Search

Constipation was shown to be associated with higher risk of end-stage kidney disease or incident chronic kidney disease, although evidence in diabetic patients is lacking. The objective of the present study was to examine the association between constipation and diabetic kidney disease (DKD). In total, 4826 Japanese outpatients with type 2 diabetes were classified according to presence or absence of constipation (defecation frequency

Our aim was to compare the contributions of impaired beta cell function (IBF) and insulin resistance with the development of type 2 diabetes in a Japanese community. A total of 2094 residents aged 40–79 years without diabetes underwent a health examination including a 75 g OGTT in 2007. Participants were divided into four groups according to the presence or absence of IBF (insulinogenic index/HOMA-IR ≤28.5) and insulin resistance (HOMA-IR ≥1.61) and were followed up for 7 years (2007–2014). Cox’s proportional hazards model was used to estimate HRs and 95% CIs for type 2 diabetes. The population attributable fractions (PAFs) due to IBF, insulin resistance, and their combination were calculated. At baseline, the prevalence of isolated IBF, isolated insulin resistance, and both IBF and insulin resistance were 5.4%, 24.1% and 9.5%, respectively. During the follow-up period, 272 participants developed type 2 diabetes. The multivariable-adjusted HRs (95% CI) and PAFs (95% CI) for type 2 diabetes were 6.3 (4.3, 9.2) and 13.3% (8.7, 17.7) in the participants with isolated IBF, 1.9 (1.3, 2.7) and 10.5% (4.0, 16.6) in those with isolated insulin resistance, and 8.0 (5.7, 11.4) and 29.3% (23.0, 35.1) in those with both IBF and insulin resistance, respectively, compared with the participants without either. The present study suggests that the combination of IBF and insulin resistance makes the main contribution to the development of type 2 diabetes in Japanese communities.

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

Aims/Introduction Patients with type 2 diabetes mellitus have an increased hip fracture risk. We investigated the relationship between hip fracture and all‐cause death in patients with type 2 diabetes in comparison with cardiovascular disease (CVD) or end‐stage renal disease (ERSD). Materials and Methods In total, 4,923 Japanese participants with type 2 diabetes (mean age 65 years, 2,790 men, 2,133 women) were followed for a median of 5.3 years (follow‐up rate 99.5%). We evaluated the associations between the presence of hip fracture (n = 110), upper limb fracture (n = 801), CVD (n = 1,344), ESRD (n = 104) and all‐cause death by logistic regression analysis. Results A total of 309 participants died during follow up. Multivariate‐adjusted odds ratios (ORs) for all‐cause mortality were significantly higher in participants with hip fractures than those without hip fractures (OR 2.67, 95% confidence interval [CI] 1.54–4.41), whereas the ORs for upper limb fracture were not significant. The ORs for all‐cause mortality were significantly higher in participants with CVD than those without CVD (OR 1.78, 95% CI, 1.39–2.70) and ESRD (OR 2.36, 95% CI 1.32–4.05). The ORs for all‐cause mortality of hip fracture were not affected by further adjustment for CVD and ESRD (OR 2.74, 95% CI 1.58–4.54). The cause of death was infection (40.0%), malignant neoplasm (25.0%) and CVD (15.0%) among participants with hip fracture. Conclusions Hip fractures were associated with an increased risk of death among Japanese patients with type 2 diabetes, independently of CVD and ESRD., Hip fracture is associated with increased mortality in the general population, although few studies have investigated the impact of hip fractures on the risk of death in patients with type 2 diabetes who also have a higher prevalence of fatal diseases, such as cardiovascular disease, renal disease or malignant neoplasia. In this study, the presence of hip fracture was associated with an increased risk of death among Japanese patients with type 2 diabetes, independently of cardiovascular disease and end‐stage renal disease. It should be emphasized that hip fracture is a critical event in the aging population of patients with type 2 diabetes.

AIM The impact of glycaemic control on fracture risk is controversial, which may be due to the possible presence of hypoglycaemia. The aim of this study was to separately investigate the impacts of severe hypoglycaemia and poor glycaemic control on fracture risk in people with type 2 diabetes. METHODS Overall, 4706 Japanese participants (2755 men and 1951 postmenopausal women) with type 2 diabetes (mean age 66 years) were followed prospectively (a median of 5.3 years; follow-up rate, 97.6%), and were stratified by severe hypoglycaemia status and glycaemic control. The primary outcome was fractures at any anatomic site. RESULTS Fractures occurred in 662 participants (249 men and 413 women). The age- and sex-adjusted incidence rates (expressed per 1000 person-years) were: 71.2 (multiple episodes of severe hypoglycaemia), 43.1 (one episode), 25.2 [HbA1c

Epidemiological data regarding diabetic kidney disease are accumulated insufficiently in Japan. We prospectively investigated the incidence of end-stage renal disease (ESRD) and risk factors for progression of renal dysfunction in Japanese patients with type 2 diabetes. 4904 participants with type 2 diabetes (mean age 65 years, mean estimated glomerular filtration rate (eGFR) 75 mL/min/1.73 m2, proportion of eGFR

Constipation was shown to be associated with higher risk of end-stage kidney disease or incident chronic kidney disease, although evidence in diabetic patients is lacking. The objective of the present study was to examine the association between constipation and diabetic kidney disease (DKD).In total, 4826 Japanese outpatients with type 2 diabetes were classified according to presence or absence of constipation (defecation frequency 3 times/week and/or taking laxative medication). DKD was defined as presence of decreased estimated glomerular filtration rate (eGFR 60 ml/min/1.73 mCompared with participants without constipation, the age- and sex-adjusted odds ratio for presence of DKD was 1.58 (95% confidence interval 1.38-1.82) for those with constipation. This association persisted following adjustment for potential confounding factors. Decreased defecation frequency and laxative use were also significantly associated with higher prevalence of DKD. Overall, these findings were identical even when decreased eGFR and albuminuria were separately analyzed.Constipation was associated with higher likelihood of DKD in patients with diabetes, suggesting the importance of clinical assessment of constipation to identify patients at high risk of progression of kidney disease.

