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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., (© 2024 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Aims: We aimed to explore the association between short-term exposure to temperature variability (TV), and cardiovascular hospitalization stratified by the presence of comorbid diabetes., Methods: We collected data on nationwide hospitalization for cardiovascular diseases and daily weather conditions during 2011-2018 in Japan. TV was calculated as the standard deviation of daily minimum and maximum temperatures within 0-7 lag days. We applied a two-stage time-stratified case-crossover design to estimate the association between TV and cardiovascular hospitalization with and without comorbid diabetes, adjusting for temperature and relative humidity. Furthermore, specific cardiovascular disease causes, demographic characteristics, and seasons were used for stratification., Results: In 3,844,910 hospitalizations for cardiovascular disease, each 1 °C increase in TV was associated with a 0.44% (95% CI: 0.22%, 0.65%) increase in the risk of cardiovascular admission. We observed a 2.07% (95% CI: 1.16%, 2.99%) and 0.61% (95% CI: -0.02%, 1.23%) increase per 1 °C in risk of heart failure admission in individuals with and those without diabetes, respectively. The higher risk among individuals with diabetes was mostly consistent in the analyses stratified by age, sex, body mass index, smoking status, and season., Conclusion: Comorbid diabetes may increase susceptibility to TV in relation to acute cardiovascular disease hospitalization., 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 © 2023 Elsevier B.V. All rights reserved.)

Aims/introduction: Regular screening for diabetic retinopathy is essential. This study aimed to show the process and current situation of diabetic retinopathy screening prescribed by physicians (internists) and ophthalmologists for Japanese patients with diabetes., Materials and Methods: This retrospective cohort study used data from the Japanese National Database of Insurance Claims between April 2016 and March 2018. Ophthalmology visits and fundus examinations are defined using specific medical procedure codes. The proportion of ophthalmology visits for patients with diabetic medication and for fundus examination among those who visited ophthalmologists was calculated in the fiscal year 2017. A modified Poisson regression analysis was carried out to identify factors associated with retinopathy screening. Similarly, quality indicators by prefectures were also calculated., Results: Among 4,408,585 patients receiving diabetic medications (57.8% men, 14.1% insulin use), 47.4% visited the ophthalmology department and 96.9% of those underwent fundus examination. Regression analysis showed that female sex, older age, insulin use, medical facilities with Japan Diabetes Society certification and large medical facilities were predictors of fundus examination. By prefecture, the ophthalmology consultation rate and the fundus examination ranged 38.5-51.0% and 92.1-98.7%, respectively., Conclusions: Less than half of the patients who were prescribed antidiabetic medication by their physicians visited an ophthalmologist. However, most of the patients who visited an ophthalmologist had a fundus examination carried out. A similar tendency was noted for each prefecture. It is essential to reaffirm the necessity of recommending ophthalmologic examinations to physicians and healthcare professionals who care for patients with diabetes., (© 2023 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Aims: Glycated albumin (GA) is a biomarker, whose level reflects glycemic control status over the previous 2 weeks. To develop a non-invasive method for evaluating glycemic control in people with diabetes mellitus, we investigated the measurement of GA levels in tears and saliva, which could be collected noninvasively., Methods: Tear and saliva samples were collected from 48 participants with diabetes mellitus. The GA levels in the tear and saliva specimens were measured by Liquid Chromatography-Mass Spectrometry (LC-MS/MS)., Results: GA levels in both tear and saliva samples were significantly correlated with the GA levels in the blood (P < 0.001). Multiple regression analysis revealed that these correlations were maintained even after adjustments for the BMI, age, and nephropathy stage (P < 0.001)., Conclusion: GA levels in tear and saliva specimens, as diabetes-related biomarkers, can be measured non-invasively. Since this measurement can be performed noninvasively and not as frequently as compared with the more invasive finger prick method, it is expected to reduce the burden on people with diabetes in terms of both the invasiveness and cost-effectiveness. In the future, we would like to verify the effect of regular GA measurement on the glycemic control while considering the clinical cost-effectiveness., 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 © 2023 Elsevier B.V. All rights reserved.)

Background: Home blood glucose monitoring can be effective for the self-management of diabetic patients. Hemoglobin A1c (HbA1c) is a widely used marker that reflects the average blood glucose within 1-2 months but does not sensitively respond to behavioral changes. Self-monitoring of blood glucose, continuous glucose monitoring, and flush glucose monitoring are sensitive; however, the cost and invasiveness of these tests prevent their widespread use. We focused on glycated albumin (GA), which reflects the average blood glucose levels over 1-2 weeks, and established a GA measurement method for self-sampling, finger-prick blood, which may be submitted for testing through postal service to receive weekly results., Methods: A high-performance liquid chromatography assay was established to measure GA levels in finger-prick blood samples from 103 diabetic patients and the results were compared with venous blood measurements using an enzymatic method. Furthermore, conditions for sending blood samples by mail were evaluated. Under these conditions, samples from 27 healthy and 32 patient volunteers sent through postal service were compared with samples stored in the laboratory., Results: GA levels were measured in samples containing > 20 μg albumin, which resulted in a CV less than 0.3%. The correlation between the GA levels of finger-prick blood measured using HPLC and the GA levels of venous blood measured using the enzymatic method was R 2  = 0.988 with the slope ∼ 1.0, suggesting that the two were nearly equivalent. GA levels were stable for four days at 30 °C and two days at 37 °C. Mail-delivered samples exhibited a high correlation with samples that were not sent (R 2  > 0.99)., Conclusions: We established a method to measure GA levels in self-sampled, finger-prick blood sent through postal service in Japan. The method is applicable for weekly feedback of GA levels, which is potentially useful for motivating behavioral changes. In addition to markers such as HbA1c and blood glucose, GA can be used as a marker for assessing dietary and physical activities. This study highlighted the importance of GA monitoring by developing a suitable measurement method for weekly monitoring of GA levels., Competing Interests: Declaration of Competing Interest Provigate Inc. has sponsored the joint research project with Naoto Kubota, Masakazu Aihara, Keiko Yasukawa, and Yutaka Yatomi of the University of Tokyo Hospital. No other potential conflicts of interest relevant to this article are reported., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background There have been limited data examining the age-dependent relationship of wide-range risk factors with the incidence of each subtype of cardiovascular disease (CVD) event. We assessed age-related associations between modifiable risk factors and the incidence of CVD. Methods and Results We analyzed 3 027 839 participants without a CVD history enrolled in the JMDC Claims Database (mean age, 44.8±11.0 years; 57.6% men). Each participant was categorized as aged 20 to 49 years (n=2 008 559), 50 to 59 years (n=712 273), and 60 to 75 years (n=307 007). Using Cox proportional hazards models and the relative risk reduction, we identified associations between risk factors and incident CVD, consisting of myocardial infarction, angina pectoris, stroke, and heart failure (HF). We assessed whether the association of risk factors for developing CVD would be modified by age category. Over a mean follow-up of 1133 days, 6315 myocardial infarction, 56 447 angina pectoris, 28 079 stroke, and 56 369 HF events were recorded. The incidence of myocardial infarction, angina pectoris, stroke, and HF increased with age category. Hazard ratios of obesity, hypertension, and diabetes in the multivariable Cox regression analyses for myocardial infarction, angina pectoris, stroke, and HF decreased with age category. The relative risk reduction of obesity, hypertension, and diabetes for CVD events decreased with age category. For example, the relative risk reduction of hypertension for HF decreased from 59.2% in participants aged 20 to 49 years to 38.1% in those aged 60 to 75 years. Conclusions The contribution of modifiable risk factor to the development of CVD is greater in younger compared with older individuals. Preventive efforts for risk factor modification may be more effective in younger people.

