A consensus statement from the Japan Diabetes Society: A proposed algorithm for pharmacotherapy in people with type 2 diabetes - 2nd edition (English version).

This algorithm was issued for the appropriate use of drugs for the treatment of type 2 diabetes mellitus in Japan. The revisions include safety considerations, fatty liver disease as a comorbidity to be taken into account and the position of tirzepatide.

Body mass index stratification optimizes polygenic prediction of type 2 diabetes in cross-biobank analyses.

Type 2 diabetes (T2D) shows heterogeneous body mass index (BMI) sensitivity. Here, we performed stratification based on BMI to optimize predictions for BMI-related diseases. We obtained BMI-stratified datasets using data from more than 195,000 individuals (nT2D = 55,284) from BioBank Japan (BBJ) and UK Biobank. T2D heritability in the low-BMI group was greater than that in the high-BMI group. Polygenic predictions of T2D toward low-BMI targets had pseudo-R2 values that were more than 22% higher than BMI-unstratified targets. Polygenic risk scores (PRSs) from low-BMI discovery outperformed PRSs from high BMI, while PRSs from BMI-unstratified discovery performed best. Pathway-specific PRSs demonstrated the biological contributions of pathogenic pathways. Low-BMI T2D cases showed higher rates of neuropathy and retinopathy. Combining BMI stratification and a method integrating cross-population effects, T2D predictions showed greater than 37% improvements over unstratified-matched-population prediction. We replicated findings in the Tohoku Medical Megabank (n = 26,000) and the second BBJ cohort (n = 33,096). Our findings suggest that target stratification based on existing traits can improve the polygenic prediction of heterogeneous diseases.

Efficacy of Self-Review of Lifestyle Behaviors with Once-Weekly Glycated Albumin Measurement in People with Type 2 Diabetes: A Randomized Pilot Study.

INTRODUCTION: Lifestyle management, including appropriate modifications of nutrition, exercise, and medication behaviors, is essential for optimal glycemic control. The absence of appropriate monitoring methods to validate the lifestyle change may hinder the modification and continuation of behaviors. In this study, we evaluated whether once-weekly glycated albumin (GA) measurement received via a smartphone application could improve glycemia management in patients with type 2 diabetes mellitus by supporting self-review and modification of lifestyle behaviors. METHODS: This open-label, randomized controlled, single-center study in Japan with an 8-week intervention period was conducted in individuals with type 2 diabetes mellitus and HbA1c levels between 7.0 and 9.0% (53‒75 mmol/mol). The intervention was once-weekly home monitoring of GA with a daily self-review of lifestyle behaviors using a smartphone application, in addition to conventional treatment. RESULTS: A total of 98 participants (72.0% males; age 63.2 ± 11.4 years; HbA1c 7.39 ± 0.39% [57.3 ± 4.3 mmol/mol]) were randomly assigned to the intervention or control group. Significant decreases of the GA and HbA1c levels from the baseline to the last observation day were observed in the intervention group (- 1.71 ± 1.37% [- 39.1 ± 31.3 mmol/mol] and - 0.32 ± 0.32% [- 3.5 ± 3.5 mmol/mol], respectively). Significant decreases of the body weight, waist circumference, and caloric expenditure (p < 0.0001 and p = 0.0003, p = 0.0346, respectively), but not of the caloric intake (p = 0.678), were also observed in the intervention group as compared with the control group. CONCLUSIONS: Self-review of lifestyle behaviors in combination with once-weekly GA home testing received via a smartphone application might potentially benefit glycemic management in people with type 2 diabetes mellitus. TRIAL REGISTRATION: jRCTs042220048.

Effectiveness of DialBetesPlus, a self-management support system for diabetic kidney disease: Randomized controlled trial.

