Kazuo Izumi

Switch to anaerobic glucose metabolism with NADH accumulation in the beta-cell model of mitochondrial diabetes. Characteristics of betaHC9 cells deficient in mitochondrial DNA transcription.

To elucidate the mechanism underlying diabetes caused by mitochondrial gene mutations, we created a model by applying 0.4 μg/ml ethidium bromide (EtBr) to the murine pancreatic β cell line βHC9; 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 βHC9 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 β 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 [Ca2+] 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.

A cluster randomized trial on the effect of a multifaceted intervention improved the technical quality of diabetes care by primary care physicians: The Japan Diabetes Outcome Intervention Trial-2 (J-DOIT2).

To evaluate the effect of multifaceted interventions using the Achievable Benchmark of Care (ABC) method for improving the technical quality of diabetes care in primary care settings.

Design of and rationale for the Japan Diabetes Optimal Integrated Treatment study for 3 major risk factors of cardiovascular diseases (J-DOIT3): a multicenter, open-label, randomized, parallel-group trial

Objective Multifactorial intervention including the management of levels of blood glucose (BG), blood pressure (BP), and lipids has been suggested to decrease cardiovascular disease (CVD) risk. However, the target ideal and feasible levels for these individual parameters have not been fully evaluated. In this study, we examine the hypothesis that stricter control compared with the current targets in the Japanese guideline for BG, BP, and lipids could efficiently and safely reduce CVD risk. Research Design and Methods We screened patients with type 2 diabetes and hypertension and/or dyslipidemia among 81 hospitals in Japan and allocated them into 2 groups: the intensive therapy group (ITG) and the conventional therapy group (CTG). For the 2 respective groups, the target for glycated hemoglobin (HbA1c) is <6.2% (44 mmol/mol) and <6.9% (52 mmol/mol), for BP it is <120/75 mm Hg and <130/80 mm Hg, and for low-density lipoprotein cholesterol it is <80 mg/dL (<70 mg/dL in the presence of CVD history) and <120 mg/dL (<100 mg/dL in the presence of CVD history). The primary end point is the occurrence of CVD events or death by any cause. These patients are scheduled for stepwise intensifications of medication for BG, BP, and lipid control in the ITG, until the number of primary end point events reaches 250. Results We recruited 2542 patients and randomly allocated 1271 into the ITG and 1271 into the CTG between June 2006 and March 2009. The mean HbA1c was 8.0% (64 mmol/mol) and the mean duration of diabetes was 8.3 years. Conclusions This randomized controlled study will test the hypothesis that strict multifactorial intervention therapy is effective for the prevention of CVDs in patients with type 2 diabetes who are at high CVD risk. Trial registration number NCT00300976.

Effects of telephone-delivered lifestyle support on the development of diabetes in participants at high risk of type 2 diabetes: J-DOIT1, a pragmatic cluster randomised trial

Objectives To examine the effects of telephone-delivered lifestyle coaching on preventing the development of type 2 diabetes mellitus (T2DM) in participants with impaired fasting glucose (IFG). Design Cluster randomised trial. Setting 40 groups from 17 healthcare divisions in Japan: companies (31), communities (6) and mixed settings (3). Participants Participants aged 20–65 years with fasting plasma glucose (FPG) of 5.6–6.9 mmol/L were invited from the 17 healthcare divisions. Randomisation The groups were then randomly assigned to an intervention or a control arm by independent statisticians according to a computer-generated list. Intervention The intervention arm received a 1-year telephone-delivered intervention provided by three private lifestyle support centres (at different frequencies: low-frequency (3 times), middle-frequency (6 times) and high-frequency (10 times) support calls). The intervention and control arms both received self-help devices such as a weight scale and pedometer. Outcomes Participants were followed up using data from annual health check-ups and a questionnaire regarding lifestyle. The primary outcome was the development of T2DM defined as FPG ≥7.0 mmol/L, the diagnosis of diabetes, or use of an antidiabetic drug, confirmed by referring to medical cards. Results Of 14 473 screened individuals, participants were enrolled in either the intervention (n=1240) arm or control (n=1367) arm. Overall, the HR for the development of T2DM in the intervention arm during 5.5 years was 1.00 (95% CI 0.74 to 1.34). In the subanalysis, the HR was 0.59 (95% CI 0.42 to 0.83) in the subgroup that received phone calls the most frequently, compared with the control arm. A limitation of the study includes a lack of blinding. Conclusions High-frequency telephone-delivered lifestyle support could effectively prevent T2DM in participants with IFG in a primary healthcare setting, although low-frequency and middle-frequency phone calls did not. Trial registration number This trial has been registered with the University Hospital Medical Information Network (UMIN000000662).