We prospectively investigated the association of urinary tubule injury markers with estimated glomerular filtration rate (eGFR) decline in Japanese patients with type 2 diabetes.Urinary kidney injury molecule 1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), liver-type fatty-acid-binding protein (L-FABP), and urinary albumin-to creatinine ratio (UACR) were measured in 2,685 participants with type 2 diabetes. Renal outcomes were ≥ 30% decline in eGFR from the baseline and annual eGFR decline for 5 years.In normoalbuminuric participants, no tubular markers were associated with ≥ 30% decline in eGFR or annual eGFR changes. In those with UACR ≥ 30 mg/gCr, hazard ratios for ≥ 30% eGFR decline were 1.37 (95% confident interval (CI) 1.07-1.75) for urinary KIM-1 (1.5 µg/gCr), 1.46 (95% CI 1.13-1.66) for urinary NGAL (16.4 µg/gCr), and 1.26 (95% CI 0.94-1.66) for urinary L-FABP (12.5 µg/gCr), 2.61 (95% CI 1.64-4.17) for the combination of 3 tubular markers above the cutoff after multivariable adjustments including UACR and eGFR.The current study demonstrated that urinary tubule injury markers and their combination were significant predictors for the future eGFR decline in those with type 2 diabetes and albuminuria independently of UACR and eGFR. Urinary tubular markers may be useful to identify high-risk patients with albuminuria.

OBJECTIVE: We estimated secular trends in the prevalence of type 2 diabetes (T2DM) and prediabetes, and examined potential explanatory factors for these trends in a Japanese community. METHODS: 4 cross-sectional examinations were conducted among subjects aged 40–79 years in 1988 (n = 2,490), 2002 (n = 2,856), 2007 (n = 2,761), and 2012 (n = 2,644). Glucose tolerance status was defined by a 75g oral glucose tolerance test. RESULTS: The age-standardized prevalence of T2DM increased significantly in both sexes from 1988 to 2002, and thereafter it remained stable in men, and decreased nonsignificantly in women from 2002 to 2012. The age-standardized prevalence of prediabetes in men increased significantly between 1988 and 2002, but then decreased significantly. A similar trend was observed in women. The age-specific prevalence of T2DM increased greatly in men aged 60–79 years and women aged 70–79 years from 1988 to 2002, and then plateaued at a high level, while a significant decreasing trend was observed in women aged 40–49 years. The mean values of body mass index (BMI) increased steeply in these elderly subjects from 1988 to 2002, and remained at a high level, whereas those in middle-aged women decreased appreciably over the study period. CONCLUSIONS: Our findings suggest that in Japanese, there was no further increase in the prevalence of T2DM or prediabetes in either men or women in the 2000s. Secular change in the BMI level was likely to contribute to trends in the prevalence of T2DM, and thus the management of obesity may be important to reduce the prevalence of T2DM. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13340-018-0380-0) contains supplementary material, which is available to authorized users.

Our aim was to compare the contributions of impaired beta cell function (IBF) and insulin resistance with the development of type 2 diabetes in a Japanese community.A total of 2094 residents aged 40-79 years without diabetes underwent a health examination including a 75 g OGTT in 2007. Participants were divided into four groups according to the presence or absence of IBF (insulinogenic index/HOMA-IR ≤28.5) and insulin resistance (HOMA-IR ≥1.61) and were followed up for 7 years (2007-2014). Cox's proportional hazards model was used to estimate HRs and 95% CIs for type 2 diabetes. The population attributable fractions (PAFs) due to IBF, insulin resistance, and their combination were calculated.At baseline, the prevalence of isolated IBF, isolated insulin resistance, and both IBF and insulin resistance were 5.4%, 24.1% and 9.5%, respectively. During the follow-up period, 272 participants developed type 2 diabetes. The multivariable-adjusted HRs (95% CI) and PAFs (95% CI) for type 2 diabetes were 6.3 (4.3, 9.2) and 13.3% (8.7, 17.7) in the participants with isolated IBF, 1.9 (1.3, 2.7) and 10.5% (4.0, 16.6) in those with isolated insulin resistance, and 8.0 (5.7, 11.4) and 29.3% (23.0, 35.1) in those with both IBF and insulin resistance, respectively, compared with the participants without either.The present study suggests that the combination of IBF and insulin resistance makes the main contribution to the development of type 2 diabetes in Japanese communities.

IntroductionThe impact of consuming green tea or coffee on mortality in patients with diabetes is controversial. We prospectively investigated the impact of each beverage and their combination on mortality among Japanese patients with type 2 diabetes.Research design and methodsIn all, 4923 patients (2790 men, 2133 women) with type 2 diabetes (mean age, 66 years) were followed prospectively (median, 5.3 years; follow-up rate, 99.5%). We evaluated the amount of green tea and coffee consumed using self-administered questionnaires.ResultsDuring the follow-up period, 309 participants died. The consumption of green tea, coffee, and a combination of the beverages was associated with reduced all-cause mortality. Multivariable-adjusted hazard ratios (95% CIs) for green tea were as follows: none 1.0 (referent); 0.85 (0.60–1.22) for ≤1 cup/day; 0.73 (0.51–1.03) for 2–3 cups/day; 0.60 (0.42–0.85) for ≥4 cups/day; and P for trend, 0.002. For coffee, they were: none 1.0 (referent); 0.88 (0.66–1.18) for ConclusionsHigher consumption of green tea and coffee was associated with reduced all-cause mortality: their combined effect appeared to be additive in patients with type 2 diabetes.

