Search

Introduction: Incretin-based drugs are extensively utilized in the treatment of type 2 diabetes (T2D), with remarkable clinical efficacy. These drugs were developed based on findings that the incretin effect is reduced in T2D. The incretin effect in East Asians, whose pancreatic β-cell function is more vulnerable than that in Caucasians, however, has not been fully examined. In this study, we investigated the effects of incretin in Japanese subjects., Methods: A total of 28 Japanese subjects (14 with normal glucose tolerance [NGT], 6 with impaired glucose tolerance, and 8 with T2D) were enrolled. Isoglycemic oral (75 g glucose tolerance test) and intravenous glucose were administered. The numerical incretin effect and gastrointestinally-mediated glucose disposal (GIGD) were calculated by measuring the plasma glucose and entero-pancreatic hormone concentrations., Results and Discussion: The difference in the numerical incretin effect among the groups was relatively small. The numerical incretin effect significantly negatively correlated with the body mass index (BMI). GIGD was significantly lower in participants with T2D than in those with NGT, and significantly negatively correlated with the area under the curve (AUC)-glucose, BMI, and AUC-glucagon. Incretin concentrations did not differ significantly among the groups. We demonstrate that in Japanese subjects, obesity has a greater effect than glucose tolerance on the numerical incretin effect, whereas GIGD is diminished in individuals with both glucose intolerance and obesity. These findings indicate variances as well as commonalities between East Asians and Caucasians in the manifestation of incretin effects on pancreatic β-cell function and the integrated capacity to handle glucose., Competing Interests: NI received clinical commissioned/joint research grants from Terumo, Asken, and Drawbridge Health Inc.; speaker honoraria from MSD, Astellas Pharma, Novo Nordisk Pharma, Ono Pharmaceutical, Nippon Boehringer Ingelheim, Takeda, Eli Lilly Japan, Sumitomo Dainippon Pharma, and Mitsubishi Tanabe Pharma, Kyowa Kirin, Sanofi; and scholarship grants from Kissei Pharmaceutical, Sanofi, Daiichi Sankyo, Mitsubishi Tanabe Pharma, Takeda, Japan Tobacco, Kyowa Kirin, Sumitomo Dainippon Pharma, Astellas Pharma, MSD, Eli Lilly Japan, Ono Pharmaceutical, Sanwa Kagaku Kenkyusho, Nippon Boehringer Ingelheim, Novo Nordisk Pharma, Novartis Pharma, Kowa and Life Scan Japan. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hamasaki, Harada, Muraoka, Yamane, Joo, Suzuki and Inagaki.)

Aims: The aim of the present study is to estimate insulin resistance (IR) using clinically available parameters except for serum insulin or C-peptide concentration to overcome the limitation of homeostasis model assessment of IR (HOMA-IR), which has been widely used in clinical practice. Patients and Methods: Fifty-two admitted patients with type 2 diabetes or impaired glucose tolerance were enrolled, and steady state plasma glucose (SSPG) method and cookie meal tolerance test were performed together with fasting blood sampling and anthropometric measurements. Insulin sensitivity measured by SSPG was estimated as glucose clearance corrected by the excretion of glucose into urine (C-GC). Results: Log-transformed (C-GC) was negatively correlated with fasting plasma glucose (FPG), log (Fasting triglyceride: TG), log (Fasting TG/Fasting high-density lipoprotein cholesterol: HDLC), and their area under the curves (AUCs). Fasting and AUC-HDLC was positively and fasting free fatty acid (FFA) was negatively correlated with log (C-GC). Body fat (%) was negatively correlated with log (C-GC). Multiple regression analysis on log (C-GC) as an outcome variable revealed that FPG, log (AUC-TG/AUC-HDLC), body fat (%), and fasting FFA were selected as significant predictive variables and contributed to log (C-GC) by 60% (adjusted R 2 ). Replacing log (AUC-TG/AUC-HDLC) with its fasting value, log (Fasting TG/Fasting HDLC), this model still showed a strong contribution to log (C-GC) by 57% (adjusted R It is plausible that our estimation for IR without the inclusion of plasma insulin concentration can be applied in Japanese patients whose HOMA-IR is not appropriately available. The model using fasting values is less complicated and could be the best way for the estimation of IR.2 ). These contributions were stronger than those in log (HOMA-IR) (52.5%), log (Fasting C-peptide) (45.7%) to log (C-GC). Conclusions: It is plausible that our estimation for IR without the inclusion of plasma insulin concentration can be applied in Japanese patients whose HOMA-IR is not appropriately available. The model using fasting values is less complicated and could be the best way for the estimation of IR.

Protein intake reportedly increases the risk of diabetes; however, the results have been inconsistent. Diabetes in adulthood may be attributed to early life dietary amino acid composition. This study aimed to investigate the association between amino acid composition and glycemic biomarkers in adolescents. Dietary intake was assessed using a food frequency questionnaire, and fasting glucose and insulin levels were measured in 1238 eighth graders. The homeostatic model assessment (HOMA) indices (insulin resistance and β-cell function) were calculated. Anthropometrics were measured and other covariates were obtained from a questionnaire. Amino acid composition was isometric log transformed according to the compositional data analysis, which was used as explanatory variables in multivariate linear regression models for glucose, insulin, and HOMA indices. Only the association between glucose and leucine was significant. In replacement of other amino acids with leucine, an increase of 0.1% of total amino acids correlated with a lower glucose level (-1.02 mg/dL). One-to-one substitution of leucine for isoleucine or methionine decreased glucose (-2.98 and -2.28 mg/dL, respectively). Associations with other biomarkers were not observed. In conclusion, compositional data analysis of amino acids revealed an association only with glucose in adolescents; however, the results of this study should be verified in other populations.

Background and Objective: Several associations between diabetes mellitus and delirium have been reported; however, they have been inconsistent, and evidence on the effects of antidiabetic medications on delirium is also limited. This study aimed to investigate whether the use of antidiabetic drugs is a risk factor for delirium development., Methods: Using the Japanese Adverse Event Reporting Database, we analyzed 662,899 reports between 2004 and 2022. Reporting odds ratios (RORs) and 95% confidence intervals (CIs) for delirium associated with diabetes and using each antidiabetic medication were calculated after adjusting for potential confounders., Results: Overall, 8892 of the reports analyzed were associated with delirium. A comparison of the incidence of delirium between patients with and without diabetes showed no significant difference, with 1.34% in patients without diabetes and 1.37% in those with diabetes. In each antidiabetic medication, signals for delirium were detected for sulfonylurea (crude ROR, 1.35; 95% CI 1.21-1.51) and insulin (crude ROR, 1.28; 95% CI 1.13-1.44). These results were maintained even after adjusting for factors with potential confounders (sulfonylurea: adjusted ROR, 1.75; 95% CI 1.54-2.00, insulin: adjusted ROR, 1.35; 95% CI 1.20-1.54)., Conclusions: Our results suggest no association between diabetes and delirium; however, using sulfonylurea and insulin may be associated with delirium development. Nonetheless, these findings should be validated in future studies., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The advantages of real-time continuous glucose monitoring (rtCGM) over intermittently scanned CGM (isCGM) reportedly include lower glycated hemoglobin (HbA1c) levels as well as reduced glycemic variability. However, there have been few studies of the effect of switching from isCGM to rtCGM on glycemic control, as well as the specific factors underlying any observed improvements. To that end, all patients with type 1 diabetes mellitus who used the DEXCOM rtCGM device (Terumo Corporation, Tokyo, Japan) at our institution were reviewed, and 16 individuals with type 1 diabetes who switched from isCGM to rtCGM were investigated. The patients' HbA1c decreased in 75% of the cases (p = 0.02). On the other hand, GMI increased in 75% of the cases (p = 0.01). Intriguingly, the percentage of time below range and coefficient of variation were significantly improved with rtCGM compared to isCGM (2.9% vs. 7.6%, p = 0.016 and 35% vs. 40%, p = 0.0019, respectively). We also found that the discrepancy between HbA1c and GMI among users of isCGM was a key indicator that improved when switching to rtCGM. If discrepancies are observed between HbA1c and GMI when using isCGM, switching to rtCGM should be considered for improving glycemic control.

