers and metabolic variables in type 1 diabetes. Methods We examined serum DPP-4 activity in Japanese young-adult type 1 diabetes ( n =76, females 69.7%, age 30.9±6.2 years, duration of diabetes 16.5±11.1 years; mean±SD) and healthy controls ( n =22). Association of the enzymatic activity with diabetic micro- and macro- vascular complication markers and clinical parameters was also assessed. Results Subjects with type 1 diabetes displayed significantly higher serum DPP-4 activity than healthy controls (relative value, control: 1.00±0.28, T1D, 1.29±0.38; p =0.0011) independent of other clinical parameters. In type 1 diabetes, DPP-4 activity was positively correlated with duration of diabetes ( r =0.248, p =0.031), while not correlated with HbA1c level. In univariate correlation analysis of diabetic complication markers and other metabolic parameters, coefficient of variation of R-R intervals (CVR-R) and gamma (γ)-glutamyltransferase (GGT) levels were correlated with DPP-4 activity. GGT was extracted as an independent variable of DPP-4 activity in multivariate analysis ( β =0.213, p =0.035). Conclusions Serum DPP-4 activity is significantly elevated in Japanese type 1 diabetes, suggesting pathophysiological significance of the enzyme in type 1 diabetes.

Aim To compare efficacy and safety of new insulin glargine 300 U/ml (Gla-300) with that of insulin glargine 100 U/ml (Gla-100) in Japanese adults with type 1 diabetes. Methods The EDITION JP 1 study (NCT01689129) was a 6-month, multicentre, open-label, phase III study. Participants (n = 243) were randomized to Gla-300 or Gla-100 while continuing mealtime insulin. Basal insulin was titrated with the aim of achieving a fasting self-monitored plasma glucose target of 4.4-7.2 mmol/l. The primary endpoint was change in glycated haemoglobin (HbA1c) over 6 months. Safety measures included hypoglycaemia and change in body weight. Results Gla-300 was non-inferior to Gla-100 for the primary endpoint of HbA1c change over the 6-month period {least squares [LS] mean difference 0.13 % [95 % confidence interval (CI) -0.03 to 0.29]}. The annualized rate of confirmed (≤3.9 mmol/l) or severe hypoglycaemic events was 34 % lower with Gla-300 than with Gla-100 at night [rate ratio 0.66 (95 % CI 0.48-0.92)] and 20 % lower at any time of day [24 h; rate ratio 0.80 (95 % CI 0.65-0.98)]; this difference was most pronounced during the first 8 weeks of treatment. Severe hypoglycaemia was infrequent. The basal insulin dose increased in both groups (month 6 dose: Gla-300 0.35 U/kg/day, Gla-100 0.29 U/kg/day). A between-treatment difference in body weight change over 6 months favouring Gla-300 was observed [LS mean difference -0.6 kg (95 % CI -1.1 to -0.0); p = 0.035]. Adverse event rates were comparable between the groups. Conclusions In Japanese adults with type 1 diabetes using basal plus mealtime insulin, less hypoglycaemia was observed with Gla-300 than with Gla-100, particularly during the night, while glycaemic control did not differ.

A 78-year-old Japanese man showed suppression of the hypothalamic-pituitary-adrenal axis during maximum androgen blockade (MAB) therapy including chlormadinone acetate (CMA) for prostate cancer. After stopping the MAB therapy, both the basal ACTH level and the response to CRH recovered. While no reports have indicated that CMA suppresses the hypothalamic-pituitary-adrenal axis in patients with prostate cancer, CMA has been shown to inhibit this axis in animals. These observations suggest that we must monitor the hypothalamic-pituitary-adrenal axis in patients treated with CMA, especially under stressful conditions.

Glomerular filtration rate (GFR) and urinary albumin excretion rate (UAER) are used to diagnose and classify the severity of chronic kidney disease. Total adiponectin (T-AN) and high molecular weight adiponectin (H-AN) assays were developed using the fully automated immunoassay system, HI-1000 and their significance over conventional biomarkers were investigated. The T-AN and H-AN assays had high reproducibility, good linearity, and sufficient sensitivity to detect trace amounts of adiponectin in the urine. Urine samples after gel filtration were analyzed for the presence of different molecular isoforms. Low molecular weight (LMW) forms and monomers were the major components (93%) of adiponectin in the urine from a diabetic patient with normoalbuminuria. Urine from a microalbuminuria patient contained both high molecular weight (HMW) (11%) and middle molecular weight (MMW) (28%) adiponectin, although the LMW level was still high (52%). The amount of HMW (32%) and MMW (42%) were more abundant than that of LMW (24%) in a diabetic patient with macroalbuminuria. T-AN (r = − 0.43) and H-AN (r = − 0.38) levels showed higher correlation with estimated GFR (eGFR) than UAER (r = − 0.23). Urinary levels of both T-AN and H-AN negatively correlated with renal function in diabetic patients and they may serve as new biomarkers for diabetic kidney disease.