We evaluated the effectiveness of a mobile health (mHealth) intervention for diabetic kidney disease patients by conducting a 12-month randomized controlled trial among 126 type 2 diabetes mellitus patients with moderately increased albuminuria (urinary albumin-to-creatinine ratio (UACR): 30-299 mg/g creatinine) recruited from eight clinical sites in Japan. Using a Theory of Planned Behavior (TPB) behavior change theory framework, the intervention provides patients detailed information in order to improve patient control over exercise and dietary behaviors. In addition to standard care, the intervention group received DialBetesPlus, a self-management support system allowing patients to monitor exercise, blood glucose, diet, blood pressure, and body weight via a smartphone application. The primary outcome, change in UACR after 12 months (used as a surrogate measure of renal function), was 28.8% better than the control group's change (P = 0.029). Secondary outcomes also improved in the intervention group, including a 0.32-point better change in HbA1c percentage (P = 0.041). These improvements persisted when models were adjusted to account for the impacts of coadministration of drugs targeting albuminuria (GLP-1 receptor agonists, SGLT-2 inhibitors, ACE inhibitors, and ARBs) (UACR: -32.3% [95% CI: -49.2%, -9.8%] between-group difference in change, P = 0.008). Exploratory multivariate regression analysis suggests that the improvements were primarily due to levels of exercise. This is the first trial to show that a lifestyle intervention via mHealth achieved a clinically-significant improvement in moderately increased albuminuria.

Implementation rate of diabetic self-management education and support for Japanese people with diabetes using the National Database.

People with diabetes are encouraged to receive diabetes self-management education and support (DSMES) appropriately. However, in Japan, the implementation rates of DSMES are not known. DSMES implementation rates were calculated using the National Database of claims data, which included nearly all insurance-covered medical procedures. The study enrolled participants who received regular antidiabetic medications between April 2017 and March 2018. The implementation rates of DSMES-related care were calculated by characteristics, visiting medical facilities and prefectures. In 4,465,513 participants receiving antidiabetic medications (men, 57.8%; insulin use, 14.1%), nutrition guidance (5.6%) was the most frequently provided care type. Insulin users and participants visiting Japan Diabetes Society-certified and large medical institutions had higher implementation rates of nutrition guidance. DSMES-related care might not be provided adequately for Japanese people with diabetes. Further studies are needed to develop an optimal diabetes care system.

Decreased AdipoR1 signaling and its implications for obesity-induced male infertility.

Obesity is among the risk factors for male infertility. Although several mechanisms underlying obesity-induced male subfertility have been reported, the entire mechanism of obesity-induced male infertility still remains unclear. Here, we show that sperm count, sperm motility and sperm fertilizing ability were decreased in male mice fed a high-fat diet and that the expression of the AdipoR1 gene and protein was decreased, and the expression of pro-apoptotic genes and protein increased, in the testis from mice fed a high-fat diet. Moreover, we demonstrate that testes weight, sperm count, sperm motility and sperm fertilizing ability were significantly decreased in AdipoR1 knockout mice compared to those in wild-type mice; furthermore, the phosphorylation of AMPK was decreased, and the expression of pro-apoptotic genes and proteins, caspase-6 activity and pathologically apoptotic seminiferous tubules were increased, in the testis from AdipoR1 knockout mice. Furthermore, study findings show that orally administrated AdipoRon decreased caspase-6 activity and apoptotic seminiferous tubules in the testis, thus ameliorating sperm motility in male mice fed a high-fat diet. This was the first study to demonstrate that decreased AdipoR1/AMPK signaling led to increased caspase-6 activity/increased apoptosis in the testis thus likely accounting for male infertility.

Modification effect of receipt of diabetes care on the association between COVID-19 infection and HbA1c level during the first year of the coronavirus pandemic using a nationwide population-based database.