Aims We prospectively investigated the incidence of stroke and its subtypes, risk factors and prognosis in Japanese patients with type 2 diabetes. Methods A total of 4,875 participants with type 2 diabetes (mean age 65.4 years, male 57%, previous stroke 10%) were investigated for the development of stroke for 5 years. Risk factors were evaluated using multivariable adjusted Cox proportional models. Results The incidence rates per 1,000 person-years were 6.7 for new-onset stroke (ischemic 5.5, hemorrhagic 1.2) and 22.7 for recurrent stroke (ischemic 18.8, hemorrhagic 3.8), respectively. Ischemic stroke was significantly associated with age, male, reduced regular physical activity, HbA1c, diabetic kidney disease and previous stroke. Lacunar infarction was significantly associated with obesity, reduced regular physical activity, HbA1c and diabetic kidney disease, whereas atherothrombotic stroke was significantly associated with age, reduced intake of dietary fiber, reduced regular physical activity, HbA1c and previous stroke. Recurrent stroke was significantly associated with depressive symptom. Thirty-day and one-year survival was 76% and 64% for hemorrhagic stroke, and 96% and 91% for ischemic stroke, respectively. Conclusions The current study reemphasized the importance of glycemic control and lifestyle modification such as regular physical exercise for stroke prevention in patients with type 2 diabetes.

IntroductionGiven an increasing use of dipeptidyl peptidase-4 (DPP-4) inhibitors to treat patients with type 2 diabetes mellitus in the real-world setting, we conducted a prospective observational study (Japan-based Clinical Research Network for Diabetes Registry: J-BRAND Registry) to elucidate the safety and efficacy profile of long-term usage of alogliptin.Research design and methodsWe registered 5969 patients from April 2012 through September 2014, who started receiving alogliptin (group A) or other classes of oral hypoglycemic agents (OHAs; group B), and were followed for 3 years at 239 sites nationwide. Safety was the primary outcome. Symptomatic hypoglycemia, pancreatitis, skin disorders of non-extrinsic origin, severe infections, and cancer were collected as major adverse events (AEs). Efficacy assessment was the secondary outcome and included changes in hemoglobin A1c (HbA1c), fasting blood glucose, fasting insulin and urinary albumin.ResultsOf the registered, 5150 (group A: 3395 and group B: 1755) and 5096 (3358 and 1738) were included for safety and efficacy analysis, respectively. Group A patients mostly (>90%) continued to use alogliptin. In group B, biguanides were the primary agents, while DPP-4 inhibitors were added in up to ~36% of patients. The overall incidence of AEs was similar between the two groups (42.7% vs 42.2%). Kaplan-Meier analysis revealed the incidence of cancer was significantly higher in group A than in group B (7.4% vs 4.8%, p=0.040), while no significant incidence difference was observed in the individual cancer. Multivariate Cox regression analysis revealed that the imbalanced patient distribution (more elderly patients in group A than in group B), but not alogliptin usage per se, contributed to cancer development. The incidence of other major AE categories was with no between-group difference. Between-group difference was not detected, either, in the incidence of microvascular and macrovascular complications. HbA1c and fasting glucose decreased significantly at the 0.5-year visit and nearly plateaued thereafter in both groups.ConclusionsAlogliptin as a representative of DPP-4 inhibitors was safe and durably efficacious when used alone or with other OHAs for patients with type 2 diabetes in the real world setting.

In ectopic ACTH-secreting pheochromocytoma, combined ACTH-driven hypercortisolemia and hypercatecholaminemia are serious conditions, which can be fatal if not diagnosed and managed appropriately, especially when glucocorticoid-driven positive feedback is suggested with a high ACTH/cortisol ratio. A 46-year-old man presented with headache, rapid weight loss, hyperhidrosis, severe hypertension and hyperglycemia without typical Cushingoid appearance. Endocrinological examinations demonstrated elevated plasma and urine catecholamines, serum cortisol and plasma ACTH. Moreover, his ACTH/cortisol ratio and catecholamine levels were extremely high, suggesting catecholamine-dominant ACTH-secreting pheochromocytoma. Computed tomography revealed a large right adrenal tumor. 18F-FDG positron emission tomography showed uptake in the area of the adrenal tumor, while 123I-metaiodobenzylguanidine scintigraphy showed no accumulation. His plasma ACTH level paradoxically became elevated after a dexamethasone suppression test. After metyrapone administration, not only serum cortisol but also plasma ACTH levels were exponentially decreased almost in parallel, suggesting a glucocorticoid-driven positive-feedback regulation in this rapidly exacerbated ectopic ACTH-producing pheochromocytoma. Interestingly enough, plasma catecholamine levels were also decreased by metyrapone, although they remained extremely high. He became severely dehydrated due to hypoadrenalism requiring hydrocortisone supplementation. His clinical signs and symptoms were improved, and right adrenalectomy was performed uneventfully, resulting in complete remission of pheochromocytoma and Cushing's syndrome. A glucocorticoid-driven positive-feedback regulation in this ectopic ACTH-secreting pheochromocytoma created a vicious cycle with rapid exacerbation of both hypercortisolemia and hypercatecholaminemia with extremely elevated plasma ACTH level. Metyrapone was clinically effective to stop this vicious cycle; nonetheless, great care must be taken to avoid hypoadrenalism especially when hypercatecholaminemia remained.