Objective: Reportedly, two-thirds of the patients who were positive for diabetes during screening failed to attend a follow-up visit for diabetes care in Japan. We aimed to develop a machine-learning model for predicting people's failure to attend a follow-up visit., Research Design and Methods: We conducted a retrospective cohort study of adults with newly screened diabetes at a national screening program using a large Japanese insurance claims database (JMDC, Tokyo, Japan). We defined failure to attend a follow-up visit for diabetes care as no physician consultation during the 6 months after the screening. The candidate predictors were patient demographics, comorbidities, and medication history. In the training set (randomly selected 80% of the sample), we developed two models (previously reported logistic regression model and Lasso regression model). In the test set (remaining 20%), prediction performance was examined., Results: We identified 10,645 patients, including 5,450 patients who failed to attend follow-up visits for diabetes care. The Lasso regression model using four predictors had a better discrimination ability than the previously reported logistic regression model using 13 predictors (C-statistic: 0.71 [95% CI 0.69-0.73] vs. 0.67 [0.65-0.69]; P < 0.001). The four selected predictors in the Lasso regression model were lower frequency of physician visits in the previous year, lower HbA1c levels, and negative history of antidyslipidemic or antihypertensive treatment., Conclusions: The developed machine-learning model using four predictors had a good predictive ability to identify patients who failed to attend a follow-up visit for diabetes care after a screening program., (© 2022 by the American Diabetes Association.)

Aims/introduction: Discontinuation of diabetes care has been studied mostly in patients with prevalent diabetes and not in patients with newly diagnosed diabetes, whose dropout risk is highest. Because enrolling patients in a prospective study will influence adherence, we retrospectively examined whether guideline-recommended practices, defined as nutritional guidance or ophthalmological examination, can prevent patient discontinuation of diabetes care after its initiation., Materials and Methods: We retrospectively identified adults with newly screened diabetes during checkups using a large Japanese administrative claims database (JMDC, Tokyo, Japan) that contains laboratory data and lifestyle questionnaires. We defined discontinuation of physician visits as a follow-up interval exceeding 6 months. We divided the patients into those who received guideline-recommended practices (nutritional guidance or ophthalmology consultation) within the same month as the first visit and those who did not. We calculated propensity scores and carried out inverse probability of treatment weighting analyses to compare discontinuation between the two groups., Results: We identified 6,508 patients with at least one physician consultation for diabetes care within 3 months after their checkup, including 4,574 patients without and 1,934 with guideline-recommended practices. After inverse probability of treatment weighting, patients with guideline-recommended practices had a significantly lower proportion of discontinuation than those without (17.2% vs 21.8%; relative risk 0.79, 95% confidence interval 0.69-0.91)., Conclusions: This study is the first to show that after adjustment for both patient and healthcare provider factors, guideline-recommended practices within the first month of physician consultation for diabetes care can decrease subsequent discontinuation of physician visits in patients with newly diagnosed diabetes., (© 2021 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Aims/introduction: To prevent diabetic complications, strict glucose control and frequent monitoring of blood glucose levels with invasive methods are necessary. We considered the monitoring of tear glucose levels might be a possible method for non-invasive glucose monitoring. To develop tear glucose monitoring for clinical application, we investigated the precise correlation between the blood and tear glucose concentrations., Materials and Methods: A total of 10 participants and 20 participants with diabetes were admitted, and blood and tear samples were collected. Before statistical analysis, we eliminated tear samples contaminated with blood. We observed the daily blood and tear glucose dynamics, and carried out a random intercept model analysis to examine the association between the blood and tear glucose concentrations., Results: Tear occult blood tests showed that the tear glucose concentrations and their variation increased in both participants with and without diabetes as contamination of blood increased. In both participants with and without diabetes, fluctuations of the plasma glucose concentrations were observed depending on the timing of collection of the samples, and the dynamics of the tear glucose concentrations paralleled those of the plasma glucose concentrations. The random intercept model analysis showed a significant association between the plasma and tear glucose concentrations in participants with diabetes (P < 0.001). This association still existed even after adjusting for the glycated hemoglobin levels and the prandial state (P < 0.001)., Conclusions: It is important to eliminate the tear samples contaminated with blood. Tear glucose monitoring might be a reliable and non-invasive substitute method for monitoring the blood glucose concentrations for diabetes patients, irrespective of glycated hemoglobin levels and timing of sample collection., (© 2020 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Aims: Monogenic diabetes is clinically heterogeneous and differs from common forms of diabetes (type 1 and 2). We aimed to investigate the clinical usefulness of a comprehensive genetic testing system, comprised of targeted next-generation sequencing (NGS) with phenotype-driven bioinformatics analysis in patients with monogenic diabetes, which uses patient genotypic and phenotypic data to prioritize potentially causal variants., Methods: We performed targeted NGS of 383 genes associated with monogenic diabetes or common forms of diabetes in 13 Japanese patients with suspected (n = 10) or previously diagnosed (n = 3) monogenic diabetes or severe insulin resistance. We performed in silico structural analysis and phenotype-driven bioinformatics analysis of candidate variants from NGS data., Results: Among the patients suspected having monogenic diabetes or insulin resistance, we diagnosed 3 patients as subtypes of monogenic diabetes due to disease-associated variants of INSR, LMNA, and HNF1B. Additionally, in 3 other patients, we detected rare variants with potential phenotypic effects. Notably, we identified a novel missense variant in TBC1D4 and an MC4R variant, which together may cause a mixed phenotype of severe insulin resistance., Conclusions: This comprehensive approach could assist in the early diagnosis of patients with monogenic diabetes and facilitate the provision of tailored therapy., 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 © 2020 Elsevier B.V. All rights reserved.)

