Incidence of end-stage renal disease and risk factors for progression of renal dysfunction in Japanese patients with type 2 diabetes: the Fukuoka Diabetes Registry.

BACKGROUND: 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. METHODS: 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 < 60 mL/min/1.73 m2 21%) were investigated for the progression to ESRD requiring dialysis in multicenter outpatients registry for 5 years. Risk factors for progression of renal dysfunction (≥ 30% decline in eGFR from the baseline and annual eGFR decline rates) were evaluated. RESULTS: The incidence rates of ESRD and all-cause mortality were 4.1/1000 person-years and 12.3/1000 person-years, respectively, and increased according to stages of chronic kidney disease (eGFR < 30 mL/min/1.73 m2, incidence of ESRD 176.6/1000 person-years, all-cause mortality 57.4/1000 person-years). Incidence of ≥ 30% decline in eGFR from the baseline was 16.4% at 5 years, and the mean annual decline rate was -1.84 mL/min/1.73 m2/year. The progression of renal dysfunction was significantly associated with older age, poor glycemic control, blood pressure, albuminuria, eGFR, previous cardiovascular disease, lifestyle factors (body mass index, reduced intake of dietary fiber, increased intake of sodium, no regular exercise), and depressive symptoms. CONCLUSIONS: This prospective study has emphasized the importance of multifactorial interventions on risk factors to suppress the high incidence of ESRD in Japanese patients with type 2 diabetes.

Comparison of the contributions of impaired beta cell function and insulin resistance to the development of type 2 diabetes in a Japanese community: the Hisayama Study.

AIMS/HYPOTHESIS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS/INTERPRETATION: 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.

Constipation and diabetic kidney disease: The Fukuoka Diabetes Registry.

BACKGROUND: 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). METHODS: 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 m2), and/or albuminuria (urinary albumin-to-creatinine ratio ≥ 30 mg/g). Odds ratios for the presence of DKD were computed by a logistic regression model. RESULTS: Compared 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. CONCLUSIONS: 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.

Metyrapone-responsive ectopic ACTH-secreting pheochromocytoma with a vicious cycle via a glucocorticoid-driven positive-feedback mechanism.

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.

Serum adiponectin predicts fracture risk in individuals with type 2 diabetes: the Fukuoka Diabetes Registry.

AIMS/HYPOTHESIS: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS/INTERPRETATION: 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.

The gene-treatment interaction of paraoxonase-1 gene polymorphism and statin therapy on insulin secretion in Japanese patients with type 2 diabetes: Fukuoka diabetes registry.

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-%ß, 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-%ß (all P < 0.01 for trends), while such associations were not observed among those without statin therapy. These differences were statistically significant only for serum C peptide and HOMA2-%ß (P < 0.01 for interactions). These associations remained significant after multiple explanatory variable adjustment. Sensitivity analyses using propensity score showed broad consistency of these associations. CONCLUSIONS: Patients with the Q allele of the PON1 Q192R polymorphism who were treated with statins exhibited improvement in glucose metabolism, especially in insulin secretion, suggesting the importance of genotyping PON1 Q192R to identify those who could benefit from statin therapy.

Comparison of cystatin C- and creatinine-based estimated glomerular filtration rates for predicting all-cause mortality in Japanese patients with type 2 diabetes: the Fukuoka Diabetes Registry.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Repeated Paradoxical Brain Infarctions in a Patient on Self-Managed Home Hemodialysis Using a Long-Term Indwelling Catheter.

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.

Association of hemoglobin A1c and glycated albumin with carotid atherosclerosis in community-dwelling Japanese subjects: the Hisayama Study.