AIMS To prospectively investigate the association between the number of prescribed drugs and the fracture risk in patients with type 2 diabetes. METHODS Japanese participants with type 2 diabetes (n = 4,706; 2,755 men, 1,951 postmenopausal women; mean age, 66 years) were followed for a median of 5.3 years and grouped on the basis of the number of prescribed drugs at baseline. The main outcomes were fractures at any anatomic site and fragility fractures (fractures at hip and spine sites). RESULTS During follow-up, any fracture occurred in 662 participants. The overall age- and sex-adjusted fracture incidence rates per 1,000 person-years were 21.2 (0-2 drugs), 28.1 (3-5 drugs), 37.7 (6-8 drugs), and 44.0 (≥9 drugs) (p for trend

Background Although statins deteriorate glucose metabolism, their glucose-lowering effects have emerged in some situations. Here, we assessed whether these effects are a consequence of statins’ interaction with paraoxonase (PON)1 enzyme polymorphism. Methods Adult Japanese type 2 diabetes patients (n = 3798) were enrolled in a cross-sectional study. We used Q192R polymorphism of the PON1 gene as a representative single-nucleotide polymorphism and focused on the effects of the wild-type Q allele, in an additive manner. For patients with and without statin therapy, the associations of this allele with fasting plasma glucose (FPG), HbA1c, C-peptide, HOMA2-%β, and HOMA2-IR were investigated separately using a linear regression model, and were compared between groups by testing interactions. Sensitivity analyses were performed using propensity score to further control the imbalance of characteristics between groups. Results Among patients with statin therapy, there were linear associations of the number of Q alleles with decreased FPG and HbA1c, and with increased serum C peptide and HOMA2-%β (all P

Little is known about the combined effects of unhealthy lifestyle behaviors on glycemia. The objective of this study was to examine the association between combined modifiable lifestyle and glycemic control, as well as markers of insulin resistance and secretion. In total, 4,870 patients with type 2 diabetes were sorted by lifestyle scores. Scores were determined by summing the number of unhealthy lifestyle factors that showed a significant association with hemoglobin A1c (HbA1c) (current smoking, decreased dietary fiber intake, eating quickly, inadequate sleep duration, and obesity). The associations between lifestyle score and hemoglobin A1c (HbA1c), homeostasis model assessment of insulin resistance (HOMA2-IR), and β-cell function (HOMA2-%B) were cross-sectionally analyzed. HbA1c increased progressively with increases in lifestyle score (p for trend

Background: Cholesterol uptake capacity (CUC) is a novel index of the functionality of serum high-density lipoprotein (HDL), which has been reported to be associated with insulin resistance and the cardiovascular risk. However, only a few studies investigated the association of CUC with the development of diabetes. Herein, we assessed the association of CUC with incident type 2 diabetes in a general Japanese population. Methods: A total of 2,162 subjects aged 40-79 years without diabetes underwent comprehensive health examination including 75g OGTT and were followed-up prospectively for a median of 6.0 years. The amount of HDL-contained cholesterol per apolipoprotein A1 levels after incubating the participants’ HDL with cholesterol as CUC were measured at baseline. CUC levels were categorized into quartiles (Q1: Results: During the follow-up period, 219 subjects experienced diabetes. The multivariable-adjusted HR (95% CI) was significantly decreased with elevating levels of CUC: 1.00 (reference) in Q1, 0.83 (0.57, 1.20) in Q2, 0.77 (0.52, 1.14) in Q3 and 0.64 (0.42, 0.98) in Q4 (p=0.04 for trend). In the analysis combined serum HDL cholesterol level (≤50mg/dl [25 percentile value] vs. >51 mg/dl) and CUC (Q1-Q3 vs. Q4), HRs (95% CIs) for the incident diabetes compared to both low group were 0.72 (0.36, 1.45) in isolated high CUC group, 0.73 (0.50, 1.06) in isolated high HDL cholesterol group, and 0.56 (0.34, 0.93) in both high group (p=0.88 for interaction). Conclusion: Our findings suggest that the risk of diabetes decreased with elevating CUC levels independent of HDL cholesterol levels in the general Japanese population. Disclosure Y. Hirakawa: None. R. Toh: Other Relationship; Self; Sysmex Corporation. M. Higashioka: None. M. Yoshinari: None. T. Honda: None. D. Yoshida: None. J. Hata: None. U. Nakamura: None. T. Kitazono: None. T. Ninomiya: Research Support; Self; Asahi Kasei Corporation, Denka Company Limited, DeSC Healthcare, Inc, Mochida Pharmaceutical Co., Ltd., Suntory Beverage & Food Limited, Sysmex Corporation. Funding Japan Ministry of Education, Culture, Sports, Science and Technology; Japan Ministry of Health, Labour and Welfare; Japan Agency for Medical Research and Development

Objective: Impaired insulin secretion (IIS) and insulin resistance (IR) are the two main mechanisms for type 2 diabetes (T2D), but IIS has been reported to contribute to incident T2D more than IR in Asian populations. However, we assumed that the impact of IR on the incident T2D was being greater in the recent Japanese population, because the burden of obesity increased. Herein, we addressed the magnitude of the contribution of IIS and IR to the development of T2D in a Japanese community. Methods: In 2007, a total of 2,108 residents aged 40-79 years (participation rate 77.1%) without diabetes at baseline underwent health examination including 75g OGTT, insulinogenic index (IGI), and HOMA-IR. Subjects were divided into 4 groups according to the presence or absence of IIS (IGI ≤ 0.4) and IR (1.6 ≤ HOMA-IR) and were followed-up prospectively for a median of 6.9 years. A Cox’s proportional hazards model was used to estimate the hazard ratios and 95% confidential intervals (CIs) for incident T2D with adjustment for confounders. The population attributable fraction (PAF) for the development of diabetes due to IS, IR and their combination were calculated. Result: At baseline, the proportions of subjects with neither of IIS nor IR, isolated IIS, isolated IR, and both IIS and IR were 45.5%, 21.0%, 28.7%, and 4.8%, respectively. During follow-up period, 273 subjects developed T2D. The risk of incident T2D was 5.3 (95% CI 3.6-7.9) times higher in subjects with isolated IIS, 4.1 (2.8-6.2) times higher in subjects with isolated IR, and 13.5 (8.5-21.5) times higher in subjects with both IIS and IR than subjects with neither of IIS nor IR. The PAFs on the excess risk of T2D among subjects with isolated IIS, isolated IR and both IIS and IR were 25.8%, 29.1%, and 15.9%, respectively. Conclusion: Our finding suggests that IIS and IR contributed equally to the development of T2D in the recent general Japanese population. Disclosure M. Yoshinari: None. Y. Hirakawa: None. J. Hata: None. M. Higashioka: None. T. Honda: None. D. Yoshida: None. N. Mukai: None. U. Nakamura: None. T. Kitazono: None. T. Ninomiya: Research Support; Self; Asahi Kasei Corporation, Denka Company Limited, DeSC Healthcare, Inc, Mochida Pharmaceutical Co., Ltd., Suntory Beverage & Food Limited, Sysmex Corporation.