Objective: We assessed whether alanine aminotransferase/aspartate aminotransferase (ALT/AST), a marker of hepatic steatosis, may be associated with adipose tissue dysfunction more closely than hepatic and muscle insulin resistance (IR). Methods: Associations with adipose tissue IR index (AT-IR) calculated as a product of fasting insulin and free fatty acids, leptin/adiponectin ratio, a proxy of adipocyte dysfunction, homeostasis model assessment IR (HOMA-IR), hepatic and muscle IR inferred from plasma insulin kinetics during a 75 grams oral glucose tolerance test (OGTT) were studied in nondiabetic 307 young and 148 middle-aged Japanese women, whose body mass index averaged 20 and 22 kilograms/m 2 , respectively. Results: On multivariate linear regression analysis in young women, ALT/AST was associated with trunk/leg fat ratio (standardized β  = 0.202, P  = 0.007), a marker of abdominal fat accumulation, and AT-IR (standardized β  = 0.185, P  = 0.003) independently of HOMA-IR and Matsuda index ( R 2  = 0.07). In middle-aged women, leptin/adiponectin ratio (standardized β  = 0.446, P  < 0.001) and AT-IR (standardized β  = 0.292, P  = 0.009) emerged as determinants of ALT/AST independently of trunk/leg fat ratio, OGTT-derived hepatic IR, leptin, and adiponectin ( R 2  = 0.34). Conclusions: ALT/AST was associated with AT-IR and adipocyte dysfunction more closely than hepatic and muscle IR even in nondiabetic lean Japanese women.

Background: In patients with type 1 diabetes mellitus (T1D), sodium-glucose cotransporter 2 (SGLT2) inhibitors are associated with an increased risk of diabetic ketoacidosis (DKA). Ipragliflozin is an SGLT2 inhibitor approved in Japan in combination with insulin for patients with T1D., Research Design and Methods: Spontaneous safety reports of ipragliflozin adverse drug reactions (ADRs) in patients with T1D were collected during early post-marketing phase vigilance (EPPV; 21 December 2018-20 June 2019). For patients with T1D prescribed ipragliflozin who experienced DKA, we examined DKA event data registered in the manufacturer's safety database (21 December 2018-31 December 2021), including patient background characteristics., Results: During EPPV, there were 189 total events (45 serious) of ADRs, including 32 serious events of ketoacidosis. From 2018 to 2021, the major DKA risk factors were sick days, stopping or inappropriately decreasing insulin, insulin pump trouble, and low carbohydrate diet, with substantial overlap among these factors., Conclusions: In Japanese patients with T1D using ipragliflozin, DKA events were linked to several overlapping factors, including sick days and reduced dose/interruption of insulin, whether intentional or unexpected. These results highlight the need for improved patient education regarding ipragliflozin use and appropriate self-management of ketosis from an early stage.

Background: Both decreased insulin sensitivity and impaired insulin secretion are common in Asian populations with diabetes, in contrast to Western populations. There is limited evidence regarding the association between insulin response in diabetes in Asian populations and serum 25-hydroxyvitamin D 3 (25[OH]D 3 ) insufficiency., Methods: The present cross-sectional study compared the prevalence of diabetes, defined as a fasting plasma glucose level ≥126 mg/dL and/or a HbA1c level ≥6.5%, among 480 participants aged 35-79 years not taking anti-diabetes medications, based on serum 25(OH)D 3 levels. A logistic regression model was used to calculate the odds ratios for diabetes in each serum 25(OH)D 3 group. Furthermore, this study examined the association between serum 25(OH)D 3 levels and the index of homeostasis model assessment of insulin resistance (HOMA-IR) using a linear regression model., Results: The prevalence of diabetes was 7.29% in the study population, and was higher in lower serum 25(OH)D 3 quartile groups. The odds ratios for diabetes in the first, second, and third serum 25(OH)D 3 quartile groups (25[OH]D 3 : ≤18.10, 18.11-22.90, and 22.91-28.17 ng/mL) were 4.02 (95% confidence interval [CI], 1.25-12.92), 2.50 (95% CI, 0.77-8.10), and 1.91 (95% CI, 0.60-6.09), respectively, with the fourth quartile group (⩾28.18 ng/mL) serving as the reference group, after adjusting for sociodemographic, lifestyle, physical and environmental factors. Serum 25(OH)D 3 levels showed an inverse association with log-transformed HOMA-IR after adjusting for similar factors (standardized β = -0.08; 95% CI, -0.14 to -0.02)., Conclusion: Serum 25(OH)D 3 levels were inversely associated with diabetes prevalence in a general Japanese population, with a slight inverse association between serum 25(OH)D 3 levels and HOMA-IR.

To elucidate the age-related sex difference in glucose tolerance, we conducted 75 g oral glucose tolerance tests in 1156 participants. Participants were divided into four groups, namely, young (22−29) males, young females, middle-aged (>50) males, and middle-aged females. According to the Japanese Clinical Practice Guideline for Diabetes 2019, the prevalence of normal glucose tolerance (NGT) was significantly lower in middle-aged than in young participants. The prevalence of high-normal fasting plasma glucose (FPG) was higher, and NGT was lower in young males (high-normal FPG 15.2%, NGT 82.0%) than young females (high-FPG 3.9%, NGT 94.3%). Combined glucose intolerance (CGI) was higher and NGT was lower in middle-aged males (CGI 10.2%, NGT 25.2%) than in middle-aged females (CGI 3.3%, NGT 39.8%). FPG and body mass index (BMI) were the lowest and Homeostatic model assessment beta cell function (HOMA-β) was the highest in young females, followed by young males, middle-aged females, and middle-aged males. Multiple linear regression analysis revealed that BMI weakly correlated with HOMA-β and Matsuda index in all subjects except young females. The superior glucose tolerance in females was apparent in young, but attenuated in middle-aged females. The differences are due to the higher insulin secretion potential and lower BMI in young females.

Plasma and liver SerpinB1 levels are elevated in mice with insulin resistance and promote β-cell proliferation in human islets. We measured serum SerpinB1 levels in Japanese subjects with or without type 2 diabetes (T2DM). We enrolled 12 normal glucose tolerance (NGT) and 51 T2DM subjects. There was no difference in serum SerpinB1 levels between the 2 groups (T2DM, 1.3 ± 0.9 ng/mL vs. NGT, 1.8 ± 1.7 ng/mL; P = 0.146). After adjusting for age and sex, the serum SerpinB1 levels were positively correlated with HOMA2-%S (β = 0.319, P = 0.036), and negatively correlated with fasting blood glucose (β = -0.365, P = 0.010), total cholesterol (β = -0.396, P = 0.006), low-density lipoprotein (LDL) cholesterol (β = -0.411, P = 0.004), triglycerides (β = -0.321, P = 0.026), and γGTP (β = -0.322, P = 0.026) in subjects with T2DM. Thus, circulating SerpinB1 is possibly associated with insulin sensitivity and better blood glucose level in Japanese subjects with T2DM. Trial registration: UMIN Clinical Trials Registry, UMIN000020453., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Kyohara et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background & Aims: Limited evidence exists regarding the prospective associations between amino acids and insulin resistance. In addition, amino acids have been suggested to promote insulin resistance with the requirement of obesity in animal studies, but the interaction between amino acids and obesity on the development of insulin resistance has not been examined in epidemiological studies. We aimed to investigate the differences in the prospective associations of serum amino acids with insulin resistance among adults with and without overweight or obesity., Methods: Fasting serum concentrations of 25 amino acids were quantified in 1131 non-diabetic Japanese workers aged 22-71 years at baseline. The homeostasis model assessment of insulin resistance (HOMA-IR) was estimated at baseline and the 3-year follow-up. Generalized linear models were used to assess the associations between amino acids at baseline and HOMA-IR at follow-up with adjustment for potential confounding factors. A Bonferroni-corrected threshold of p = 0.001 was considered significant for multiple tests., Results: The associations for the following amino acids with HOMA-IR at the 3-year follow-up significantly varied by obesity status: isoleucine, valine, tyrosine, alanine, and methionine (all p for interaction <0.05). Higher concentrations of serum isoleucine, valine, tyrosine, and alanine (per 1SD) were significantly associated with higher HOMA-IR levels in overweight/obese participants (multivariable-adjusted β coefficients ranging from 0.09 to 0.12; all p < 0.001), but no association was observed in the underweight/normal-weight participants. The associations for serum methionine were direct among overweight/obese participants, but inverse among underweight/normal-weight participants (all p < 0.001)., Conclusions: This study demonstrated the prospective associations of different individual serum amino acids with insulin resistance, with most pronounced associations being for overweight/obese adults. Our findings support the possibility of heterogeneous effects of individual amino acids, as well as their interplay with obesity in the progression of insulin resistance., Competing Interests: Conflict of interest We have no competing interests to declare., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aims: To investigate the baseline demographic and clinical characteristics of patients with type 1 diabetes mellitus (T1DM) newly treated with a sodium-glucose cotransporter 2 inhibitor (SGLT2i) as an add-on to insulin, or treated with insulin alone or in combination with oral anti-diabetic drugs other than an SGLT2i., Methods: Retrospective study using data from the JMDC database (December 21, 2018, to October 31, 2020). Included patients with T1DM treated with an SGLT2i (add-on to insulin) (n = 1027) or with insulin (n = 4320). Baseline demographic and clinical characteristics were summarized, and change in insulin dose and efficacy outcomes, including hemoglobin A1c (HbA1c) and body mass index (BMI), before and after the first SGLT2i or insulin prescription were evaluated., Results: The SGLT2i add-on group had higher HbA1c and BMI than the insulin group. Daily insulin doses decreased from immediately before to after the first SGLT2i prescription. HbA1c and BMI improved from baseline to after the first SGLT2i prescription., Conclusions: This large real-world study reported the baseline demographic and clinical characteristics of patients with T1DM newly treated with an SGLT2i in Japan. The findings may guide the appropriate use of SGLT2i and support large-scale database studies in T1DM research., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Purpose: To study the association between different hypoglycemic regimens and postoperative diabetic macular edema (DME)., Methods: A secondary analysis based on a retrospective cohort study., Results: In this secondary analysis, 124 eyes from patients with proliferative diabetic retinopathy (PDR) who underwent pars plana vitrectomy (PPV) between January 2008 and September 2012 were included. We found that compared with oral hypoglycemic medication, oral hypoglycemic medication plus insulin treatment revealed an insignificant relationship with postoperative DME (odds ratio [OR]=0.8, 95% confidence interval [CI]: 0.12-5.21, P=0.8167), only insulin treatment revealed a significant association with postoperative DME (OR=0.10, 95% CI: 0.01-0.84, P=0.0337) after adjusted age, sex. After adjusted age, sex, diabetes mellitus (DM) duration, glycosylated hemoglobin (HbA1c), the results did not have obvious changes (OR=0.61, 95% CI: 0.09-4.26, P=0.6187; OR=0.07, 95% CI: 0.01-0.65, P=0.0197). Furthermore, after adjusted age, sex, DM duration, HbA1c, hypertension, intraoperative retinal photocoagulation, vitreous hemorrhage, macular detachment, fibrovascular membrane, intraocular lens implantation and microincision vitrectomy surgery, the results were consistent (OR=0.66, 95% CI: 0.05-9.49, P=0.7621; OR=0.06, 95% CI: 0.00-0.81, P=0.0342). The same trend was observed in these adjusted models as well (p for trend was 0.0254, 0.0141, and 0.0311, respectively)., Conclusion: In conclusion, our results of the secondary analysis should be interpreted as a significant association between insulin treatment and reduced risks of postoperative DME in Japanese PDR patients with PPV surgery, compared with oral medications. Well glycemic control with longstanding insulin therapy may be beneficial to reduce the risks of postoperative DME in PDR patients. Our investigation calls for large-scale and long-term prospective clinical studies for a full evaluation of the exact role of insulin in the progression of postoperative DME., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lei, Zhang and Zhang.)