AIMS/INTRODUCTION: We assessed the modification effect of adherence to diabetes care on the association between HbA1c levels and the risk of coronavirus disease 2019 (COVID-19) among individuals with diabetes using a population-based database. MATERIAL AND METHODS: We retrospectively identified individuals with diabetes during routine health checkups performed in 2019 in Japan using a population-based claims database (JMDC, Tokyo, Japan). We assessed the risk of COVID-19 infection in 2020 in relation to HbA1c levels during routine checkups, stratified by the presence/absence of follow-up for diabetes care in 2019. Several sensitivity analyses were performed. RESULTS: We identified 65,956 individuals with an HbA1c ≥6.5% and fasting glucose ≥126 mg/dL in routine checkups, including 52,637 and 13,319 with and without at least one physician consultation for diabetes care in 2019, respectively. Although high HbA1c levels were associated with an increased risk of COVID-19 infection in a dose-dependent manner among individuals without diabetes care in 2019 (odds ratios, 1.53 and 2.17 in individuals with HbA1c of 7.0-7.9% and ≥8.0%, respectively) with a reference to HbA1c of 6.5-6.9%, individuals with diabetes care had no such trend in 2019 (odds ratios, 0.99 and 0.97 among individuals with HbA1c of 7.0-7.9% and ≥8.0%, respectively). Sensitivity analyses yielded consistent results when the variable definitions were changed and after multivariable adjustment with multiple imputation. CONCLUSIONS: This population-based study suggests that adherence to diabetes care may modify the association between HbA1c levels and the risk of COVID-19 infection.

Efficacy of StepAdd, a Personalized mHealth Intervention Based on Social Cognitive Theory to Increase Physical Activity Among Patients With Type 2 Diabetes Mellitus: Protocol for a Randomized Controlled Trial.

BACKGROUND: Increasing physical activity improves glycemic control in patients with type 2 diabetes (T2D). Mobile health (mHealth) interventions have been proven to increase exercise, but engagement often fades with time. As the use of health behavior theory in mHealth design can increase effectiveness, we developed StepAdd, an mHealth intervention based on the constructs of social cognitive theory (SCT). StepAdd improves exercise behavior self-efficacy and self-regulation through the use of goal-setting, barrier-identifying, and barrier-coping strategies, as well as automatic feedback functions. A single-arm pilot study of StepAdd among 33 patients with T2D showed a large increase in step count (mean change of 4714, SD 3638 daily steps or +86.7%), along with strong improvements in BMI (mean change of -0.3 kg/m2) and hemoglobin A1c level (mean change of -0.79 percentage points). OBJECTIVE: In this study, we aim to investigate the efficacy and safety of StepAdd, an mHealth exercise support system for patients with T2D, via a large, long, and controlled follow-up to the pilot study. METHODS: This is a randomized, open-label, multicenter study targeting 160 patients with T2D from 5 institutions in Japan with a 24-week intervention. The intervention group will record daily step counts, body weight, and blood pressure using the SCT-based mobile app, StepAdd, and receive feedback about these measurements. In addition, they will set weekly step count goals, identify personal barriers to walking, and define strategies to overcome these barriers. The control group will record daily step counts, body weight, and blood pressure using a non-SCT-based placebo app. Both groups will receive monthly consultations with a physician who will advise patients regarding lifestyle modifications and use of the app. The 24-week intervention period will be followed by a 12-week observational period to investigate the sustainability of the intervention's effects. The primary outcome is between-group difference in the change in hemoglobin A1c values at 24 weeks. The secondary outcomes include other health measures, measurements of steps, measurements of other behavior changes, and assessments of app use. The trial began in January 2023 and is intended to be completed in December 2025. RESULTS: As of September 5, 2023, we had recruited 44 patients. We expect the trial to be completed by October 8, 2025, with the follow-up observation period being completed by December 31, 2025. CONCLUSIONS: This trial will provide important evidence about the efficacy of an SCT-based mHealth intervention in improving physical activities and glycemic control in patients with T2D. If this study proves the intervention to be effective and safe, it could be a key step toward the integration of mHealth as part of the standard treatment received by patients with T2D in Japan. TRIAL REGISTRATION: Japan Registry of Clinical Trials (JRCT) jRCT2032220603; https://rctportal.niph.go.jp/en/detail?trial_id=jRCT2032220603. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/53514.

Corticosteroid-triggered acute skeletal muscle loss in lipodystrophy: A case report.