Background: To prevent the end-stage renal failure, it is important to identify the high-risk patients with rapid decline of renal function (RDRF). Aim: We intended to clarify the risk factors for RDRF in Japanese patients with diabetes. Methods: One hundred sixteen out-patients with diabetes (type 1/2, 38/78; M/F, 60/56; age 60.1±12.3 years; BMI, 25.3±4.8; HbA1c, 7.3±1.0%; eGFR, 68±22mL/min/1.73m2) were enrolled in this study, and were followed for one year. We defined RDRF as more than 20% of annual decline of eGFR. The sodium intake was estimated from the urine sodium excretion from early morning urine specimen according to previous report (J Hum Hypertens. 2002). The visceral fat area (VFA) was determined by the impedance method (HDS-2000, Omron Healthcare, Japan) Results: 8.6% of participants were matched to the criteria of RDRF. In subjects with RDRF, the energy intake (45.6±10.6 kcal/kg BW/day), sodium intake (12.5±1.8 g/day), VFA (157±51 cm2) and prevalence of hypertension (100%) were higher than those without RDRF. Annual decline of eGFR was significantly correlated with the stage of diabetic nephropathy, VFA, systolic and diastolic blood pressure, urinary albumin excretion rate, triglyceride, and daily intake of energy, sodium and protein (p Conclusion: Visceral obesity, and high intake of energy and sodium contributed to rapid decline of renal function in Japanese patients with diabetes. Body weight management with adequate energy and sodium intake, therefore, may contribute to prevent progression of diabetic kidney disease. Disclosure M. Matsuhisa: None. H. Mori: None. M. Ohishi: None. M. Ishizu: None. R. Suzuki: None. I. Takikawa: None. S. Taniguchi: None. M. Tamaki: None. Y. Akehi: None. K. Kurahashi: None. S. Yoshida: None. I. Endo: None. K. Aihara: None. M. Funaki: Research Support; Self; Otsuka Holdings Co., Ltd., The Knowledge Cluster from the Ministry of Education, Science, and Culture of Japan. Board Member; Self; Mechanogenic C.C.. A. Kuroda: None.

Background: CpG cytosine in the human insulin gene (INS) is uniquely unmethylated in pancreatic β-cells. It has been reported that a few unmethylated CpG specific PCR in circulating cell-free DNA could detect injury of pancreatic β-cells. However, the same CpG methylation pattern with these CpG sites are also existing in non-β-cells, thus the false positive results might be involved in these reports. Aim: To develop a precise method for detecting pancreatic β-cell DNA in the circulation. Methods: We have developed the dual Amplification Refractory Mutation System (ARMS) PCR, which amplifies only if 4 CpG sites were all unmethylated. The first ARMS PCR amplifies if 2 CpG sites (+331, 404bp of transcription start sites (TSS) of INS) are unmethylated simultaneously, and followed by the second ARMS PCR, which amplifies if 2 CpG sites (+367, 374bp of TSS of INS) are unmethylated simultaneously. This method was applied to 52 patients with type 1 diabetes (T1D) (duration 12.6 +/- 10.1 years). We confirmed the positive samples using DNA sequence analysis. Results: Pancreatic β-cell DNA were detected in 3 T1D (11.8, 2.5, 912.7 copies in 0.1mL of serum) who are diagnosed as slowly progressive T1D, and 4 among 16 healthy control subjects (1.2, 2.2, 1.9, 3.7 copies in 0.1mL of serum). Conclusion: We have developed the dual ARMS PCR which is a precise method to detect circulating pancreatic β-cell DNA. Almost no β-cell DNA was circulating in the long standing T1D, however, β-cell DNA was detectable in slowly progressive T1D. Also, there were not so many, but a few β-cell DNA in the circulation of healthy control subjects. Therefore, this method is useful to evaluate pathogenesis of type 1 diabetes. Disclosure A. Kuroda: None. M.Y. Yamada: None. Y. Tominaga: None. R. Suzuki: None. M. Tamaki: None. Y. Akehi: None. Y. Takashi: None. D. Koga: Employee; Self; Otsuka Pharmaceutical Co.,Ltd.. E. Shimokita: None. F. Tanihara: None. K. Kurahashi: None. S. Yoshida: None. I. Endo: None. K. Aihara: None. M. Abe: None. K. Ferreri: None. M. Matsuhisa: None.