An increasing number of Japanese women of childbearing age are underweight (BMI <18.5), but the association between this and the increased number of low-birth-weight babies born remains unclear. Here, a rat model was established to mimic the undernutrition (85% of the energy required for those with normal activity levels) experienced by such women and to evaluate the associated impaired glucose tolerance. The undernourished Wistar rat group showed increased serum corticosterone level reflecting stress, and greater adrenal weight and size. It also showed greater insulin resistance, higher expression of FOXO-1, a transcription factor related to muscle atrophy, and lower expression of p-Akt, an insulin-dependent signaling factor. Overall, this work shows the key role of undernutrition during pregnancy as a cause of impaired glucose tolerance and increased diabetes risk in offspring. The findings of this study may inform preemptive measures to prevent the development of metabolic syndrome in offspring of undernourished mothers., (© The Author(s) 2022. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Introduction: We investigated trends in the proportion of diabetes treatment and glycemic control, which may be altered by recent advances in insulin and non-insulin drugs, in Japanese patients with type 2 diabetes., Research Design and Methods: A serial cross-sectional study was performed using a multicenter large-population database from the Japan Diabetes Clinical Data Management study group. Patients with type 2 diabetes who attended clinics belonging to the study group between 2002 and 2018 were included to examine trends in glycated hemoglobin A1c (HbA1c) by treatment group using multivariable non-linear regression model., Results: The proportion of patients with insulin only decreased from 15.0% to 3.6%, patients with insulin+non-insulin drugs increased from 8.1% to 15.1%, patients with non-insulin drugs increased from 50.8% to 67.0%, and those with no drugs decreased from 26.1% to 14.4% from 2002 to 2018, respectively. The HbA1c levels of each group, except for no drugs, continued to decrease until 2014 (unadjusted mean HbA1c (%) from 2002 to 2014: from 7.89 to 7.45 for insulin only, from 8.09 to 7.63 for insulin+non-insulin, and from 7.51 to 6.98 for non-insulin) and remained unchanged thereafter. Among insulin-treated patients, use of human insulin decreased, use of long-acting analog insulin increased, and concomitant use of non-insulin drugs increased (from 35.1% in 2002 to 80.9% in 2018), which included increased use of dipeptidyl peptidase 4 inhibitors, sodium-glucose cotransporter 2 inhibitors, and glucagon-like peptide 1 receptor agonists, and the persistently high use of metformin., Conclusions: During the past two decades, combined use of insulin and non-insulin drugs increased and glycemic control improved and leveled off after 2014 in Japanese patients with type 2 diabetes. Further studies of the trend in association with age and factors related to metabolic syndrome are necessary to investigate strategies aiming at personalized medicine in diabetes care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims/introduction: We aimed to replicate a new diabetes subclassification based on objective clinical information at admission in a diabetes educational inpatient program. We also assessed the educational outcomes for each cluster., Methods: We included diabetes patients who participated in the educational inpatient program during 2009-2020 and had sufficient clinical information for the cluster analysis. We applied a data-driven clustering method proposed in a previous study and further evaluated the clinical characteristics of each cluster. We investigated the association between the clusters and changes in hemoglobin A1c level from the start of the education program. We also assessed the risk of re-admission for the educational program., Results: We divided a total of 651 patients into five clusters. Their clinical characteristics followed the same pattern as in previous studies. The intercluster ranking of the cluster center coordinates showed strong correlation coefficients with those of the previous studies (mean ρ = 0.88). Patients classified as severe insulin-resistant diabetes (cluster 3) showed a more pronounced progression of renal dysfunction than patients classified as the other clusters. The patients classified as severe insulin-deficient diabetes (cluster 2) had the highest rate of reduction in hemoglobin A1c level from the start of the program (P < 0.01) and a tendency toward a lower risk of re-admission for the education program (hazard ratio 0.47, P = 0.09)., Conclusion: We successfully replicated the diabetes subclassification using objective clinical information at admission for the education program. In addition, we showed that severe insulin-deficient diabetes patients tended to have better educational outcomes than patients classified as the other clusters., (© 2021 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Objective: We aimed to classify Japanese adults without diabetes into different categories based on the oral glucose tolerance test (OGTT) and characterize their insulin sensitivity and insulin secretion., Patients and Methods: The OGTT was performed on 1,085 Japanese individuals without diabetes (aged 20-64 years); blood glucose and insulin levels were measured at 0, 30-, 60-, 90-, and 120-min. Fasting blood chemistry, hematology, and urine were analyzed. The participants were classified into four categories based on the following: (A) 30 min post-load plasma glucose levels < 157 mg/dL and/or (B) 120 min post-load plasma glucose levels < 126 mg/dL and Matsuda index > 4.97. Category 1 satisfied both conditions, category 2 satisfied condition A but not B, category 3 satisfied condition B but not A, and category 4 satisfied neither condition., Results: Overall, 46%, 21%, 13%, and 20% of the participants were classified into categories 1, 2, 3, and 4, respectively. Compared with category 1, the characteristics of the other categories were: 2, low insulin sensitivity and high blood glucose levels during the later period; 3, low insulin secretion and a rapid increase in blood glucose levels; and 4, combined characteristics of categories 2 and 3. Most blood test values besides glucose metabolism in category 4 were also worse than those in category 1. Categories 1 and 2 had a high proportion of females, whereas categories 3 and 4 had a low proportion., Conclusions: Japanese adults without diabetes are classified into four categories with different insulin sensitivities and insulin secretion using OGTT results. Each category has different characteristics of age and sex distribution and clinical values besides glucose metabolism.