Japan Diabetes Outcome Intervention Trial-1(J-DOIT1), a nationwide cluster randomized trial of type 2 diabetes prevention by telephone-delivered lifestyle support for high-risk subjects detected at health checkups: rationale, design, and recruitment

BackgroundLifestyle modifications are considered the most effective means of delaying or preventing the development of type 2 diabetes (T2DM). To contain the growing population of T2DM, it is critical to clarify effective and efficient settings for intervention and modalities for intervention delivery with a wide population reach.The Japan Diabetes Outcome Intervention Trial-1 (J-DOIT1) is a cluster randomized controlled trial to test whether goal-focused lifestyle coaching delivered by telephone can prevent the development of T2DM in high-risk individuals in a real-world setting. This paper describes the study design and recruitment of the study subjects.MethodsFor the recruitment of study subjects and their follow-up annually over 3 years, we employed health checkups conducted annually at communities and worksites. Health care divisions recruited from communities and companies across Japan formed groups as a cluster randomization unit. Candidates for the study, aged 20-65 years with fasting plasma glucose (FPG) of 5.6-6.9 mmol/l, were recruited from each group using health checkups results in 2006. Goal-focused lifestyle support is delivered by healthcare providers via telephone over a one-year period. Study subjects will be followed-up for three years by annual health checkups. Primary outcome is the development of diabetes defined as FPG≥7.0 mmol/l on annual health checkup or based on self-report, which is confirmed by referring to medical cards.ResultsForty-three groups (clusters), formed from 17 health care divisions, were randomly assigned to an intervention arm (22 groups) or control arm (21 clusters) between March 2007 and February 2008. A total of 2840 participants, 1336 from the intervention and 1504 from the control arm, were recruited. Consent rate was about 20%, with no difference between the intervention and control arms. There were no differences in cluster size and characteristics of cluster between the groups. There were no differences in individual characteristics between the study arms.ConclusionWe have launched J-DOIT1, a nation-wide trial to prevent the development of T2DM in high-risk individuals using telephone-delivered intervention. This trial is expected to contribute to evidence-based real-world preventive practices.Trial registrationUMIN000000662.

Depressive symptoms, not completing a depression screening questionnaire, and risk of poor compliance with regular primary care visits in patients with type 2 diabetes: the Japan Diabetes Outcome Intervention Trial 2 (J-DOIT2) study group.

OBJECTIVES To explore the association between depressive symptoms as measured by the Center for Epidemiologic Studies Depression Scale or not completing the questionnaire and subsequent risk of poor compliance with regular visits to primary care physician in patients with type 2 diabetes. METHODS Using data from patients with type 2 diabetes who participated in the Japan Diabetes Outcome Intervention Trial 2 (J-DOIT2) Pilot Study, which was conducted at primary care settings, we examined the association between depressive symptoms or not completing the questionnaire and risk of poor compliance with regular visits as an event. RESULTS Among 1 584 patients who participated in the J-DOIT2 Pilot Study, we excluded 140 who did not meet inclusion criteria or who declined participation after randomization, leaving 1 444 for entry in the present analysis. During 1 409 person-years of follow-up (median 1 year), 90 events were observed (incidence rate 63.9/1 000 person-years). The multivariable-adjusted hazard ratio of poor compliance with regular visits in those having depressive symptoms was 1.23 (95% CI: 0.46-3.31). In contrast, the multivariable-adjusted hazard ratio of poor compliance in those not completing the questionnaire was 2.26 (95% CI: 1.94-2.63). CONCLUSION Not completing a questionnaire was significantly associated with an increased risk of poor compliance with the maintenance of regular visits to a primary care physician in patients with type 2 diabetes. Patients who do not comply with questionnaire surveys require increased attention to ensure their compliance with regular visits, and thereby ensure better diabetes outcomes.

Duration of diabetes and types of diabetes therapy in Japanese patients with type 2 diabetes: The Japan Diabetes Complication and its Prevention prospective study 3 (JDCP study 3)

To analyze the association between the duration of diabetes and selection of diabetes therapy in a large database of Japanese patients with type 2 diabetes.

Risk perception, self-efficacy, trust for physician, depression, and behavior modification in diabetic patients:

We evaluated the associations of risk perception, self-efficacy, and trust with two health promotion behaviors (food habits and exercise) and depressive mood. Diabetic patients aged between 40 and 64 (n = 1195) were included in the analyses. Risk perception worsened behavioral changes in terms of food habits and depression, whereas self-efficacy and trust improved food habits, exercise, and depression; trust improved exercise and depression. In conclusion, self-efficacy and trust appear to be more beneficial than risk perception for positive behavioral changes and for improving depression in diabetic patients. However, their influence on behavioral changes may be different according to the types of behaviors.