BACKGROUND: Although the association between type 2 diabetes and cancer has been reported, few epidemiological studies have been conducted in Japanese patients whose leading cause of death is cancer. We prospectively studied the incidence of site-specific cancer, risk factors for developing cancer, cancer death, and survival in Japanese patients with type 2 diabetes. METHODS: We followed 4923 participants (mean age, 65 years) with type 2 diabetes attending an outpatient diabetes clinic for a median of 5.3 years (follow-up rate, 99.0%). RESULTS: During the follow-up period, cancer occurred in 450 participants (incidence rate, 22.3/1000 person-years in men and 12.2/1000 person-years in women). In men, prostate cancer was the most common cancer (4.3/1000 person-years), colorectal cancer was the second (3.6/1000 person-years), and gastric cancer was the third (3.3/1000 person-years). In women, colorectal cancer was the most common cancer (2.6/1000 person-years), gastric cancer was the second (2.0/1000 person-years), and breast cancer was the third (1.4/1000 person-years). Smoking, male sex, low-density lipoprotein cholesterol, family history of cancer, and reduced intake of isoflavone daidzein were significant risk factors for developing cancer using multivariable Cox proportional hazards models. The leading cancer death was lung cancer in men and pancreatic cancer in women. The survival was the best for prostate cancer and the worst for pancreatic cancer (2-year cancer-specific survival 95.4%, 30.0%, respectively). CONCLUSIONS: Since the leading cause of death in patients with type 2 diabetes is cancer in Japan, clinicians should be aware of epidemiological data regarding cancer besides diabetic complications.

Aims Constipation has been shown to be associated with a higher risk of diabetes. However, few studies have evaluated the relationship between defecation frequency, one of the major symptoms of constipation, and glycemic control in patients with diabetes. The aim of the present study was to determine the relationship between defecation frequency and HbA1c in patients with diabetes. Methods We determined the relationship between defecation frequency and HbA1c in 5029 patients with diabetes in the Fukuoka Diabetes Registry, a multi-center prospective cohort study conducted in diabetes specialist outpatient clinic (mean age 64.9 years, men 55%). Participants were classified according to their defecation frequency: ≥7, 3– Results Low defecation frequency was linearly associated with high HbA1c, with mean levels of 7.41% (95% confidence interval, 7.37–7.44%), 7.54% (7.49–7.60%) and 7.63% (7.52–7.74%) for patients with defecation frequencies of ≥7 times/week, 3– Conclusions The present study suggests the importance of assessing defecation frequency in the management of diabetes.

Cigarette smoking is an important modifiable risk factor for lifestyle diseases. The smoking rate remains high, and the prevalence of diabetes mellitus is increasing in Asian countries; however, few studies have examined the effects of smoking on chronic kidney disease (CKD) in Asian diabetic patients. The aim of the present study was to investigate the association between smoking and its cessation with CKD and its components in patients with type 2 diabetes. A total of 2770 Japanese male patients with type 2 diabetes aged ⩾20 years were divided according to the amount of cigarette smoking and the years since cessation. The associations with CKD, the urinary albumin-creatinine ratio (UACR) and the estimated glomerular filtration rate (eGFR) were cross-sectionally examined. The proportions of CKD and the mean UACR dose-dependently increased with increases in both the number of cigarettes per day and the Brinkman index compared with the never smokers. The creatinine-based eGFR also increased with increases in the amount of smoking, whereas the cystatin C-based eGFR decreased, and their average did not significantly change. These parameters exhibited inverse associations with the years after smoking cessation compared with the association with the amount of smoking. A dose-dependent association of active smoking and a graded inverse association of the years since quitting with CKD enhance the merit of smoking cessation in patients with type 2 diabetes.

Aims Sarcopenia is involved in the pathogenesis of increased fracture risk associated with diabetes. The serum creatinine to cystatin C (Cr/CysC) ratio has been reported as a surrogate marker for muscle mass. We aimed to prospectively investigate the relationship between the Cr/CysC ratio and fracture risk. Methods We followed 1911 postmenopausal women and 2689 men with type 2 diabetes (mean age, 66 years) for a median of 5.3 years, and divided into Cr/CysC ratio quartiles by sex. The primary outcome was fragility fractures and the secondary outcome was any fracture. Results Fragility fractures occurred in 192 participants, and any fracture occurred in 645 participants. Multivariate-adjusted hazard ratios (95% CI) for fragility fractures were 2.15 (1.19–3.88) (Q1), 1.63 (0.89–2.98) (Q2), 1.34 (0.72–2.51) (Q3) and 1.0 (ref.) (Q4) in postmenopausal women, and 1.75 (0.64–4.50) (Q1), 2.09 (0.83–5.26) (Q2), 1.56 (0.58–4.18) (Q3) and 1.0 (ref.) (Q4) in men. Those for any fracture were 1.46 (1.07–1.98) (Q1), 1.33 (0.98–1.81) (Q2), 1.40 (1.03–1.88) (Q3) and 1.0 (ref.) (Q4) in postmenopausal women, and 2.33 (1.54–3.54) (Q1), 2.02 (1.54–3.04) (Q2), 1.13 (0.71–1.78) (Q3) and 1.0 (ref.) (Q4) in men. Conclusions A lower Cr/CysC ratio is a significant risk factor for fractures in patients with type 2 diabetes.