Background: No study has previously investigated insulin resistance in collegiate baseball players. The purposes of this study were to examine: 1) the insulin resistance; and 2) the usefulness of the adiponectin/leptin (A/L) ratio compared with the homeostasis model assessment of insulin resistance (HOMA-IR) for assessing insulin resistance in collegiate baseball players., Methods: Twenty collegiate baseball players with abdominal obesity (AO group) defined by a waist circumference (WC) ≥85 cm, 65 lean baseball players with a WC<85 cm (L group), and 20 controls who were sedentary for at least 1 year (C group) were compared. The Body Mass Index, WC, systolic and diastolic blood pressures, fasting plasma glucose, total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, apolipoprotein B, insulin, leptin, adiponectin, and high-sensitivity C-reactive protein (hs-CRP) were measured., Results: The AO group had a significantly higher insulin level, HOMA-IR, and leptin level, and lower A/L ratio than the L and C groups. The AO group had a significantly higher prevalence of insulin resistance (50%) than the L (14%) group. The A/L ratio was significantly negatively correlated with body weight, Body Mass Index, WC, triglycerides, triglycerides/HDL-C ratio, apolipoprotein B, hs-CRP, insulin, HOMA-IR, and leptin, and positively correlated with HDL-C, whereas HOMA-IR was significantly positively correlated with body weight, Body Mass Index, WC, systolic and diastolic blood pressures, fasting plasma glucose, and insulin, and negatively correlated with adiponectin and the A/L ratio. In the forward stepwise multiple regression analysis, WC, triglycerides, and hs-CRP were the significant determinants for the A/L ratio, whereas diastolic blood pressure and WC were the significant determinants for HOMA-IR. This model explained 53.7% of the variance in the A/L ratio and 13.6% of the variance in HOMA-IR., Conclusions: The present study suggested that the baseball players with abdominal obesity had a significantly higher prevalence of insulin resistance than the lean baseball group. The A/L ratio may be more useful than HOMA-IR to accurately assess insulin resistance in male collegiate baseball players.

Associations of arterial stiffness with glucose, insulin, and proinsulin dynamics during the oral glucose tolerance test (OGTT) remain under debate. The aim of this study was to investigate whether plasma glucose (PG), insulin, and proinsulin (Pro) contribute to arterial stiffness, measured by pulse wave velocity (PWV), in young Japanese persons. PG, immunoreactive insulin (IRI), and Pro levels were determined in 1193 young Japanese subjects (<40 years of age) with normal glucose tolerance or nondiabetic hyperglycemia before and at 30, 60, and 120 min during a 75-g OGTT. Participants were divided into two groups according to the median PWV. Background factors, PG, IRI, and Pro levels during the OGTT, and insulin sensitivity (SI) indices in each group were compared. Several multiple regression analysis models were used to evaluate factors contributing to PWV. All IRI and Pro levels before and after glucose loading and the area under the curve (AUC) values for IRI and Pro increased with higher PWV. 1/HOMA-IR and ISI-Matsuda as measures of SI decreased with higher PWV. The IRI AUC and Pro level before glucose loading (Pro0) were independently associated with PWV, in addition to male sex, heart rate, and mean blood pressure. The IRI AUC had a stronger relationship with PWV than Pro0. The IRI AUC had an independent relationship with PWV, whereas both SI indices did not. Postloading insulinemia, but not reduced SI, was independently associated with arterial stiffness in young Japanese persons., (© 2021. The Author(s).)

Introduction: Newly developed anti-diabetic medications have had multiple activities, beyond a blood glucose-lowering effect. Current drugs for treating type 2 diabetes mellitus (T2DM) are based on the use of gastrointestinal hormones. Representative incretin preparations, such as those with glucagon-like peptide (GLP)-1 or gastric inhibitory polypeptide (GIP) activity, aim to provide new means of controlling blood glucose levels, body weight, and lipid metabolism., In this manuscript, the pathophysiology of T2DM and the activities and characteristics of novel diabetic drugs are reviewed in the context of the Japanese population. This review also highlights the need for novel medicines to overcome the accompanying challenges. Finally, the author provides the reader with their expert perspectives., The incidence of T2DM has been increasing in the aging of Japanese society. In older people, medical development should focus on safety, easier self-administration, and the relief of caregiver burden in terms of continuous administration. In the young, the focus should be on effectiveness, with a particular emphasis on the protection of organs, increasing the ease of adherence, and safety. Novel medicines will need to push the envelope in these areas.

Introduction: Prevalence rates for diabetes mellitus continue to rise, which, coupled with increasing costs of complications, has appreciably increased expenditure in recent years. Poor glycaemic control including hypoglycaemia enhances complication rates and associated morbidity, mortality and costs. Consequently, this needs to be addressed. Whilst the majority of patients with diabetes have type-2 diabetes, a considerable number of patients with diabetes require insulin to help control their diabetes. Long-acting insulin analogues were developed to reduce hypoglycaemia associated with insulin and help improve adherence, which can be a concern. However, their considerably higher costs have impacted on their funding and use, especially in countries with affordability issues. Biosimilars can help reduce the costs of long-acting insulin analogues thereby increasing available choices. However, the availability and use of long-acting insulin analogues can be affected by limited price reductions versus originators and limited demand-side initiatives to encourage their use. Consequently, we wanted to assess current utilisation rates for long-acting insulin analogues, especially biosimilars, and the rationale for patterns seen, across multiple Asian countries ranging from Japan (high-income) to Pakistan (lower-income) to inform future strategies., Methodology: Multiple approaches including assessing utilization and prices of insulins including biosimilars among six Asian countries and comparing the findings especially with other middle-income countries., Results: Typically, there was increasing use of long-acting insulin analogues among the selected Asian countries. This was especially the case enhanced by biosimilars in Bangladesh, India, and Malaysia reflecting their perceived benefits. However, there was limited use in Pakistan due to issues of affordability similar to a number of African countries. The high use of biosimilars in Bangladesh, India and Malaysia was helped by issues of affordability and local production. The limited use of biosimilars in Japan and Korea reflects limited price reductions and demand-side initiatives similar to a number of European countries., Conclusions: Increasing use of long-acting insulin analogues across countries is welcomed, adding to the range of insulins available, which increasingly includes biosimilars. A number of activities are needed to enhance the use of long-acting insulin analogue biosimilars in Japan, Korea and Pakistan.

Aim: To evaluate the efficacy and safety of adding the once-weekly oral dipeptidyl peptidase-4 inhibitor omarigliptin to treatment of Japanese patients with type 2 diabetes and inadequate glycaemic control on insulin monotherapy., Materials and Methods: In a 52-week clinical trial, Japanese patients on insulin monotherapy were randomized to once-weekly omarigliptin 25 mg (N = 123) or placebo (N = 61) for a 16-week, double-blind, placebo-controlled period. After Week 16, patients continued or switched to omarigliptin for a 36-week open-label period., Results: From a mean baseline of approximately 8.8%, the Week 16 least squares mean changes in HbA1c were -0.61% (omarigliptin) and 0.29% (placebo); the between-group difference was -0.90% (p < .001). At Week 52, the mean change from baseline in HbA1c was -0.57% in both the group on omarigliptin for 52 weeks and the group on omarigliptin for 36 weeks (switched from placebo at Week 16). During the first 16 weeks of treatment, the incidences of adverse events (AEs), serious AEs, drug-related AEs and discontinuation from trial medication because of an AE were similar in both groups. A slight increase in incidence of symptomatic hypoglycaemia was observed in the omarigliptin group (n = 13 [10.6%]) compared with placebo (n = 4 [6.6%]). No severe hypoglycaemia was reported during the study. No new safety signals emerged with treatment beyond Week 16 through Week 52., Conclusion: The addition of once-weekly omarigliptin to insulin therapy for up to 52 weeks was generally well tolerated and provided clinically meaningful improvement in glycaemic control throughout the trial period. ClinicalTrials.gov: NCT02906709., (© 2021 Merck Sharp & Dohme Corp. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Objectives: Continuous postprandial hyperglycemia is associated with the onset of cardiovascular disease. In recent years, the mRNA expression of inflammation-related genes in peripheral blood leukocytes has been shown to be induced by an increase in blood glucose levels. The aim of this study was to investigate differences in the expression of inflammation-related genes in peripheral blood leukocytes in response to an increase in blood glucose from individuals who consumed two kinds of breakfast meals with different glycemic indexes (GIs)., Methods: Twenty healthy Japanese men 40 to 70 y of age were given low- or high-GI meals for breakfast for 14 d. Clinical examinations were performed on days 7 and 14. Their blood glucose levels and insulin concentrations were measured from before breakfast ingestion to 120 min after. Additionally, using the blood obtained before and 120 min after breakfast, the mRNA expression levels of inflammation-related genes in peripheral leukocytes were measured., Results: The blood glucose levels were significantly lower in the low-GI meal intake group at 30, 60, and 120 min after breakfast than in the high-GI meal intake group. The intake of high-GI meals for 6 d led to an increase in the mRNA levels of interleukin-1β, S100A4, and CD18 compared with the period of low-GI meals., Conclusion: The intake of a low-GI breakfast for 1 wk in healthy Japanese men resulted in lower postprandial blood glucose and insulin levels, which were accompanied by a reduced expression of inflammation-related genes in peripheral blood leukocytes., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aim: To clarify whether maternal characteristics or laboratory parameters could help predict the onset of recurrent gestational diabetes mellitus (GDM)., Methods: We enrolled 615 women with consecutive singleton deliveries at or after 28 GW from two perinatal medical centers between 2011 and 2019 and divided them into four groups according to whether they had GDM in the first and second pregnancies. The outcome of this study was to clarify the incidence and the predictors of recurrent GDM., Results: We found that among 72 women (11.7%) who had GDM during their first pregnancy, the rate of recurrent GDM was 47.2%. The 34 women (5.5%) with recurrent GDM gained significantly less weight in the first and second pregnancies and lost less weight between the first delivery and the second conception compared with those women without GDM in both pregnancies. Of women with GDM during the first pregnancy, 21 scored 2 or 3 (multiple) positive points on a 75-g oral glucose tolerance test (OGTT) during their first pregnancies; the GDM recurrence rate among these women (66.7%) was significantly higher than that among the 51 women who scored 1 positive point (39.2%; p = 0.0411). During the first pregnancy, insulin administration therapy was significantly more frequent in women with recurrent GDM than in women without recurrent GDM (23.5% vs. 5.3%, p = 0.0396, respectively)., Conclusion: A predictor of recurrent GDM onset was a score of 2 or 3 positive points on the OGTT during the first pregnancy., (© 2021 Japan Society of Obstetrics and Gynecology.)