Callus has been identified as a risk factor leading to severe diabetic foot ulcer; thus, it is necessary to prevent its formation. Callus formation under the first, second, and fifth metatarsal heads (MTHs) is associated with external forces (pressure and shear stress) during walking. However, the gait factors increasing the external forces remain undetermined. Thus, this study aims to identify the factors increasing the external forces to prevent callus formation. In 59 patients with diabetic neuropathy wearing their usual shoes, the external forces, and the lower extremity joint angles were measured using MEMS force sensors and motion sensors. The external forces and their relationship with the lower extremity joint angles and footwear size were determined. Risk factors causing high external forces on the first MTH included small flexion of the knee joint ( p = 0.015) and large ankle pronation motion ( p = 0.034) to obtain propulsion. For the second MTH, wearing excessively long footwear was identified ( p = 0.026). For the fifth MTH, high external force was related to tight width footwear ( p = 0.005). An effective intervention for preventing callus formation for the first MTH would involve assisting the push-off foot motion using rocker-sole footwear or gait training. For the second and fifth MTHs, wearing appropriate size footwear would be effective.

The World Health Organization (WHO) declared a pandemic, the highest risk level in the infectious disease alert phase, on 11 March 2020. In the Western Pacific Region (WPR), 192,016 confirmed cases with 7125 deaths had been reported as of 8 June 2020. In people with diabetes COVID-19 can be more difficult to treat due to the wide fluctuations in blood glucose levels or presence of comorbidities such as diabetes complications, including cardiovascular disease and renal damage, which are recognized risks for adverse outcomes. National diabetes associations and governments have established guidelines for subjects with diabetes in relation to COVID-19, and are trying to supply emergency and their regularly required medical products for them. The WPR is so large and composed of such diverse countries and COVID-19 situations, no one conclusion or program applies. Instead we could see a diverse COVID-19 pandemic profile in the WPR, and several creative diagnostic and therapeutic measures undertaken. This includes drive-through screening facilities, high-speed RT-PCR technologies, convalescent patients' plasma therapy, which potentially had some positive contributions in combatting COVID-19 in the WPR as well as globally. Although the numbers of confirmed cases are currently decreasing in the region, the COVID-19 pandemic is not over, and many experts are recommending to prepare measures for potential second or third waves of COVID-19., 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 © 2020 Elsevier B.V. All rights reserved.)

Aims: To calculate process quality measures of diabetes care in Japan using nationwide exclusive claims database., Methods: Using the National Database of health insurance claims during 2015-2016, the proportions of outpatients who received recommended examinations at least annually among those with regular antidiabetic medication were calculated as quality indicators, reported altogether and by prefecture and institutional certification (from the Japan Diabetes Society). Distributions of institutional-level quality indicators were also reported., Results: Among 4,154,452 outpatients, 96.7% underwent HbA1c or glycated albumin examination. Retinopathy examination was conducted among 46.5% of patients [prefecture (range): 37.5%-51.0%, institutional certification: 44.8% (without) vs. 59.8% (with)]. Urinary qualitative examination was conducted among 67.3% of patients at institutions with <200 beds (prefecture: 54.1%-81.9%, institutional certification: 66.8% vs. 92.8%), whereas urinary quantitative albumin or protein examination was conducted among 19.4% of patients (prefecture: 10.8%-31.6%, institutional certification: 18.7% vs. 54.8%). Distributions of institutional-level quality indicators showed that most institutions without institutional certification seldomly order urinary quantitative examination., Conclusions: Although the quality indicator for glycaemic control examination was favourable, some aspects of diabetes care were suboptimal and varied greatly by prefecture and institution; individual and organisational efforts to improve quality of diabetes care would be needed in Japan., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

To ensure that experiences and lessons learned from the unprecedented 2011 Great East Japan Earthquake are used to improve future disaster planning, the Japan Diabetes Society (JDS) launched the "Research and Survey Committee for Establishing Disaster Diabetes Care Systems Based on Relevant Findings from the Great East Japan Earthquake" under the supervision of the Chairman of the JDS. The Committee conducted a questionnaire survey among patients with diabetes, physicians, disaster medical assistance teams (DMATs), nurses, pharmacists, and nutritionists in disaster areas about the events they saw happening, the situations they found difficult to handle, and the needs that they felt required to be met during the 2011 Great East Japan Earthquake. A total of 3,481 completed questionnaires were received. Based on these and other experiences and lessons reported following the 2011 Great East Japan Earthquake and the 2004 Niigata-Chuetsu Earthquakes, the current "Manual for Disaster Diabetes Care" has been developed by the members of the Committee and other invited authors from relevant specialties. To our knowledge, the current Manual is the world's first to focus on emergency diabetes care, with this digest English version translated from the Japanese original. It is sincerely hoped that patients with diabetes and healthcare providers around the world will find this manual helpful in promoting disaster preparedness and implementing disaster relief., (© 2019 Japan Diabetes Society (JDS). Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Plasma adiponectin levels and expression of its receptors, AdipoRs are decreased in obesity, which cause insulin resistance and diabetes. AdipoR-deficient mice exhibit insulin resistance and impaired glucose tolerance. Moreover, newly identified AdipoR agonists not only improve insulin resistance but prolong lifespan shortened by obesity via AdipoR. Furthermore, efforts to promote structure-based drug discovery research at our laboratory have led to the first ever successful crystallization of AdipoR as well as to clarification of their structures. Structural analysis of AdipoRs as key molecules in lifestyle-related diseases is thus expected to lead not only to the acceleration of structure-based drug discovery but to the elucidation of novel aspects of the AdipoR structures and functions in the years to come. Finally, with the development of novel AdipoR-targeted antidiabetic agents also capable of prolonging lifespan, the attainment of healthy longevity may finally be brought within reach.