The potential liability to hypercatabolism in lipodystrophy remains to be fully elucidated. Here we report a 28-year-old Japanese woman with acquired generalized lipodystrophy, who presented with recurrence of panniculitis and anemia. After corticosteroid treatment was started, she showed rapid reductions in body weight and lean mass by 15% at maximum, accompanied by an elevated urea nitrogen/creatinine ratio, which recovered almost fully as the corticosteroid treatment was tapered and discontinued. She had multiple risk factors for hypercatabolism: lack of metabolic reserves, insulin resistance, and hyperglycemia due to lipodystrophy, lowered daily activity due to anemia, persistent inflammation, and wasting associated with panniculitis, and relatively insufficient energy and protein intake during hospitalization. More attention should be paid to the potential liability to hypercatabolism in patients with lipodystrophy, and to skeletal muscle loss as an adverse effect of corticosteroid treatment in patients at high risk, such as those with diabetes or decreased metabolic reserves.

Impact of the COVID-19 Pandemic on Health Check-ups in 2021 and 2022: A Nationwide Follow-up Survey of Healthcare Facilities in Japan Society of Ningen Dock.

Introduction: Preventive programs, including screenings for cancer and diabetes, were disrupted globally due to the coronavirus disease 2019 (COVID-19) pandemic in 2020. We previously conducted a nationwide survey to investigate the initial impact of the pandemic on health check-ups; however, the impact in the second and third years of the pandemic has not yet been elucidated. Here, we conducted a follow-up survey targeting healthcare facilities to evaluate the impact of the pandemic until the end of 2022. Methods: A questionnaire survey was conducted between December 15, 2022, and February 10, 2023, targeting member facilities of Japan Society of Ningen Dock. The survey consisted of two parts. Part I comprised a web-based questionnaire, in which the facilities were asked about their commitment to COVID-19-related care, precautions against COVID-19, and whether the pandemic had a negative financial impact on the management of health check-ups. In Part II, the facilities were asked about the number of examinees who underwent health check-ups between 2019 and 2022, the proportion of those who needed and adhered to follow-up visits, and the number of cancer cases found between 2019 and 2021. Results: Of the 1,343 eligible facilities, 885 participated (response rate: 65.9%). The observation that the number of people undergoing mandatory check-ups increased while those undergoing nonmandatory check-ups (e.g., cancer screenings by local governments) decreased in 2021, compared with that of 2019, persisted into 2022. Approximately 60% of the facilities reported a negative financial impact on the management of health check-ups, even in 2022. Conclusions: In 2022, the pandemic's detrimental effects on health check-ups persisted.

Effect of Step Count Measurement on Glycemic Control: Secondary Analysis of a Randomized Controlled Trial.

Although walking has proven efficacy for glycemic control, patients struggle to meet daily step goals. This secondary analysis investigated the effect of step count measurement rate on glycemic control. Patients with type 2 diabetes from eight hospitals in Japan participated in a 12-month randomized controlled trial. The intervention group received DialBetesPlus, a self-management support system that allowed patients to monitor step count using a pedometer. We divided the intervention group into two groups based on whether daily step count measurement rate (the percentage of days with pedometer use) increased or decreased during the last three months of the intervention (month 10-12), relative to the first three months of the intervention (month 1-3). Patients with a reduced measurement rate experienced a worsening in glycemic control, with between-group difference of 0.516% in the amount of change in HbA1c (p=0.012). We conclude that step count measurement may lead to a better glycemic profile.

Proteinuria screening and risk of bone fracture: a retrospective cohort study using a nationwide population-based database.

Background and hypothesis: Proteinuria is associated with an increased risk of kidney function deterioration, cardiovascular disease, or cancer. Previous reports suggesting an association between kidney dysfunction and bone fracture may be confounded by concomitant proteinuria and were inconsistent regarding the association between proteinuria and bone fracture. Therefore, we aimed to evaluate the association using a large administrative claims database in Japan. Methods: Using the DeSC database, we retrospectively identified individuals with laboratory data including urine dipstick test between August 2014 and February 2021. We evaluated the association between proteinuria and vertebral or hip fracture using multivariable Cox regression analyses adjusted for various background factors including kidney function. We also performed subgroup analyses stratified by sex and kidney function and sensitivity analyses with Fine & Gray models considering death as a competing risk. Results: We identified 603 766 individuals and observed 21 195 fractures. With reference to the negative proteinuria group, the hazard ratio for hip or vertebral fracture was 1.10 [95% confidence interval (CI), 1.05-1.14] and 1.16 (95%CI, 1.11-1.22) in the trace and positive proteinuria group, respectively, in the Cox regression analysis. The subgroup analyses showed similar trends. The Fine & Gray model showed a subdistribution hazard ratio of 1.09 (95%CI, 1.05-1.14) in the trace proteinuria group and 1.15 (95% CI, 1.10-1.20) in the positive proteinuria group. Conclusions: Proteinuria was associated with an increased risk of developing hip or vertebral fractures after adjustment for kidney function. Our results highlight the clinical importance of checking proteinuria for predicting bone fractures.