In ectopic ACTH-secreting pheochromocytoma, combined ACTH-driven hypercortisolemia and hypercatecholaminemia are serious conditions, which can be fatal if not diagnosed and managed appropriately, especially when glucocorticoid-driven positive feedback is suggested with a high ACTH/cortisol ratio. A 46-year-old man presented with headache, rapid weight loss, hyperhidrosis, severe hypertension and hyperglycemia without typical Cushingoid appearance. Endocrinological examinations demonstrated elevated plasma and urine catecholamines, serum cortisol and plasma ACTH. Moreover, his ACTH/cortisol ratio and catecholamine levels were extremely high, suggesting catecholamine-dominant ACTH-secreting pheochromocytoma. Computed tomography revealed a large right adrenal tumor.

Background Several studies have suggested that decreased muscle volume is associated with attenuation of immune function. The recipient's immune system is responsible for rejection of transplanted organs, which is a major cause of graft loss after transplantation. We aimed to determine whether muscle volume is correlated with graft survival after pancreas transplantation (PT). Methods Forty-three patients underwent PT for type 1 diabetes mellitus at our institution from August 2001 to May 2016. The quantity of skeletal muscle was evaluated using the psoas muscle mass index (PMI). The correlation between PMI and outcome after PT was assessed. Results A total of 32 and 11 recipients underwent simultaneous pancreas–kidney transplantation (SPK) and PT alone/pancreas after kidney transplantation, respectively. Patients with a surviving graft showed a significantly lower PMI than those with graft loss (P = .0451). We divided the recipients into two groups according to the PMI cutoff values, which were established using receiver operating characteristic curves. The cumulative graft survival rate was significantly higher in patients with a low PMI (P = .0206). A multivariate Cox regression analysis revealed that a low PMI (P = .0075) is an independent predictive factor for better graft survival. A low PMI was not a significant predictive factor for acute rejection, but was an independent predictive factor for graft survival after the first acute rejection (P = .0025). Conclusions Our data suggest that muscle volume could be a predictor of graft survival after PT.

Aims/Introduction A younger age at menarche is associated with obesity and type 2 diabetes in adult life. The impact of early‐onset menarche on obesity and glycemic control in type 2 diabetes has not been investigated. The present study examined the relationship between age at menarche and obesity and glycemic control in type 2 diabetes. Materials and Methods A total of 2,133 patients with type 2 diabetes aged ≥20 years were divided into groups according to age at menarche (≤11, 12, 13, 14 and ≥15 years). A retrospective cohort study examined the association of menarcheal age with adiposity and hemoglobin A1c. Results Age at menarche was inversely associated with body mass index (BMI) and abdominal circumference (P < 0.001). Each 1‐year decrease in age at menarche was associated with a 0.25‐kg/m2 and 0.6‐cm increase in BMI and abdominal circumference, respectively, using a multivariate‐adjusted model. Odds ratios for obesity and abdominal obesity significantly increased in participants with age at menarche ≤11 years after multivariable adjustments when age at menarche of 13 years was used as the reference (odds ratio 1.95, 95% CI 1.33–2.88, odds ratio 1.95, 95% CI 1.32–2.87, respectively). Younger age at menarche was significantly associated with higher hemoglobin A1c (P < 0.001); however, the association was not statistically significant after adjusting for BMI. Conclusions Age at menarche of ≤11 years was associated with obesity after adjusting for confounding factors, and poor glycemic control associated with high BMI in type 2 diabetes. Age at menarche should be considered during clinical assessments.

Background Renal transplantation has been established as a treatment for end-stage renal disease (ESRD) due to diabetic nephropathy. However, few studies have focused on the outcome after renal transplantation in patients with ESRD and type 2 diabetic nephropathy. To investigate the effect of renal transplantation on ESRD with type 2 diabetic nephropathy, we retrospectively analyzed patients who received renal transplantation at our facility. This study aimed to compare the outcome of renal transplantation for type 2 diabetic nephropathy with that for nondiabetic nephropathy. Methods We studied 290 adult patients, including 65 with type 2 diabetic nephropathy (DM group) and 225 with nondiabetic nephropathy (NDM group), who underwent living-donor renal transplantation at our facility from February 2008 to March 2013. We compared the 2 groups retrospectively. Results In the DM and NDM groups, the 5-year patient survival rates were 96.6% and 98.7%, and the 5-year graft survival rates were 96.8% and 98.0%, respectively, with no significant differences between the groups. There were no significant differences in the rates of surgical complications, rejection, and infection. The cumulative incidence of postoperative cardiovascular events was higher in the DM group than in the NDM group (8.5% vs 0.49% at 5 years; P = .002). Conclusions Patient and graft survival rates after renal transplantation for type 2 diabetic nephropathy are not inferior to those for recipients without diabetic nephropathy. Considering the poor prognosis of patients with diabetic nephropathy on dialysis, renal transplantation can provide significant benefits for these patients.

Background Simultaneous pancreas-kidney transplantation (SPK) is a definitive treatment for type 1 diabetics with end-stage renal disease (ESRD). Because of the shortage of deceased donors in Japan, the mortality rate during the waiting period is high. We evaluated mortality risk in patients with type 1 diabetes waiting for SPK, and the benefit of living-donor kidney transplantation (LDK) preceding pancreas transplantation, which may reduce mortality in patients awaiting SPK. Methods This retrospective study included 71 patients with type 1 diabetes. Twenty-six patients underwent SPK, 15 underwent LDK, and 30 were waiting for SPK. Their cumulative patient and graft survival rates were retrospectively evaluated. Risk factors contributing to mortality in patients with type 1 diabetes awaiting SPK were evaluated with the use of a Cox proportional hazards model. Results The 5-year cumulative patient survival rates in the SPK and LDK groups were 100% and 93.3%, respectively (P = .19), and 5-year kidney graft survival rates were 95.7% and 100% (P = .46), respectively. The cumulative survival rate in patients awaiting SPK was 77.7% at 5 years after registration. Duration of dialysis was the only factor significantly associated with patient and graft survivals according to both univariate and multivariate analyses. Conclusions Patient and graft survival rates were similar in the SPK and LDK groups, but the survival rate of patients awaiting SPK decreased over time. Duration of dialysis was an independent risk factor for patient and graft survival. LDK preceding pancreas transplantation may be an effective therapeutic option for patients with type 1 diabetes and ESRD.