Biosimilar insulins have expanded the treatment options for diabetes. We compared the clinical efficacy and safety of biosimilar insulins with those of originator insulins by conducting a meta-analysis. A random-effects meta-analysis was performed on randomized controlled trials comparing biosimilar and originator insulins in adults with diabetes. Studies were obtained by searching electronic databases up to December 2017. Ten trials, in a total of 4935 patients, were assessed (2 trials each on LY2963016, MK-1293, Mylan's insulin glargine and SAR342434, and 1 trial each on FFP-112 and Basalog). The meta-analysis found no differences between long-acting biosimilar and originator insulins with regard to reduction in glycated haemoglobin at 24 weeks (0.04%, 95% confidence interval [CI] -0.01, 0.08; P for efficacy = .14, I 2 = 0%) or at 52 weeks (0.03%, 95% CI -0.04, 0.1), or reduction in fasting plasma glucose (0.08 mmol/L, 95% CI 0.36, 0.53), hypoglycaemia (odds ratio 0.99, 95% CI 0.96, 1.03), mortality, injection site reactions, insulin antibodies and allergic reactions. Analyses stratified by type of diabetes and prior insulin use yielded similar findings. Similarly, no significant differences were found between short-acting biosimilar and originator insulins. In summary, our meta-analysis showed no significant differences in clinical efficacy and safety, including immune reactions, between biosimilar and originator insulins. Biosimilar insulins can increase access to modern insulin therapy and reduce medical costs., (© 2018 John Wiley & Sons Ltd.)

Aims/introduction: Preventing dropout is crucial in managing diabetes. Accordingly, we investigated whether patients who had dropped out of diabetic care are suitable candidates for the use of mobile technologies - such as smartphone applications - to support self-management (mHealth), which might help prevent dropout., Materials and Methods: We carried out a cross-sectional study in Tokyo, Japan. Patients aged 20 years or older who were clinically diagnosed as diabetic and who regularly visited the outpatient unit at the University of Tokyo Hospital were recruited between August 2014 and March 2015. Data were collected through face-to-face structured interviews, physical measurements and medical records. Participants were asked whether they were willing to use mHealth after being shown DialBetics - an mHealth application for diabetics - as an example, and about their history of dropout and previous mHealth experience. Data were analyzed by multivariate logistic regression models., Results: Of 307 patients with type 1 and type 2 diabetes, 34 (11.1%) had previously dropped out from diabetic care. Multivariate analysis identified previous mHealth experience as a negative predictor of dropout (odds ratio 0.211, P = 0.023). Of those 34 patients, 27 (79.4%) expressed willingness to use mHealth, a significantly higher percentage than for those who had never dropped out (51.5%, P = 0.002). After adjusting for confounders, history of dropout remained a strong predictor of willingness (odds ratio 3.870, P = 0.004)., Conclusions: Patients who previously dropped out of diabetic care are suitable candidates for mHealth. Future studies must evaluate whether mHealth is effective for preventing repeated dropout and improving glycemic control among this population., (© 2016 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

In the 'Evidence-based Practice Guideline for the Treatment for Diabetes in Japan 2013', a new concept of the glycemic control in patients with diabetes in Japan has been declared from the Japan Diabetes Society. The main objective value of HbA1c was set to <7% from the perspective of preventing microvascular complications. On the other hand, the objective in cases where objectives can be attained by appropriate dietary or exercise therapy, or during pharmacotherapy without the occurrence of side effects such as hypoglycemia was set to <6%, and the objective in cases where intensification of treatment was considered difficult due to side effects such as hypoglycemia or for other reasons was set to <8%. Treatment objectives should be established individually, in consideration of age, duration of disease, organ damage, risk of hypoglycemia, support structure, and etc., (© 2016 Japan Diabetes Society (JDS). Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Hepatic insulin signalling involves insulin receptor substrates (Irs) 1/2, and is normally associated with the inhibition of gluconeogenesis and activation of lipogenesis. In diabetes and obesity, insulin no longer suppresses hepatic gluconeogenesis, while continuing to activate lipogenesis, a state referred to as 'selective insulin resistance'. Here, we show that 'selective insulin resistance' is caused by the differential expression of Irs1 and Irs2 in different zones of the liver. We demonstrate that hepatic Irs2-knockout mice develop 'selective insulin resistance', whereas mice lacking in Irs1, or both Irs1 and Irs2, develop 'total insulin resistance'. In obese diabetic mice, Irs1/2-mediated insulin signalling is impaired in the periportal zone, which is the primary site of gluconeogenesis, but enhanced in the perivenous zone, which is the primary site of lipogenesis. While hyperinsulinaemia reduces Irs2 expression in both the periportal and perivenous zones, Irs1 expression, which is predominantly in the perivenous zone, remains mostly unaffected. These data suggest that 'selective insulin resistance' is induced by the differential distribution, and alterations of hepatic Irs1 and Irs2 expression.

Background: The association between time spent walking and risk of diabetes was investigated in a Japanese population-based cohort., Methods: Data from the Japan Public Health Center-based Prospective Diabetes cohort were analyzed. The surveys of diabetes were performed at baseline and at the 5-year follow-up. Time spent walking per day was assessed using a self-reported questionnaire (<30 minutes, 30 minutes to <1 hour, 1 to <2 hours, or ≥2 hours). A cross-sectional analysis was performed among 26 488 adults in the baseline survey. Logistic regression was used to examine the association between time spent walking and the presence of unrecognized diabetes. We then performed a longitudinal analysis that was restricted to 11 101 non-diabetic adults who participated in both the baseline and 5-year surveys. The association between time spent walking and the incidence of diabetes during the 5 years was examined., Results: In the cross-sectional analysis, 1058 participants had unrecognized diabetes. Those with time spent walking of <30 minutes per day had increased odds of having diabetes in relation to those with time spent walking of ≥2 hours (adjusted odds ratio [OR] 1.23; 95% CI, 1.02-1.48). In the longitudinal analysis, 612 participants developed diabetes during the 5 years of follow-up. However, a significant association between time spent walking and the incidence of diabetes was not observed., Conclusions: Increased risk of diabetes was implied in those with time spent walking of <30 minutes per day, although the longitudinal analysis failed to show a significant result.