Introduction: The aim of this study was to evaluate the glycemic control and safety of insulin degludec/insulin aspart (IDegAsp) co-formulation in Japanese patients with type 2 diabetes (T2D) in a real-world clinical setting, including elderly patients (aged > 75 years)., Methods: Patients (≥ 18 years) diagnosed with T2D, previously treated with insulin were included from the Japanese Medical Data Vision database. Baseline data were taken at the index date, defined as the first IDegAsp prescription claim. Change in glycated hemoglobin (HbA 1c ) at 12 months was estimated using a mixed model repeated measures analysis. The proportion of patients achieving target HbA 1c  < 8.0% without experiencing hypoglycemia (identified by International Classification of Disease codes) was calculated at 12 months (365 ± 90 days) after baseline., Results: Overall, 10,798 patients were included, 3940 were aged > 75 years, and 913 had baseline HbA 1c values available. Switching to IDegAsp was associated with significantly improved HbA 1c values at 12 months (- 1.23% [- 1.43, - 1.02] 95%CI , p < 0.001) versus baseline. Moreover, relative to baseline, a significantly greater proportion of patients achieved HbA 1c  < 8.0% without hypoglycemia at 12 months, relative rate (RR) 1.30 [1.15, 1.45] 95%CI , p < 0.001. Results were similar for patients aged ≤ 75 years and aged > 75 years; 66% and 64% of patients, respectively, achieved HbA 1c  < 8.0% without hypoglycemia at 12 months., Conclusion: Switching from insulin to IDegAsp co-formulation was associated with significantly improved glycemic control and a reduction in hypoglycemia rate during 12 months of follow-up in Japanese patients with T2D, including those aged > 75 years.

Introduction: 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)., Methods: 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., Results: 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., Conclusions: 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.

Background: No case definition of Type 1 diabetes (T1D) for the claims data has been proposed in Japan yet. This study aimed to evaluate the performance of candidate case definitions for T1D using Electronic health care records (EHR) and claims data in a University Hospital in Japan., Methods: The EHR and claims data for all the visiting patients in a University Hospital were used. As the candidate case definitions for claims data, we constructed 11 definitions by combinations of International Statistical Classification of Diseases and Related Health Problems, Tenth Revision. (ICD 10) code of T1D, the claims code of insulin needles for T1D patients, basal insulin, and syringe pump for continuous subcutaneous insulin infusion (CSII). We constructed a predictive model for T1D patients using disease names, medical practices, and medications as explanatory variables. The predictive model was applied to patients of test group (validation data), and performances of candidate case definitions were evaluated., Results: As a result of performance evaluation, the sensitivity of the confirmed disease name of T1D was 32.9 (95% CI: 28.4, 37.2), and positive predictive value (PPV) was 33.3 (95% CI: 38.0, 38.4). By using the case definition of both the confirmed diagnosis of T1D and either of the claims code of the two insulin treatment methods (i.e., syringe pump for CSII and insulin needles), PPV improved to 90.2 (95% CI: 85.2, 94.4)., Conclusions: We have established a case definition with high PPV, and the case definition can be used for precisely detecting T1D patients from claims data in Japan.

Introduction: Determinants and correlates of a novel index of adipose tissue insulin resistance (AT-IR) (the product of fasting insulin and free fatty acid concentrations) were investigated in Japanese women without diabetes and obesity., Research Design and Methods: Cross-sectional associations of AT-IR with fat mass and distribution, and IR-related cardiometabolic variables were examined in 210 young and 148 middle-aged women whose average body mass index (BMI) was <23 kg/m 2 and waist was <80 cm. Multivariate linear regression analyses were used to identify most important determinants of AT-IR., Results: Young and middle-aged women did not differ in AT-IR (3.5±2.7 and 3.2±2.1, respectively). In both young and middle-aged women, AT-IR was positively associated with trunk/leg fat ratio, a sophisticated measure of abdominal fat accumulation, fasting plasma glucose (FPG), fasting triglycerides (FTG), serum alanine aminotransferase and γ-glutamyl-transpeptidase (all p<0.05). Furthermore, in middle-aged but not in young women, AT-IR showed positive associations with BMI, waist, fat mass index, low-density lipoprotein cholesterol, apolipoprotein B and systolic and diastolic blood pressure (BP) (all p<0.05). AT-IR showed no association with hemoglobin A1c, high-density lipoprotein (HDL) cholesterol and apolipoprotein A1 in two groups of women. On multivariate analysis including waist, FPG, FTG, HDL cholesterol and systolic BP as independent variables, FPG, FTG and HDL cholesterol emerged as independent determinants of AT-IR in young women (cumulative R 2 =0.141) and waist in middle-aged women (cumulative R 2 =0.056). In a model which included trunk/leg fat ratio instead of waist, trunk/leg fat ratio and systolic BP were determinants of AT-IR in middle-aged women (cumulative R 2 =0.093). Results did not alter in young women., Conclusions: AT-IR may be a simple and useful surrogate index of adipose tissue insulin resistance even in populations without diabetes and obesity., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims/introduction: The incidence of severe hypoglycemia and its risk factors including an insulin-sensitizing adipokine, adiponectin, were prospectively investigated in Japanese patients with type 1 or insulin-treated type 2 diabetes., Materials and Methods: A total of 207 participants with type 1 diabetes (mean age 55 years) and 1,396 with insulin-treated type 2 diabetes (mean age 65 years) from the local diabetes registry were followed for 5 years (follow-up rate 99%). Severe hypoglycemia was defined as events requiring the assistance of others for recovery from hypoglycemia., Results: The incidence of severe hypoglycemia was 9.2 per 100 person-years in those with type 1 diabetes, and 2.3 per 100 person-years in those with insulin-treated type 2 diabetes, respectively. For type 1 diabetes, the risk was significant in those with a history of severe hypoglycemia within the previous year, slow eating and higher serum adiponectin (the highest vs the lowest in quartile hazard ratio 2.36, 95% confidence interval 1.22-4.69). For insulin-treated type 2 diabetes, the risk included age ≥65 years, history of severe hypoglycemia within the previous year, alcohol consumption ≥60 g/day, larger insulin dose and higher serum adiponectin (the highest vs the lowest in quartile, hazard ratio 2.95, 95% confidence interval 1.22-4.69). For all participants, the incidence of severe hypoglycemia increased along with serum adiponectin (age- and sex-adjusted hazard ratio 1.65 per 1 standard deviation increase of log serum adiponectin, 95% confidence interval 1.45-1.87)., Conclusions: The incidence of severe hypoglycemia was prospectively determined, and the association between severe hypoglycemia and higher serum adiponectin was observed in Japanese patients with type 1 and insulin-treated type 2 diabetes., (© 2020 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Aims/objectives: Glycemic control varies according to stress level and the efficacy of control measures, affecting the outcomes of diabetes. Although detailed coping styles have not been well studied in patients with type 2 diabetes mellitus, problem-focused coping strategies are believed to be related to better control of blood glucose. Associations between coping profiles/dimensions and blood glucose control were examined in individuals with type 2 diabetes., Materials and Methods: The participants included 503 Japanese patients (mean age 63.9 ± 12.6 years) with type 2 diabetes. The average glycated hemoglobin A1c (HbA1c) levels were calculated from HbA1c levels measured more than four times within the 12 months before the assessment. Coping profiles were assessed using the Brief Scale for Coping Profile. Lifestyle factors were also included in the analyses., Results: Factors other than age were not associated with HbA1c levels in patients who used insulin. Conversely, habitual alcohol consumption, single status, the adaptive emotion-focused coping dimension, and changing mood and changing one's point of view profiles were associated with HbA1c levels., Conclusions: These findings suggest that adaptive emotion-focused coping supports glycemic control in type 2 diabetes patients who do not use insulin. Additional studies using a longitudinal design are required to further examine the relationships between psychological factors and glycemic control., (© 2020 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