OBJECTIVE There is growing evidence that weight loss is associated with increased fracture risk in the general population. As patients with diabetes often lose weight intentionally or unintentionally, we aimed to investigate prospectively the relationship between weight loss from maximum body weight and fracture risk. RESEARCH DESIGN AND METHODS A total of 4,706 Japanese participants with type 2 diabetes (mean age 66 years), including 2,755 men and 1,951 postmenopausal women, were followed for a median of 5.3 years and were divided according to weight loss from maximum weight: RESULTS During the follow-up period, fragility fractures occurred in 198 participants. The age- and sex-adjusted incidence rates per 1,000 person-years in all participants were 6.4 ( CONCLUSIONS The current study demonstrates that ≥20% body weight loss from maximum weight is a significant risk factor for fragility fractures in patients with type 2 diabetes, especially in men.

Aims Although diabetic foot ulcer (DFU) is a serious diabetic complication, there have been no large-scale epidemiological studies of DFU in Japan. We prospectively investigated the incidences of DFU and limb amputation, the risk for developing DFU, and mortality in Japanese patients with type 2 diabetes. Methods We followed 4870 participants (mean age, 65 years) with type 2 diabetes attending an outpatient diabetes clinic for a median of 5.3 years (follow-up rate, 97.7%). The primary outcome was the development of DFU. Results During the follow-up period, DFU occurred in 74 participants (incidence rate, 2.9/1000 person-years) and limb amputation in 12 (incidence rate, 0.47/1000 person-years). DFU recurrence was observed in 21.4% of participants with history of DFU. History of DFU, chronic kidney disease (estimated glomerular filtration rate Conclusions Incidences of DFU and limb amputation were 0.3% and 0.05% per year in this Japanese cohort, respectively. Mortality significantly increased approximately 2-fold in those with DFU and/or history of DFU compared with those without.

Background Living pancreas transplantation plays an important role in the treatment of patients with severe type 1 diabetes. However, pancreatectomy is very invasive for the donor, and less-invasive surgical procedures are needed. Although some reports have described hand-assisted laparoscopic surgery for distal pancreatectomy in living-donor operations, less-invasive laparoscopy-assisted (LA) procedures are expected to increase the donor pool. We herein report the outcomes of four cases of LA spleen-preserving distal pancreatectomy (Warshaw technique [WT]) in living pancreas donors. Patients and Methods Four living pancreas donors underwent LA-WT at our institution from September 2010 to January 2013. All donors fulfilled the donor criteria established by the Japan Society for Pancreas and Islet Transplantation. Results The median donor age was 54 years. Two donors underwent left nephrectomy in addition to LA-WT for simultaneous pancreas–kidney transplantation. The median donor operation time for pancreatectomy was 340.5 minutes. The median pancreas warm ischemic time was 3 minutes. The median donor blood loss was 246 g. All recipients immediately achieved insulin independence. One donor required reoperation because of obstructive ileus resulting from a port-site hernia. Another donor developed a pancreatic fistula (International Study Group of Pancreatic Fistula grade B), which was controlled with conservative management. After a maximum follow-up of 73 months, no clinically relevant adverse events had occurred. These results were comparable with those of previous studies concerning living-donor pancreas transplantation. Conclusion The LA-WT is a safe and acceptable operation for living-donor pancreas transplantation.

We describe the case of a 51-year-old Japanese man with an end-stage kidney disease caused by a 30-year history of type 1 diabetes mellitus. The patient had suffered repeated bilateral multiple brain infarctions within a short period of time after the initiation of a self-managed daily home hemodialysis regimen using a long-term indwelling catheter inserted into the right atrium. Despite extensive examinations, we could not find any embolic causes except for the catheter and a patent foramen ovale (PFO). The patient had experienced repeated brain infarctions under antiplatelet and anticoagulation therapies, but suffered no further brain infarctions after the removal of the catheter and the alteration of vascular access from the catheter to an arteriovenous fistula in the forearm. We speculate that the indwelling catheter-associated thrombi or air and the right-to-left shunt through the PFO may have caused the repeated paradoxical brain embolisms in this patient.

Serum adiponectin has been reported to impact upon fracture risk in the general population. Although type 2 diabetes is associated with increased fracture risk, it is unclear whether serum adiponectin predicts fractures in individuals with type 2 diabetes. The aim of the study was to prospectively investigate the relationship between serum adiponectin and fracture risk in individuals with type 2 diabetes. In this study, data was obtained from The Fukuoka Diabetes Registry, a multicentre prospective study designed to investigate the influence of modern treatments on the prognoses of patients with diabetes mellitus. We followed 4869 participants with type 2 diabetes (mean age, 65 years), including 1951 postmenopausal women (defined as self-reported amenorrhea for >1 year) and 2754 men, for a median of 5.3 years. The primary outcomes were fractures at any site and major osteoporotic fractures (MOFs). During the follow-up period, fractures at any site occurred in 682 participants, while MOFs occurred in 277 participants. Age-adjusted HRs (95% CIs) of any fracture and MOFs for 1 SD increment in log e -transformed serum adiponectin were 1.27 (1.15, 1.40) and 1.35 (1.17, 1.55) in postmenopausal women and 1.22 (1.08, 1.38) and 1.40 (1.15, 1.71) in men, respectively. HRs (95% CIs) of MOFs for hyperadiponectinaemia (≥ 20 μg/ml) were 1.72 (1.19, 2.50) in postmenopausal women and 2.19 (1.23, 3.90) in men. The per cent attributable risk of hyperadiponectinaemia for MOFs was as high as being age ≥70 years or female sex. Higher serum adiponectin levels were significantly associated with an increased risk of fractures at any site and with an increased risk of MOFs in individuals with type 2 diabetes, including postmenopausal women.