Background: The present study examined the prevalence of diabetes in Japan during the late 1990s and early 2000s using the Japan Public Health Center-based Prospective Diabetes cohort. We also investigated the distributions of HbA1c values in noncompliant diabetic participants in the cohort., Methods: A total of 28 183 registered inhabitants aged 46-75 years from 10 public health center areas were included in the initial survey. The 5-year follow-up survey included 20 129 participants. The prevalence of diabetes was estimated using both a self-reported questionnaire and laboratory measurements. Among the participants who reported the presence of diabetes on the questionnaire (self-reported diabetes), the distributions of HbA1c values were described according to their treatment status., Results: The age-standardized prevalence of diabetes in 55- to 74-year-old adults was 8.2% at the initial survey and 10.6% at the 5-year follow-up. At the initial survey, among participants with self-reported diabetes, the mean HbA1c values in the participants who had never and who had previously received diabetes treatment were 7.01% (standard deviation [SD] 1.56%) and 6.56% (SD 1.46%), respectively. Approximately 15% of the participants who had self-reported diabetes but had never received diabetes treatment had an HbA1c ≥ 8.4%., Conclusions: The prevalence of diabetes increased in the JPHC cohort between the late 1990s and early 2000s. A certain proportion of participants who were aware of their diabetes but were not currently receiving treatment had poor diabetic control. Efforts to promote continuous medical attendance for diabetes care may be necessary.

Background: A plantar temperature distribution can be obtained by thermography; however, the advantage has not been effectively utilized in the past. We previously proposed a classification method based on the angiosome concept, but the method was insufficient because it was too subjective and complicated for clinicians. In this study, we propose a new classification system of plantar forepart thermographic patterns using an image segmentation technique., Methods: A cross-sectional observational study was conducted including 32 healthy volunteers and 129 patients with diabetes mellitus (DM). Individual thermographic variations and trends were evaluated. A comparison was conducted between the patterns obtained by our previous angiosome-based research and the patterns found by the new classification system., Results: The system objectively found wider variations of the plantar forepart thermographic patterns in the patients with DM compared with those in the control subjects. In patients with DM, the system showed that the whole-high pattern was most frequent (46%), followed by the butterfly pattern (12%). In the control group, the butterfly pattern was most frequent (44%), followed by the whole-high pattern (19%). Both ankle and toe brachial indices were higher in feet with high temperature area in the inner side of the plantar., Conclusions: Thermographic patterns found by the new computer-based system were similar to those obtained in our previous subjective work. The classification system found forefoot-low pattern and tiptoe-low pattern objectively. The system based on infrared thermography will be a screening tool to assess circulatory status in daily foot care of patients with DM., (© 2013 Diabetes Technology Society.)

Data collected by the United Network for Organ Sharing from all approved United States transplant programs was analyzed. The data included 26,572 adult diabetic patients who received a primary pancreas transplant between January 1987 and December 2012. Simultaneous pancreas-kidney (SPK) transplantation was the major therapeutic option for diabetes patients. SPK had better graft survival than pancreas transplant alone (PTA) or pancreas-after-kidney (PAK) or pancreas-with-kidney (from a living donor, PWK). The 5-year pancreas graft survival rates for SPK, PWK, PAK, and PTA were 70.0%, 57.2%, 54.0%, and 48.2%, respectively. When long-term SPK pancreas graft survival was examined by various transplant time periods, it was found that survival has remained almost stable since 1996. Graft survival rates were high among the pancreas recipients transplanted in the periods 1996-2000, 2001-2005, and 2006-2012, and the rates were similar: the 5-year rates were 68.9%, 72.4%, and 73.8%, respectively. Technical failure was the leading cause of graft loss during the first year post-transplant, regardless of period: 61.3%, 68.6%, 64.2%, and 71.9% for 1987-1995, 1996-2000, 2001-2005, and 2006-2012, respectively. After one year, chronic rejection was the leading cause of graft loss in all periods: 51.8%, 53.2%, 44.3%, and 40.7% for 1987-1995, 1996-2000, 2001-2005, and 2006-2012, respectively. Chronic rejection accounted for around 50% (or more) of the grafts that survived over five years. Survival of long-term pancreas grafts as well as long-term causes of graft loss remained almost unchanged across the different transplant periods. Clearly, there is a need for a means to identify early markers of chronic rejection, and to control it to improve long-term survival.

Background: Several studies have shown that erectile dysfunction (ED) influences the risk of cardiovascular events (CV events). However, a meta-analysis of the overall risk of CV events associated with ED in patients with diabetes has not been performed., Methodology/principal Findings: We searched MEDLINE and the Cochrane Library for pertinent articles (including references) published between 1951 and April 22, 2012. English language reports of original observational cohort studies and cross-sectional studies were included. Pooled effect estimates were obtained by random effects meta-analysis. A total of 3,791 CV events were reported in 3 cohort studies and 9 cross-sectional studies (covering 22,586 subjects). Across the cohort studies, the overall odds ratio (OR) of diabetic men with ED versus those without ED was 1.74 (95% confidence interval [CI]: 1.34-2.27; P<0.001) for CV events and 1.72 (95% CI: 1.5-1.98; P<0.001) for coronary heart disease (CHD). The funnel plot, Begg's test, and Egger's test did not show evidence of publication bias (all P>0.05). Moreover, meta-regression analysis found no relationship between the method used to assess ED (questionnaire or interview), mean age, mean hemoglobin A(1c), mean body mass index, or mean duration of diabetes and the risk of CV events or CHD. In the cross-sectional studies, the OR of diabetic men with ED versus those without ED was 3.39 (95% CI: 2.58-4.44; P<0.001) for CV events (N = 9), 3.43 (95% CI: 2.46-4.77; P<0.001) for CHD (N = 7), and 2.63 (95% CI: 1.41-4.91; P = 0.002) for peripheral vascular disease (N = 5)., Conclusion/significance: ED was associated with an increased risk of CV events in diabetic patients. Prevention and early detection of cardiovascular disease are important in the management of diabetes, especially in view of the rapid increase in its prevalence.

Along with reduced physical activity, increased fat intake, and intensified psychological stresses associated with work and social life, the number of diabetic patients and diabetes-related complications has increased significantly in Japan. Our aim at The University of Tokyo Hospital is to provide comprehensive diabetes treatment, including the use a diabetes handbook with guidelines for the diagnosis and treatment of diabetes consistent with evidence-based medicine. Diabetes specialists and certified diabetes educators work together to provide the best possible treatment. In addition, we have established a diabetic foot care service for outpatients, with the objective of preventing diabetes-related foot disease. The inpatients wards offer the most ideal diabetes treatments, including diet therapy, exercise therapy, guided self-monitoring of blood glucose, daily body weight measurement, and diabetes seminars. All these services provide guidelines that encourage patient self-management even after discharge from hospital. Management dietitians use food samples and a Food Exchange Table to brief patients about nutrition guidelines. Exercise therapy programs are developed according to the specific needs of each individual patient. We have also established a diabetes seminar series for the patients, to which physicians, nurses, dietitians, pharmacists, clinical laboratory technicians, and other professionals are invited to give talks on their respective areas of expertise. The aim of our ongoing efforts to implement diet and exercise therapies and improve the living habits of the patients is to achieve an ideal standard for diabetes education and management., (© 2011 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd.)