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 <10%., Results: Seventy-five patients with T1DM (n = 34) or T2DM (n = 41) were enrolled; 72 patients (50 men, 22 women) received ≥1 study drug dose (T1DM, n = 33; T2DM, n = 39). Sixty-eight patients completed the study and were evaluable. All NG- and IMG-treated patients achieved treatment success (treatment arm difference: 0%; upper limit of two-sided 95% CI 1.47%); NG met prespecified conditions defining non-inferiority versus IMG. Glucagon was rapidly absorbed after both nasal and intramuscular administration; PG profiles were similar between administration routes during the first 60 minutes post dose. Study drug-related treatment-emergent adverse events affecting >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., (© 2020 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Introduction: The aim of the present study was to assess the long-term (52-week) efficacy and safety of ipragliflozin in insulin-treated Japanese patients with type 1 diabetes mellitus and inadequate glycemic control., Materials and Methods: In this 28-week, open-label extension of a multicenter, randomized, placebo-controlled, 24-week phase III study, ipragliflozin recipients continued treatment (50 mg, once daily), and placebo recipients were switched to once-daily 50 mg ipragliflozin at the start of the extension period. The ipragliflozin dose could be increased to 100 mg if warranted. The primary end-point was change in glycated hemoglobin; secondary end-points were change in insulin dose and bodyweight. Safety outcomes were monitored as treatment-emergent adverse events., Results: A total of 53 (placebo switched to ipragliflozin) and 108 (ipragliflozin) patients completed the open-label extension (treatment period 2), with 24 and 44 patients, respectively, receiving dose increases. From baseline to end of treatment, the overall mean change (standard deviation [SD]) in glycated hemoglobin was -0.33% (0.72; -3.7 mmol/mol [7.9]), with changes in basal, bolus and total insulin doses of -3.76 IU (SD 3.85 IU), -2.51 IU (SD 7.08 IU) and -6.27 IU (SD 8.16 IU), respectively. No serious drug-related treatment-emergent adverse events or deaths were reported. Treatment-emergent adverse events leading to study discontinuation occurred in zero and three (2.6%) patients in the placebo switched to ipragliflozin and ipragliflozin groups, respectively; all were considered drug-related. There were no cases of severe hypoglycemia or diabetic ketoacidosis, and no safety concerns related to dose increase., Conclusions: The efficacy and safety of 50 mg, once-daily ipragliflozin in insulin-treated type 1 diabetes mellitus patients were confirmed in this long-term, open-label extension study. No safety concerns were attributed to a dose increase to 100 mg., (© 2019 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Aims/introduction: Ultra-rapid lispro (URLi) is a novel ultra-rapid mealtime insulin. This study compared the pharmacokinetic and glucodynamic profiles, safety, and tolerability of URLi and lispro (Humalog ® ) in Japanese patients with type 1 diabetes mellitus., Materials and Methods: This was a phase I, single center, randomized, patient- and investigator-blind, two-period, cross-over study. A total of 31 patients received a single subcutaneous 15-U dose of URLi or lispro before undergoing a euglycemic clamp procedure. Primary pharmacokinetic endpoints were the time to early half-maximal drug concentration and the area under the concentration versus time curve from 0 to 30 min postdose. The glucodynamic endpoints were the time to early half-maximal glucose infusion rate before time to maximum glucose infusion rate, and the time to onset of insulin action., Results: URLi showed accelerated insulin lispro absorption compared with lispro, as shown by a decrease of 56% (URLi: 10.2 min, lispro: 23.3 min; P < 0.0001) in the early half-maximal drug concentration, and a 2.4-fold increase in the area under the concentration versus time curve from 0 to 30 min (P < 0.0001). The duration of insulin lispro exposure was 88 min shorter after URLi administration compared with lispro. URLi reduced the early half-maximal glucose infusion rate before time to maximum glucose infusion rate and the time to onset of insulin action significantly compared with lispro. The glucose infused within the first 30 min of the clamp was 2.16-fold greater with URLi compared with lispro. There was no difference in total exposure or glucose infused between treatments. All treatment-emergent adverse events were mild/moderate in severity., Conclusions: In Japanese type 1 diabetes mellitus patients, URLi showed accelerated insulin lispro absorption, reduced late exposure, overall shorter duration and faster early insulin action compared with lispro., (© 2019 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Aim: To assess the efficacy and safety of empagliflozin as add-on to insulin in Japanese patients with type 2 diabetes (T2D)., Materials and Methods: This multicentre, double-blind, parallel-group study randomized Japanese patients with T2D insufficiently controlled with insulin (1:1:1) to empagliflozin 10 mg (n=89), empagliflozin 25 mg (n=90) or placebo (n=90) for 52 weeks. The primary endpoint was change from baseline in glycated haemoglobin (HbA1c) at 16 weeks., Results: At 16 weeks, empagliflozin 10 mg and 25 mg significantly decreased HbA1c: adjusted mean difference -0.92% (95% confidence interval [CI] -1.11, -0.73) and -1.00% (95% CI -1.18, -0.82; both P<0.0001) compared with placebo. This difference was maintained up to 52 weeks: adjusted mean difference at 52 weeks -0.90% (95% CI -1.09, -0.70) and -0.96% (95% CI -1.15, -0.77; both P<0.0001). At 52 weeks, significant improvements in fasting plasma glucose (adjusted mean difference -27.62 mg/dL [95% CI -36.15, -19.08] and -31.99 mg/dL [95% CI -40.35, -23.62]) and in body weight (-1.78 kg [95% CI -2.46, -1.10] and -1.92 kg [95% CI -2.58, -1.25]) were also seen with empagliflozin 10 mg and 25 mg compared with placebo (all P<0.0001). At 52 weeks, the frequency of adverse events (AEs) and serious AEs was similar in the three treatment groups; confirmed hypoglycaemia was reported slightly more in participants in the empagliflozin 10 mg and 25 mg groups (23.3% and 22.2% vs 14.4%). All hypoglycaemic events were mild in severity; no episodes required assistance., Conclusions: In Japanese patients with insufficiently controlled T2D, adding empagliflozin 10 mg or 25 mg to insulin treatment was associated with clinically meaningful reductions in HbA1c at 16 weeks and was generally well tolerated., (© 2019 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

For the increasing number of type 1 diabetes in Japan, after 1960, a greater supply of insulin was required, accordingly the availability of insulin gradually improved, The National Health Insurance approved self-injections of insulin at home in 1981. Afterwards, intensive insulin treatment with short-acting insulin and intermediate-acting insulin became widely used. Recombinant rapid-acting insulin analog was introduced in 1986 and long-acting insulin analog was introduced in 2003. In recent years, basal-bolus insulin regimens using these insulin analogs have become popular in children and adolescents with type 1 diabetes in Japan, which can improve the metabolic state and quality of life. This also will contribute to prevent the occurrence and progression of micro- and macro-vascular complications later in life., (Copyright© of YS Medical Media ltd.)