Sleep duration is suggested to be associated with adverse health outcomes. However, few studies are available on the impact of sleep duration on metabolic syndrome in patients with diabetes, who were at high risk for cardiovascular diseases (CVD). The objective of the present study was to examine the associations of sleep duration with metabolic syndrome and insulin resistance, a major pathophysiologic feature of metabolic syndrome, in patients with type 2 diabetes.A total of 4402 Japanese patients with type 2 diabetes aged ≥20years were divided into 5 groups according to self-reported sleep duration: less than 5.5h, 5.5-6.4h, 6.5-7.4h, 7.5-8.4h, and more than 8.5h. The associations of sleep duration with metabolic syndrome and other cardiovascular risk factors were examined cross-sectionally.The proportions of patients who had metabolic syndrome increased significantly in both patients with shorter and longer sleep duration compared with those with 6.5-7.4h of sleep (P for quadratic trend0.001). This U-shaped association remained significant after adjustment for potential confounders, including total energy intake, current smoking, current drinking and depressive symptoms. Each component of metabolic syndrome also showed similar trends. Furthermore, sleep duration had a quadratic association with homeostasis model assessment of insulin resistance and high sensitivity C-reactive protein.Sleep duration was shown to have a U-shaped relationship with metabolic syndrome and insulin resistance, independent of potential confounders, and therefore may be an important modifiable risk factor for CVD prevention in patients with type 2 diabetes.

Aims/Introduction We examined secular trends in the prevalence of type 2 diabetes and prediabetes in community-dwelling Japanese subjects. Materials and Methods A total of 2,490 subjects in 1988 and 2,852 subjects in 2002 aged 40–79 years underwent a 75-g oral glucose tolerance test, and their glucose tolerance status was defined by the 1998 World Health Organization criteria. Results The age-adjusted prevalence of type 2 diabetes increased significantly from 1988 to 2002 in men (14.6% in 1988 to 20.8% in 2002, P

There is little information about the predictive ability of cystatin C-based estimated glomerular filtration rates (eGFRCys) for all-cause mortality in Asian populations. We compared the discriminatory ability of eGFRCys for all-cause mortality with that of creatinine-based estimated glomerular filtration rates (eGFRCr) in Japanese patients with type 2 diabetes. A total of 4869 participants were classified into four categories (eGFR ≤29, 30–59, 60–89, and ≥90 ml/min/1.73 m2) by eGFRCr and eGFRCys, and followed up for a median of 3.3 years. 150 deaths were identified. The multivariable-adjusted risk of all-cause mortality was significantly increased in eGFRCr ≤29 ml/min/1.73 m2 compared with eGFRCr ≥90 ml/min/1.73 m2 [hazard ratio (HR) 2.4 (95 % confidence interval (95 % CI) 1.2–5.0)], whereas it was significantly increased in eGFRCys 59 ml/min/1.73 m2 or lower [30–59 ml/min/1.73 m2, HR 1.9 (95 % CI 1.1–3.5); ≤29 ml/min/1.73 m2, HR 5.8 (95 % CI 2.8–12.0)]. Comparing eGFRCys with eGFRCr, the proportions of participants reclassified to lower and higher eGFR stages were 6.3 and 28.8 %, respectively. The multivariable-adjusted HRs for all-cause mortality were 1.8 (95 % CI 1.1–2.9) and 0.7 (95 % CI 0.4–1.1), respectively. The C statistic of the model including eGFRCys and other risk factors was significantly increased compared with the model including eGFRCr. The net reclassification improvement and the integrated discrimination improvement were significantly positive. Our findings suggest that eGFRCys has a stronger association with all-cause mortality and is superior to eGFRCr for predicting all-cause mortality in Japanese patients with type 2 diabetes.

Pancreatic islets express the superoxide-producing nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system, but its role remains unknown. To address this, we studied the mechanisms of impaired insulin secretion induced by diphenyleneiodium (DPI), an NADPH oxidase inhibitor. We investigated the effects of DPI on glucose- and nonfuel-stimulated insulin secretion, islet glucose metabolism, and intracellular Ca2+ concentration ([Ca2+]i) dynamics in rat islets and β-cell line RINm5F cells. DPI did not affect insulin secretion at 3.3 mm glucose but totally suppressed insulin secretion stimulated by 16.7 mm glucose (percentage of control, 9.2 ± 1.2%; P

Background It is not clear which glucose measure is more useful in the assessment of atherosclerosis. We investigated the associations of hemoglobin A1c (HbA1c), glycated albumin (GA), 1,5-anhydroglucitol (1,5-AG), fasting plasma glucose (FPG), and 2-hour postload glucose (PG) with carotid intima-media thickness (IMT) in community-dwelling Japanese subjects. Methods A total of 2702 subjects aged 40–79 years underwent a 75-g oral glucose tolerance test and measurements of HbA1c, GA, 1,5-AG, and carotid IMT by ultrasonography in 2007–2008. Carotid wall thickening was defined as a maximum IMT of >1.0 mm. The crude and multivariable-adjusted linear and logistic regression models were used to analyze cross-sectional associations between levels of glycemic measures and carotid IMT. Results The crude average of the maximum IMT increased significantly with rising quartiles of HbA1c, GA, FPG, and 2-hour PG levels in subjects with and without glucose intolerance (GI), while no clear association was observed for 1,5-AG. After adjustment for other confounding factors, positive trends for HbA1c, GA, and FPG (all p for trend