A semi-automatic, whole-blood aggregometer based on the screen filtration pressure (SFP) method is now widely used clinically and in research, but has not been used with hemodialysis (HD) patients. We measured whole-blood platelet aggregation in HD patients by the SFP method. This retrospective cross-sectional study included 62 HD patients, of whom 47 were non-diabetic and 15 were diabetic; we also included a control group of healthy, non-uremic subjects. With the t-test, we examined differences in the platelet aggregation threshold index (PATI) in meaningful sub-groupings of the HD patients, depending on whether or not they had diabetes, and whether or not they had been given antiplatelet agents. Considering the non-diabetic HD patients first, their PATI values were significantly higher than those values in the control subjects (3.1 [1.0-5.2] vs. 1.8 [1.3-2.3] µM, P<0.001). The non-diabetic HD patients taking antiplatelet agents showed significantly (1.9 times) higher PATI values than the non-diabetic HD patients without antiplatelet agents (4.4 [1.8-7.0] vs. 2.3 [1.3-3.3] µM, P=0.003). We observed similar trends among diabetic HD patients. Whole-blood analysis by the SPF method seems to be a promising way of monitoring platelet function for HD patients., (© 2010 The Authors. Therapeutic Apheresis and Dialysis © 2010 International Society for Apheresis.)

Aim: Gamma-glutamyltransferase (GGT) is known to correlate well with alcohol consumption; however, the relation between GGT and diabetes and that between alcohol consumption and diabetes mellitus (DM) is inconsistent. Thus, several questions, such as whether light to moderate drinkers can be considered as low risk for diabetes incidence irrespective of their GGT level, is unresolved. In this study, we investigated the relation of GGT or alcohol drinking with DM incidence considering the body mass index (BMI) in healthy Japanese workers., Methods: We followed 3095 men who did not have DM at baseline for 4 years. Incident diabetes was defined as a fasting (non-fasting) plasma glucose level of >or=7.0 (11.1) mmol/L, or treatment of diabetes. Multiple adjusted hazard ratios (HR) were calculated using Cox proportional models., Results: Participants with higher GGT (GGT >or=27 IU/L) showed an increased risk of diabetes incidence even when their BMI level was low. Although a U-shaped relation between alcohol drinking and incident diabetes was observed, the risk to light to moderate drinkers (alcohol <23 g/day) was not low if they were either overweight (BMI >or=25 kg/m(2)) or had higher GGT (HR=2.60, p=0.08) or both overweight and higher GGT (HR=3.16, p=0.07) compared with never drinkers without higher GGT and overweight., Conclusions: Higher GGT was associated with a higher incidence of DM irrespective of drinking status or obesity. Although a U-shaped relation between alcohol drinking and incident diabetes was observed, the risk to light to moderate drinkers was not low if they were either overweight or had higher GGT.

Although moderate alcohol intake in diabetic Caucasians is associated with a reduction in coronary heart disease mortality, no study in Japanese with diabetes has examined the association between alcohol intake and mortality outcomes. We analyzed the relationship between alcohol intake and all-cause and cause-specific mortality using the database from NIPPON DATA80. At the baseline in 1980, data on history, lifestyle, and physical examinations were collected on study participants aged 30 years and older from randomly selected areas in Japan. After excluding participants with comorbidities, we followed 4,018 male participants (3,614 nondiabetics, 195 with impaired glucose tolerance and 209 diabetic) for 19 years. During the 19 years of follow-up, there were 990 deaths; 328 were from cardiovascular disease and 157 from all-heart diseases. With the never-drinking category serving as a reference, the Cox multivariate-adjusted hazard ratios for non-daily and daily drinkers for cardiovascular mortality were 0.43 (95% confidence intervals: 0.19-0.95) and 0.45 (0.25-0.80), respectively, and 0.33 (0.12-0.91) and 0.31 (0.15-0.67) for all-heart disease mortality in the combined impaired glucose tolerance and diabetic Japanese men. Alcohol drinking in men with glucose intolerance was associated with a significant reduction in cardiovascular and all-heart disease mortality as seen in the general population in Japan.

Objective: We investigated the impact of active smoking and exposure to passive smoke on the risk of developing diabetes., Research Design and Methods: Data were analyzed from a cohort of participants in the High-Risk and Population Strategy for Occupational Health Promotion Study (HIPOP-OHP) conducted in Japan from 1999 to 2004. Active and passive smoking status in the workplace was evaluated at baseline., Results: Of 6,498 participants (20.9% women), a total of 229 diabetes cases were reported over a median 3.4 years of follow-up. In the workplace, compared with zero-exposure subjects, the multivariable-adjusted hazard ratios of developing diabetes were 1.81 (95% CI 1.06-3.08, P = 0.028) for present passive subjects and 1.99 (1.29-3.04, P = 0.002) for present active smokers., Conclusions: In this cohort, exposure to passive smoke in the workplace was associated with an increased risk of diabetes after adjustment for a large number of possible confounders.

Hemoglobin A1c (HbA1c) has been widely used as a measure of glycemic control in patients with diabetes mellitus. However, the role of HbA1c in the prediabetic stage has received little attention, although the effectiveness of early intensive intervention for the prediabetic patients defined by plasma glucose is well documented. In this study, routine clinical data in a Japanese university hospital were used to address whether the level of HbA1c predicted drug treatment for diabetes mellitus. The study population consisted of 38,628 adolescent and adult patients (>or=15 years old) who used routine medical care services provided by the hospital and who were prescribed no anti-diabetic drugs in the 12 months before the 3-year study period. The rates of starting anti-diabetic drugs during the study period were calculated for subgroups divided by the level of HbA1c followed by Kaplan-Meier survival analysis and Cox proportional-hazard regression. In addition, the medical records of middle-aged patients with borderline (5.6-6.4%) and high (>or=6.5%) levels of HbA1c were examined to estimate the rates of initial drug treatment for type 2 diabetes mellitus. The rate (95% confidence interval; CI) of beginning anti-diabetic drug therapy was 1.5 (0.9-2.5)/1000 patient-years in patients with a normal level of HbA1c (<5.6%), which is similar to 2.1 (1.8-2.5)/1000 patient-years in patients with no HbA1c data, but lower than the value of 23.0 (18.6-28.6) and 161.8 (144.8-180.7)/1000 patient-years in those with borderline and high levels of HbA1c, respectively (P < 0.001). In a small group of 513 middle-aged patients, the rates of initial drug treatment for type 2 diabetes mellitus were 39.4 (28.1-55.1)/1000 patient-years and 270.4 (209.4-349.0)/1000 patient-years in those with borderline and high levels of HbA1c, respectively. A borderline (5.6-6.4%) or high (>or=6.5%) level of HbA1c was found to strongly predict future drug treatment for diabetes mellitus.