Aim: Support for elderly patients using insulin to continue self-injection safely is required for clinical settings. The aim of this study was 1) to clarify the actual state of self-injection procedures for elderly people injecting insulin and 2) to verify whether or not the injection procedures can be improved by nurses' medical treatment instructions., Subjects and Methods: The subjects were outpatients at an educational facility certified by the Japan Diabetes Society. Basic clinical characteristics, the Mini-Cog cognitive function test, basic ADL and instrumental ADL, and 24 items of the self-injection procedure were evaluated by nurses. After receiving a 30-minute face-to-face session of individual instructions from trained nurses two or more times, the injection procedure was re-evaluated., Results: Of the 63 study subjects, 10 were injecting insulin with the support of others (supported injection group). The median age in the self-injection group was 72 years old, while that in the supported injection group was 82 years old. The supported injection group was older, the female ratio higher, and the Mini-Cog and ADL indices lower than in the self-injection group (p <0.05). The median history of the use of insulin was over 10 years in both groups. In the self-injection group, the degree of proficiency with the injection technique was significantly improved after receiving the instructions (p <0.05). The biggest improvement was in response to the question, "Do you know that you need to shift the site of injections?", which doubled (p <0.05). The correct answer rate for "Do you know the name of your insulin formulation?" was less than half, and it remained unchanged even after receiving instructions. In the supported injection group, 90% had a Mini-Cog of ≤2 points, but 6 subjects (60%) were able to perform an injection by themselves with others supporting the adjustments made to the amount of insulin., Conclusions: The self-injection technique improved significantly, even in elderly people, following the delivery of medical treatment instructions by nurses, and the item with the highest improvement effect was subjects' understanding of the need to shift the injection site. Our study showed that even in elderly people with cognitive dysfunction who are performing injections with the support of others, some of the injection procedures were retained by relying on procedural memory acquired in the past.

Clinical predictors for later adverse cardiovascular events in patients undergoing percutaneous coronary intervention (PCI) for silent myocardial ischemia remain undetermined. We investigated clinical features leading to later adverse cardiovascular events in patients who underwent PCI for silent myocardial ischemia. Of a total of 294 consecutive patients with a diagnosis of silent myocardial ischemia who successfully underwent contemporary PCI in our institute between January 2013 and December 2014, an initial event of any of all-cause death, hospitalized heart failure, acute coronary syndromes, and target vessel revascularization were identified as later adverse cardiovascular events and evaluated an association of them with baseline clinical characteristics. Silent myocardial ischemia was defined by an assessment of either electrocardiogram, myocardial perfusion imaging, coronary angiogram, or coronary fractional flow reserve. During a median follow-up of 565 days (interquartile range 361-816), later adverse cardiovascular events were identified in 38 patients (13%) consisting of 6 deaths, 5 hospitalized heart failures, 2 acute coronary syndromes, and 25 target vessel revascularizations. A presence of chronic kidney disease and/or insulin-treated diabetes mellitus, but not other clinical features, was strongly associated with later adverse cardiovascular events (hazard ratio 8.22; 95% confidential interval 2.95-29.25, P < 0.0001). Those events were increased in accordance with advanced stages of chronic kidney disease (P = 0.0003). A presence of chronic kidney disease and/or insulin-treated diabetes mellitus may lead the potential after-effects of PCI in the treatment of silent myocardial ischemia.

Aims/introduction: Gestational diabetes mellitus (GDM) is a risk for adverse perinatal outcomes, and patients with a history of GDM have an increased risk of impaired glucose tolerance (IGT). Here, we carried out two non-interventional and retrospective studies of GDM patients in Japan., Materials and Methods: In the first study, we enrolled 529 GDM patients and assessed predictors of the need for insulin therapy. In the second study, we enrolled 185 patients from the first study, and assessed predictors of postpartum IGT., Results: In the first study, gestational weeks at GDM diagnosis and history of pregnancy were significantly lower, and pregestational body mass index, family history of diabetes mellitus, 1- and 2-h glucose levels in a 75-g oral glucose tolerance test (OGTT), the number of abnormal values in a 75-g OGTT, and glycated hemoglobin were significantly higher in participants receiving insulin therapy. In the second study, 1- and 2-h glucose levels in a 75-g OGTT, the number of abnormal values in a 75-g OGTT, glycated hemoglobin, and ketone bodies in a urine test were significantly higher in participants with OGT. Logistic regression analysis showed that gestational weeks at GDM diagnosis, 1-h glucose levels in a 75-g OGTT and glycated hemoglobin were significant predictors of the need for insulin therapy, and 1-h glucose levels in a 75-g OGTT at diagnosis and ketone bodies in a urine test were significant predictors for postpartum IGT., Conclusions: Antepartum 1-h glucose levels in a 75-g OGTT was a predictor of the need for insulin therapy in pregnancy and postpartum IGT., (© 2018 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD).)

It has been reported that glucose responses during the oral glucose tolerance test differ between healthy women and men. However, it remains unknown what factors contribute to these differences between the sexes. The present study analyzed the insulin and glucagon responses during the oral glucose tolerance test in 25 female and 38 male healthy young adults aged 22-30 years. The plasma glucose levels at 120 min were significantly higher in women than men. Insulin secretion was significantly greater at 30, 90 and 120 min from baseline in women than men. Glucagon suppression was greater at 30 and 120 min from baseline in men than women when determined by a sandwich enzyme-linked immunosorbent assay glucagon kit. These results suggest that the differences in glucose responses during the oral glucose tolerance test are mediated by the difference between the sexes in bi-hormonal responses in healthy individuals., (© 2018 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Objective: Memantine, a drug for Alzheimer's disease, is considered to suppress excessive stimulation of N-methyl-D-aspartic acid receptors and to prevent neuronal death. However, a recent report indicated that the neuronal K ATP channel also can become a target of memantine. The K ATP channel is a key regulator of insulin secretion in pancreatic β cells. Therefore, if memantine could inhibit the K ATP channel in pancreatic β cells, it would be an effective drug for both Alzheimer's disease and diabetes. However, there is no report on the effect of memantine on the K ATP channel in pancreatic β cells. Therefore, we investigated whether memantine affect the blood glucose level, insulin secretion and K ATP channel activity in pancreatic β cells., Results: An intraperitoneal glucose tolerance test was performed with or without memantine (1 mg/kg) injection in intact mice. Insulin secretion from isolated islets was measured under low (2 mM) and high (20 mM) glucose concentrations with or without memantine (1 μM). The effect of memantine (1 μM) on K ATP channel currents in isolated pancreatic β cells was recorded using the whole-cell patch-clamp technique. Memantine had no effect on the blood glucose level, insulin secretion from isolated islets or K ATP channel current in pancreatic β cells.