Modification Effects of Albuminuria on the Association Between Kidney Function and Development of Anemia in Diabetes.

CONTEXT: Previous studies failed to adjust for estimated glomerular filtration rate (eGFR) in evaluating the association between albuminuria and anemia development, and we aimed to investigate whether albuminuria independently affects anemia development. METHODS: We conducted a retrospective cohort study and retrospectively identified adults with diabetes from a Japanese nationwide clinical database (JMDC, Tokyo, Japan). To assess the modification effects of albuminuria on the association between eGFR and anemia development, we estimated prevalence of anemia, defined as hemoglobin < 13 g/dL in men and < 12 g/dL in women, using a modified Poisson regression and marginal standardization form of predictive margins, stratified by albuminuria severity after adjusting for eGFR. Hence, we revealed at which eGFR level this modification effect appeared and the extent to which this modification effect increased the prevalence of anemia. RESULTS: We identified 327 999 data points from 48 056 individuals [normoalbuminuria: 186 472 (56.9%), microalbuminuria: 107 170 (32.7%), and macroalbuminuria: 34 357 (10.5%)]. As eGFR declined, anemia prevalence increased. Albuminuria severity modified this association induced by decreased eGFR among individuals with eGFR <30 mL/min/1.73 m2 after adjusting for multivariable factors, including age, sex, comorbidities, and medication use. Compared with the normoalbuminuric group, the macroalbuminuric group had a 5% to 20% higher anemia prevalence among individuals with eGFR of <30 mL/min/1.73 m2. CONCLUSION: We revealed that the severity of albuminuria modified the association between eGFR and anemia development among individuals with eGFR <30 mL/min/1.73 m2, highlighting the modification effect of albuminuria on the association between kidney function and anemia development in diabetes.

Overexpression of UBE2E2 in Mouse Pancreatic ß-Cells Leads to Glucose Intolerance via Reduction of ß-Cell Mass.

Genome-wide association studies have identified several gene polymorphisms, including UBE2E2, associated with type 2 diabetes. Although UBE2E2 is one of the ubiquitin-conjugating enzymes involved in the process of ubiquitin modifications, the pathophysiological roles of UBE2E2 in metabolic dysfunction are not yet understood. Here, we showed upregulated UBE2E2 expression in the islets of a mouse model of diet-induced obesity. The diabetes risk allele of UBE2E2 (rs13094957) in noncoding regions was associated with upregulation of UBE2E2 mRNA in the human pancreas. Although glucose-stimulated insulin secretion was intact in the isolated islets, pancreatic ß-cell-specific UBE2E2-transgenic (TG) mice exhibited reduced insulin secretion and decreased ß-cell mass. In TG mice, suppressed proliferation of ß-cells before the weaning period and while receiving a high-fat diet was accompanied by elevated gene expression levels of p21, resulting in decreased postnatal ß-cell mass expansion and compensatory ß-cell hyperplasia, respectively. In TG islets, proteomic analysis identified enhanced formation of various types of polyubiquitin chains, accompanied by increased expression of Nedd4 E3 ubiquitin protein ligase. Ubiquitination assays showed that UBE2E2 mediated the elongation of ubiquitin chains by Nedd4. The data suggest that UBE2E2-mediated ubiquitin modifications in ß-cells play an important role in regulating glucose homeostasis and ß-cell mass.

Definition, criteria, and core concepts of guidelines for the management of obesity disease in Japan.