Thiazolidinediones have been shown to up-regulate adiponectin expression in white adipose tissue and plasma adiponectin levels, and these up-regulations have been proposed to be a major mechanism of the thiazolidinedione-induced amelioration of insulin resistance linked to obesity. To test this hypothesis, we generated adiponectin knock-out (adipo-/-) ob/ob mice with a C57B/6 background. After 14 days of 10 mg/kg pioglitazone, the insulin resistance and diabetes of ob/ob mice were significantly improved in association with significant up-regulation of serum adiponectin levels. Amelioration of insulin resistance in ob/ob mice was attributed to decreased glucose production and increased AMP-activated protein kinase in the liver but not to increased glucose uptake in skeletal muscle. In contrast, insulin resistance and diabetes were not improved in adipo-/-ob/ob mice. After 14 days of 30 mg/kg pioglitazone, insulin resistance and diabetes of ob/ob mice were again significantly ameliorated, which was attributed not only to decreased glucose production in the liver but also to increased glucose uptake in skeletal muscle. Interestingly, adipo-/-ob/ob mice also displayed significant amelioration of insulin resistance and diabetes, which was attributed to increased glucose uptake in skeletal muscle but not to decreased glucose production in the liver. The serum-free fatty acid and triglyceride levels as well as adipocyte sizes in ob/ob and adipo-/-ob/ob mice were unchanged after 10 mg/kg pioglitazone but were significantly reduced to a similar degree after 30 mg/kg pioglitazone. Moreover, the expressions of TNFalpha and resistin in adipose tissues of ob/ob and adipo-/-ob/ob mice were unchanged after 10 mg/kg pioglitazone but were decreased after 30 mg/kg pioglitazone. Thus, pioglitazone-induced amelioration of insulin resistance and diabetes may occur adiponectin dependently in the liver and adiponectin independently in skeletal muscle.

Aims/hypothesis: Morbid obesity (BMI>40 kg/m(2)) affecting 0.5-5% of the adult population worldwide is a major risk factor for type 2 diabetes. We aimed to elucidate the genetic bases of diabetes associated with obesity (diabesity), and to analyse the impact of corpulence on the effects of diabetes susceptibility genes., Methods: We genotyped known single nucleotide polymorphisms (SNPs) in the adiponectin-encoding adipocyte C1q and collagen-domain-containing (ACDC) gene (-11,391G>A, -11,377C>G, +45T>G and +276G>T), the peroxisome proliferator-activated receptor gamma (PPARG) Pro12Ala SNP and ACDC exon 3 variants in 703 French morbidly obese subjects (BMI 47.6+/-7.4 kg/m(2)), 808 non-obese subjects (BMI<30 kg/m(2)) and 493 obese subjects (30< or =BMI<40 kg/m(2))., Results: Two 5'-ACDC SNPs -11,391G>A, -11,377C>G were associated with adiponectin levels (p=0.0003, p=0.008) and defined a "low-level" haplotype associated with decreased adiponectin levels (p=0.0002) and insulin sensitivity (p=0.01) and with a risk of type 2 diabetes that was twice as high (p=0.002). In contrast, the prevalence of the PPARG Pro12Ala was identical in diabetic and normoglycaemic morbidly obese subjects. The PPARG Pro12 allele only displayed a trend of association with type 2 diabetes in the non-obese group. ACDC exon 3 variants were associated with type 2 diabetes in the non-obese group only (odds ratio 7.85, p<0.0001). In contrast, the 5'-ACDC "low-level" haplotype was associated with type 2 diabetes in obese and morbidly obese subjects (odds ratio 1.73 and 1.92) but not in non-obese individuals., Conclusions/interpretation: These data clarify the contribution of the 5'-ACDC SNPs to the risk of diabesity. Their interaction with corpulence suggests for the first time a different genetic profile of type 2 diabetes in morbidly obese patients compared with in less obese individuals.

The peroxisome proliferator-activated receptors (PPARs) are nuclear fatty acid receptors that have been implicated to play crucial roles in metabolic diseases such as hyperlipidemia, insulin resistance, and diabetes. The three PPAR subtypes, alpha, gamma, and delta, have distinct expression patterns and regulate glucose homeostasis based on the need of a specific tissue. While PPARalpha potentiates fatty acid catabolism in the liver and is the molecular target of the lipid-lowering fibrates, PPARgamma is essential for adipocyte differentiation and hypertrophy, and mediates the activity of the insulin sensitizing thiazolidinediones. PPARdelta may be important in regulating body weight and lipid metabolism in fat tissues. Thus, uncovering the regulatory mechanisms and transcriptional targets of these PPARs will provide insights into the pathogenesis of metabolic diseases and offer valuable information for rational drug design.

Aims: Few prospective studies have examined the relationship between lifestyle characteristics and the incidence of diabetes mellitus in an Asian general population. This study was undertaken to evaluate the risk factors for Type 2 diabetes in a population-based prospective study of middle-aged Japanese., Methods: We investigated 12,913 men and 15,980 women, aged 40-59 years at baseline (year 0), who participated in the Japan Public Health Center-based prospective study on cancer and cardiovascular diseases (JPHC Study) Cohort I. The participants were followed for up to 10 years. Incident cases of diabetes were identified by self-reporting of a physician's diagnosis on two questionnaires sent to each participant, one at year 5 and the second at year 10., Results: During the 10-year follow-up, 703 men and 482 women reported newly diagnosed diabetes. Age, body mass index (BMI), family history of diabetes and cigarette smoking were independent risk factors in both genders by multivariate analysis. Among men with a BMI < or = 22 kg/m2, a significant positive association was observed between the diabetes incidence and moderate (23.0 < 46.0 g/day) to high (> 46.0 g/day) alcohol consumption, odds ratio 1.91 (95% CI, 1.05-3.46) and 2.89 (1.63-5.11), respectively. Among men with a BMI > 22 kg/m2, a small non-significant increase in odds ratio was observed with alcohol consumption., Conclusions: Established risk factors for diabetes in western populations were also identified as predictors of the disease among Japanese. Moderate to high alcohol consumption was positively associated with the incidence of diabetes in Japanese lean (BMI < or = 22 kg/m2) men.