Aims/introduction: To determine the efficacy and safety of adding liraglutide to three different insulin regimens in Japanese patients with type 2 diabetes mellitus., Materials and Methods: In this post-hoc analysis, results from a 36-week, randomized, double-blind, placebo-controlled, parallel-group trial are reported. Individuals with type 2 diabetes mellitus were stratified according to their pre-trial insulin regimen (basal, basal-bolus and premix). The primary objective was to determine whether adding liraglutide (0.9 mg/day) to fixed-dose insulin therapy was superior vs fixed-dose insulin monotherapy, assessed by the effect on glycemic control after 16 weeks of treatment., Results: The treatment effect on glycated hemoglobin reduction was independent of the pre-trial insulin regimen. Comparing liraglutide with a placebo, liraglutide was associated with glycated hemoglobin reduction in all insulin regimens, with placebo-corrected reductions at 16 weeks ranging from -1.45 to -1.17%, and maintained at 36 weeks. Liraglutide resulted in a greater reduction in mean plasma glucose obtained from seven-point self-monitoring, and greater proportions of patients achieved target glycated hemoglobin. With liraglutide, slightly higher proportions of patients receiving basal and basal-bolus insulin reported confirmed hypoglycemia from 0 to 16 weeks., Conclusions: The efficacy and safety of adding liraglutide to insulin therapy was confirmed, regardless of pre-trial insulin regimen., (© 2017 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Aims/introduction: Sodium glucose cotransporter 2 (SGLT2) inhibitors are a new class of drugs for the treatment of type 2 diabetes mellitus that improve control of plasma glucose and bodyweight, giving great hope for the clinical utility of these agents. However, it is unclear for which patients SGLT2 inhibitors will be useful., Materials and Methods: We analyzed data from long-term tofogliflozin monotherapy in an open-label, randomized controlled trial in Japanese patients with type 2 diabetes mellitus. Patients were divided into tertiles by baseline insulin level: group low (L): insulin ≤5.6 μU/mL, group medium (M): 5.6< insulin ≤10 μU/mL and group high (H): insulin >10 μU/mL., Results: Glycated hemoglobin and fasting plasma glucose levels, along with bodyweight, were significantly reduced from the baseline in all groups. The changes in levels of plasma glucose area under the curve for 2 h, C-peptide index area under the curve for 2 h during the meal tolerance tests and the insulin secretion index were the largest in the H group. The incidence of drug-related adverse events was not different among the three groups., Discussion: Although tofogliflozin was effective regardless of baseline insulin level, it showed the highest efficacy in the H group., (© 2017 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Objective: To evaluate the efficacy and safety of luseogliflozin in Japanese patients with type 2 diabetes (T2D) inadequately controlled with insulin monotherapy., Methods: This 52-week multicenter study entailed a 16-week, double-blind period followed by a 36-week, open-label period. Patients were randomized to receive either luseogliflozin 2.5 mg (n = 159) or placebo (n = 74) during the double-blind period. All patients who entered the open-label period received luseogliflozin. Major efficacy endpoints included the changes from baseline in HbA1c, fasting plasma glucose (FPG), postprandial plasma glucose (PPG) and bodyweight. Safety assessments included adverse events, laboratory tests and vital signs., Results: In the double-blind period, luseogliflozin significantly decreased HbA1c (-1.18%), FPG (-42.4 mg/dL), 2 hour PPG (-68.7 mg/dL) and bodyweight (-1.27 kg) compared with placebo (all p < .001); these reductions were maintained over 52 weeks. The changes from baseline at Week 52 were -1.00%, -35.1 mg/dL, -68.8 mg/dL and -1.81 kg, respectively (all p < .001). In the placebo group, favorable glycemic control and bodyweight reduction were also observed after switching to luseogliflozin. Most adverse events were mild in severity. During the double-blind period, the incidences of hypoglycemia were 20.8% and 13.5% in the luseogliflozin and placebo groups, respectively. During the 52 weeks of luseogliflozin treatment, the frequency of hypoglycemia was 33.3%, but no serious hypoglycemia occurred. The safety profile other than hypoglycemia was also acceptable. There were no new safety concerns about luseogliflozin added to insulin., Conclusion: Luseogliflozin added to insulin therapy significantly improved glycemic control with bodyweight reduction and was well tolerated in Japanese patients with T2D., Clinical Trial Registration: Japan Pharmaceutical Information Center (JapicCTI-142582).

Aim: The aim of this study was to assess the long-term efficacy and safety of canagliflozin as add-on therapy in Japanese patients with type 2 diabetes mellitus who had inadequate glycaemic control with insulin., Materials and Methods: The study comprised a 16-week, double-blind period in which patients were randomized to either placebo (P; N = 70) or canagliflozin (100 mg, CAN; N = 76), followed by a 36-week open-label period in which all patients received canagliflozin. The efficacy endpoints included the change in HbA1c from baseline to end of treatment. The safety endpoints were adverse events, hypoglycaemic events, and laboratory test values., Results: The changes from baseline (mean ± standard deviation, last observation carried forward) in the P/CAN and CAN/CAN groups, respectively, were -1.09% ± 0.85% and -0.88% ± 0.86% for HbA1c, -1.40% ± 2.54% and -2.14% ± 2.75% for body weight, and 7.84% ± 14.37% and 8.91% ± 10.80% for HOMA2-%B (all, P < .001). Adverse events occurred in 85.1% of the P/CAN group and 92.0% of the CAN/CAN group. Hypoglycaemic events occurred in 43.3% and 54.7%, respectively. All hypoglycaemic events were mild in severity and insulin dose reduction decreased the incidence rate of hypoglycaemic events. Post-hoc ordinal logistic modelling/logistic modelling showed that lower serum C-peptide at Week 0 was a risk factor for hypoglycaemia in both the P and CAN groups in the double-blind period as well as in the canagliflozin all-treatment period., Conclusions: This study demonstrates the long-term efficacy and safety of canagliflozin combined with insulin in Japanese patients., (© 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

We attempted to identify the predictors of an inadequate hypoglycemia in insulin tolerance test (ITT), defined as a blood glucose level higher than 2.8 mmol/L after insulin injection, in Japanese patients with suspected or proven hypopituitarism. A total of 78 patients who had undergone ITT were divided into adequate and inadequate hypoglycemia groups. The relationships between the subjects' clinical parameters and inadequate hypoglycemia in ITT were analyzed. Stepwise logistic regression analysis identified high systolic blood pressure (SBP) and high homeostasis model assessment of insulin resistance (HOMA-IR) as being independent factors associated with inadequate hypoglycemia in ITT. Receiver operating characteristic (ROC) curve analysis revealed the cutoff value for inadequate hypoglycemia was 109 mmHg for SBP and 1.4 for HOMA-IR. The areas under ROC curve for SBP and HOMA-IR were 0.72 and 0.86, respectively. We confirmed that high values of SBP and HOMA-IR were associated with inadequate hypoglycemia in ITT, regardless of the degree of reduction of pituitary hormone levels. Furthermore, the strongest predictor of inadequate hypoglycemia was obtained by using the cutoff value of HOMA-IR. Our results suggest that HOMA-IR is a useful pre-screening tool for ITT in these populations.

Aims: To evaluate the efficacy and safety of dapagliflozin as add-on to insulin in Japanese patients with type 2 diabetes., Materials and Methods: Insulin-treated Japanese patients were randomized to 5 mg dapagliflozin or placebo during a 16-week double-blind treatment period. Both groups then received dapagliflozin 5 or 10 mg (the dose was increased at or after week 24 if glycated haemoglobin [HbA1c] at the previous visit was >7.5%) during a 36-week open-label extension period. The exploratory efficacy endpoint was to assess the maintenance efficacy of 5/10 mg dapagliflozin + insulin over 52 weeks of treatment. Safety was assessed in terms of adverse events, laboratory variables and vital signs., Results: The changes in HbA1c from baseline to weeks 16 and 52 were -0.62% and -0.74%, respectively, in the dapagliflozin group, vs -0.08% and -0.83%, respectively, in the placebo-dapagliflozin group. Body weight decreased at both time points in the dapagliflozin group and after switching to open-label dapagliflozin in the placebo-dapagliflozin group. The total insulin dose decreased slightly after starting dapagliflozin. Adverse events occurred in 82.9% and 71.7% of patients in the dapagliflozin and placebo-dapagliflozin groups, respectively. Hypoglycaemia occurred in 35.0% and 41.7% of patients in the dapagliflozin and placebo-dapagliflozin groups, respectively, but the incidence was not increased by use of dapagliflozin in either trial period. Genital/urinary tract infections, renal impairment/failure, volume depletion, fracture and hepatic disorders occurred in ≤5% of patients., Conclusion: This trial showed that administration of dapagliflozin as an add-on to insulin therapy was effective, was well tolerated and had insulin-sparing effects in Japanese patients with type 2 diabetes., (© 2016 John Wiley & Sons Ltd.)

Introduction: The present study aimed to evaluate the pharmacokinetic and pharmacodynamic properties of insulin degludec (IDeg) in Japanese patients with type 1 diabetes., Materials and Methods: This was a randomized, single-center, double-blind, two-period, crossover, multiple-dose trial. Patients were randomized into two treatment sequences, and received IDeg or insulin detemir for 6 days and a washout period (7-21 days) before switching treatment. Blood samples for pharmacokinetic measurements were obtained before each dose and up to 120 h after the last dose of each treatment period. Pharmacodynamic measurements were obtained using a 26-h euglycemic clamp procedure after the last dose of each treatment period., Results: A total of 22 patients were randomized (14 men, 8 women; mean glycosylated hemoglobin at baseline of 7.5% [based on Japanese Diabetes Society value]). At steady state, total glucose-lowering effect (area under the glucose infusion rate [GIR] curve during one dosing interval [τ, 0-24 h] at steady state [AUCGIR ,τ, SS]) was 1,446 mg/kg and total exposure (geometric mean) of IDeg (AUCID eg,τ, SS) was 81,270 pmol h/L. Both the glucose-lowering effect and the exposure of IDeg were evenly distributed over the dosing interval, with AUC for the first 12-h intervals being approximately 50% of the total (geometric mean; AUCGIR ,0-12h, SS/AUCGIR ,τ, SS = 48%; AUCID eg,0-12h, SS/AUCID eg,τ, SS = 53%)., Conclusions: IDeg has a flat, consistent and ultra-long glucose-lowering effect that is evenly distributed across a 24-h interval and an ultra-long duration of action in Japanese patients with type 1 diabetes. These data support once-daily dosing of IDeg in all patients. Overall, the pharmacodynamic and pharmacokinetic end-points and safety observations are consistent with those previously reported in Caucasian patients.