To identify those who might benefit from weight reduction within a large population of obese individuals, Japan Society for the Study of Obesity (JASSO) advocated the concept of "obesity disease." Here we summarize the definition, criteria, and core concepts for the management of obesity disease based on JASSO's latest guideline. JASSO defines obesity as excessive fat storage in adipose tissue associated with a BMI of ≥25 kg/m2. The threshold BMI of obesity is low as compared to Western countries given that Japanese individuals tend to develop obesity-related health disorders at lower BMI. Obesity with a BMI of ≥35 kg/m2 is referred to as "high-degree obesity" as treatment strategies vary based on the degree of obesity. Obesity is diagnosed as "obesity disease" if accompanied by any of the 11 specific obesity-related health disorders that weight reduction can prevent or alleviate, or if it meets the criteria for visceral fat obesity with a visceral fat area of ≥100 cm2. The initial weight reduction goals for high-degree obesity disease range from 5% to 10% of their current body weight, depending on the associated health disorders. That for those with obesity disease who do not qualify as high-degree is 3% or more. If these initial goals are not achieved, intensifying dietary therapy or introducing drug therapy (or both) may be necessary. While surgical treatment is primarily indicated for high-degree obesity disease, it might be appropriate for cases of obesity disease with a BMI <35 kg/m2, depending on the accompanying health disorders. Enhancing the quality of life for individuals with obesity or obesity disease necessitates a broader societal approach, emphasizing the resolution of related stigma.

Evaluation of Age-Related Changes in Teneligliptin Pharmacokinetics in Japanese and European Descent Subjects Using a Physiologically Based Pharmacokinetic Model.

INTRODUCTION: Drugs often show differing pharmacokinetic (PK) profiles, such as higher plasma concentrations, in older people than in younger people owing to age-related decreases in physiological functions. However, it is difficult to evaluate the PK in older populations. Therefore, we simulated the plasma age-related changes in the PK of teneligliptin, a dipeptidyl peptidase-4 inhibitor, using physiologically based PK (PBPK) models. METHODS: The previously developed PBPK model was revalidated by comparison between simulated data and clinical study data that included older subjects (up to 75 years old). We then simulated the plasma concentration-time profiles for teneligliptin at a dose of 20 mg (single and multiple doses) in virtual Japanese (20-70 years old) and European descent (20-98 years old) subjects. PK parameters were calculated by race and age group. RESULTS: We confirmed the validity of the previous PBPK model by comparison between simulated data and clinical study data. In the evaluation of age-related changes in PK after single and multiple doses using the PBPK model, the area under the plasma concentration-time curve (AUC) of teneligliptin tended to increase slightly with age in both populations up to 70 years old. However, no clear age-related change in the maximum plasma concentration (Cmax) of teneligliptin was observed. In the European descent subjects aged ≥ 70 years, the AUC tended to increase but the ratio of the change in Cmax was smaller than that in AUC. In both populations, there were positive correlations between AUC and age, but not between Cmax and age. CONCLUSION: The simulation using a PBPK model showed a tendency for the AUC of teneligliptin to increase with age, whereas Cmax was less affected by age than AUC.

A monoclonal antibody activating AdipoR for type 2 diabetes and nonalcoholic steatohepatitis.

Adiponectin receptors, AdipoR1 and AdipoR2 are promising targets for the prevention and treatment of metabolic diseases. In this study, we aimed to establish agonistic antibodies against AdipoR1 and AdipoR2 with a long enough half-life to provide a means of improving poor medication adherence associated with preclinical small-molecule AdipoR agonists or existing antidiabetic drugs. Monoclonal antibodies were obtained by immunizing AdipoR knockout mice with human AdipoR-expressing cells. Of the antibodies shown to bind to both, an agonist antibody was obtained, which exhibited adenosine 5'-monophosphate-activated protein kinase-activating properties such as adiponectin and was named AdipoR-activating monoclonal antibody (AdipoRaMab). AdipoRaMab ameliorated glucose intolerance in high-fat diet-fed mice, which was not observed in AdipoR1·AdipoR2 double knockout mice. AdipoRaMab exhibited anti-inflammatory and antifibrotic effects in the nonalcoholic steatohepatitis (NASH) model, indicating its therapeutic potential in diabetes and in NASH. In addition, the results of this study indicated that AdipoRaMab may exert therapeutic effects even in a once-monthly dosing regimen through its humanization.