Adiponectin is an adipocyte-derived hormone, which has been shown to play important roles in the regulation of glucose and lipid metabolism. Eight mutations in human adiponectin have been reported, some of which were significantly related to diabetes and hypoadiponectinemia, but the molecular mechanisms of decreased plasma levels and impaired action of adiponectin mutants were not clarified. Adiponectin structurally belongs to the complement 1q family and is known to form a characteristic homomultimer. Herein, we demonstrated that simple SDS-PAGE under non-reducing and non-heat-denaturing conditions clearly separates multimer species of adiponectin. Adiponectin in human or mouse serum and adiponectin expressed in NIH-3T3 or Escherichia coli formed a wide range of multimers from trimers to high molecular weight (HMW) multimers. A disulfide bond through an amino-terminal cysteine was required for the formation of multimers larger than a trimer. An amino-terminal Cys-Ser mutation, which could not form multimers larger than a trimer, abrogated the effect of adiponectin on the AMP-activated protein kinase pathway in hepatocytes. Among human adiponectin mutations, G84R and G90S mutants, which are associated with diabetes and hypoadiponectinemia, did not form HMW multimers. R112C and I164T mutants, which are associated with hypoadiponectinemia, did not assemble into trimers, resulting in impaired secretion from the cell. These data suggested impaired multimerization and/or the consequent impaired secretion to be among the causes of a diabetic phenotype or hypoadiponectinemia in subjects having these mutations. In conclusion, not only total concentrations, but also multimer distribution should always be considered in the interpretation of plasma adiponectin levels in health as well as various disease states.

Adiponectin (also known as 30-kDa adipocyte complement-related protein; Acrp30) is a hormone secreted by adipocytes that acts as an antidiabetic and anti-atherogenic adipokine. Levels of adiponectin in the blood are decreased under conditions of obesity, insulin resistance and type 2 diabetes. Administration of adiponectin causes glucose-lowering effects and ameliorates insulin resistance in mice. Conversely, adiponectin-deficient mice exhibit insulin resistance and diabetes. This insulin-sensitizing effect of adiponectin seems to be mediated by an increase in fatty-acid oxidation through activation of AMP kinase and PPAR-alpha. Here we report the cloning of complementary DNAs encoding adiponectin receptors 1 and 2 (AdipoR1 and AdipoR2) by expression cloning. AdipoR1 is abundantly expressed in skeletal muscle, whereas AdipoR2 is predominantly expressed in the liver. These two adiponectin receptors are predicted to contain seven transmembrane domains, but to be structurally and functionally distinct from G-protein-coupled receptors. Expression of AdipoR1/R2 or suppression of AdipoR1/R2 expression by small-interfering RNA supports our conclusion that they serve as receptors for globular and full-length adiponectin, and that they mediate increased AMP kinase and PPAR-alpha ligand activities, as well as fatty-acid oxidation and glucose uptake by adiponectin.

The adipocyte-derived hormone adiponectin has been shown to play important roles in the regulation of energy homeostasis and insulin sensitivity. In this study, we analyzed globular domain adiponectin (gAd) transgenic (Tg) mice crossed with leptin-deficient ob/ob or apoE-deficient mice. Interestingly, despite an unexpected similar body weight, gAd Tg ob/ob mice showed amelioration of insulin resistance and beta-cell degranulation as well as diabetes, indicating that globular adiponectin and leptin appeared to have both distinct and overlapping functions. Amelioration of diabetes and insulin resistance was associated with increased expression of molecules involved in fatty acid oxidation such as acyl-CoA oxidase, and molecules involved in energy dissipation such as uncoupling proteins 2 and 3 and increased fatty acid oxidation in skeletal muscle of gAd Tg ob/ob mice. Moreover, despite similar plasma glucose and lipid levels on an apoE-deficient background, gAd Tg apoE-deficient mice showed amelioration of atherosclerosis, which was associated with decreased expression of class A scavenger receptor and tumor necrosis factor alpha. This is the first demonstration that globular adiponectin can protect against atherosclerosis in vivo. In conclusion, replenishment of globular adiponectin may provide a novel treatment modality for both type 2 diabetes and atherosclerosis.

To elucidate the mechanism underlying diabetes caused by mitochondrial gene mutations, we created a model by applying 0.4 microg/ml ethidium bromide (EtBr) to the murine pancreatic beta cell line betaHC9; in this model, transcription of mitochondrial DNA, but not that of nuclear DNA, was suppressed in association with impairment of glucose-stimulated insulin release (Hayakawa, T., Noda, M., Yasuda, K., Yorifuji, H., Taniguchi, S., Miwa, I., Sakura, H., Terauchi, Y., Hayashi, J.-I., Sharp, G. W. G., Kanazawa, Y., Akanuma, Y., Yazaki, Y., and Kadowaki, T. (1998) J. Biol. Chem. 273, 20300-20307). To elucidate fully the metabolism-secretion coupling in these cells, we measured glucose oxidation, utilization, and lactate production. We also evaluated NADH autofluorescence in betaHC9 cells using two-photon excitation laser microscopy. In addition, we recorded the membrane potential and determined the ATP and ADP contents of the cells. The results indicated 22.2 mm glucose oxidation to be severely decreased by EtBr treatment compared with control cells (by 63% on day 4 and by 78% on day 6; both p < 0.01). By contrast, glucose utilization was only marginally decreased. Lactate production under 22.2 mm glucose was increased by 2.9- and 3.5-fold by EtBr treatment on days 4 and 6, respectively (both p < 0.01). Cellular NADH at 2.8 mm glucose was increased by 35 and 43% by EtBr on days 4 and 6 (both p < 0.01). These data suggest that reduced expression of the mitochondrial electron transport system causes NADH accumulation in beta cells, thereby halting the tricarboxylic acid cycle on one hand, and on the other hand facilitating anaerobic glucose metabolism. Glucose-induced insulin secretion was lost rapidly along with the EtBr treatment with concomitant losses of membrane potential depolarization and the [Ca(2+)](i) increase, whereas glibenclamide-induced changes persisted. This is the first report to demonstrate the connection between metabolic alteration of electron transport system and that of tricarboxylic acid cycle and its impact on insulin secretion.