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 < 0.05), but not 2-hour PG (p = 0.07) remained robust in subjects with GI, but no such associations were found in those without GI. When estimating multivariable-adjusted ß values for the associations of 1 SD change in glycemic measures with the maximum IMT in subjects with GI, the magnitude of the influence of HbA1c (ß = 0.021), GA (ß = 0.024), and FPG (ß = 0.024) was larger than that of 2-hour PG (ß = 0.014) and 1,5-AG (ß = 0.003). The multivariable-adjusted odds ratios for the presence of carotid wall thickening increased significantly with elevating HbA1c, GA, and FPG levels only in subjects with GI (all p for trend < 0.001). Among subjects with GI, the area under the receiver operating characteristic curve significantly increased by adding HbA1c (p = 0.04) or GA (p = 0.04), but not 1,5-AG, FPG, or 2-hour PG, to the model including other cardiovascular risk factors. CONCLUSIONS: In community-dwelling Japanese subjects with GI, elevated HbA1c, GA, and FPG levels were significantly associated with increased carotid IMT, and HbA1c and GA provided superior discrimination for carotid wall thickening compared to 1,5-AG, FPG, and 2-hour PG, suggesting that HbA1c and GA are useful for assessing carotid atherosclerosis.

Thresholds of various glycemic measures for diagnosing diabetes based on prevalence of retinopathy in community-dwelling Japanese subjects: the Hisayama Study.

BACKGROUND: There has been controversy over the diagnostic thresholds of hemoglobin A1c (HbA1c) for diabetes. In addition, no study has examined the thresholds of glycated albumin (GA) and 1,5-anhydroglucitol (1,5-AG) for diagnosing diabetes using the presence of diabetic retinopathy (DR). We examined the optimal thresholds of various glycemic measures for diagnosing diabetes based on the prevalence of DR in community-dwelling Japanese subjects. METHODS: A total of 2,681 subjects aged 40-79 years underwent a 75-g oral glucose tolerance test, measurement of HbA1c, GA, and 1,5-AG, and an ophthalmic examination in 2007-2008. The associations of glycemic measures with DR status were examined cross-sectionally. DR was assessed by an examination of the fundus photograph of each eye and graded according to the International Clinical Diabetic Retinopathy Disease Severity Scale. We divided the values of glycemic measures into ten groups on the basis of deciles. The receiver operating characteristic (ROC) curve analysis was performed to determine the optimal threshold of each glycemic measure for detecting the presence of DR. RESULTS: Of the subjects, 52 had DR. The prevalence of DR increased steeply above the ninth decile for fasting plasma glucose (FPG) (6.2-6.8 mmol/l), for 2-hour postload glucose (PG) (9.2-12.4 mmol/l), for HbA1c (5.9-6.2% [41-44 mmol/mol]), and for GA (16.2-17.5%), and below the second decile for 1,5-AG (9.6-13.5 µg/mL). The ROC curve analysis showed that the optimal thresholds for DR were 6.5 mmol/l for FPG, 11.5 mmol/l for 2-hour PG, 6.1% (43 mmol/mol) for HbA1c, 17.0% for GA, and 12.1 µg/mL for 1,5-AG. The area under the ROC curve (AUC) for 2-hour PG (0.947) was significantly larger than that for FPG (0.908), GA (0.906), and 1,5-AG (0.881), and was marginally significantly higher than that for HbA1c (0.919). The AUCs for FPG, HbA1c, GA, and 1,5-AG were not significantly different. CONCLUSIONS: Our findings suggest that the FPG and HbA1c thresholds for diagnosing diabetes in the Japanese population are lower than the current diagnostic criterion, while the 2-hour PG threshold is comparable with the diagnostic criterion. 2-hour PG had the highest discriminative ability, whereas FPG, HbA1c, GA, and 1,5-AG were similar in their ability.

Impact of dietary fiber intake on glycemic control, cardiovascular risk factors and chronic kidney disease in Japanese patients with type 2 diabetes mellitus: the Fukuoka Diabetes Registry.

BACKGROUND: Dietary fiber is beneficial for the treatment of type 2 diabetes mellitus, although it is consumed differently in ethnic foods around the world. We investigated the association between dietary fiber intake and obesity, glycemic control, cardiovascular risk factors and chronic kidney disease in Japanese type 2 diabetic patients. METHODS: A total of 4,399 patients were assessed for dietary fiber intake using a brief self-administered diet history questionnaire. The associations between dietary fiber intake and various cardiovascular risk factors were investigated cross-sectionally. RESULTS: Body mass index, fasting plasma glucose, HbA1c, triglyceride and high-sensitivity C-reactive protein negatively associated with dietary fiber intake after adjusting for age, sex, duration of diabetes, current smoking, current drinking, total energy intake, fat intake, saturated fatty acid intake, leisure-time physical activity and use of oral hypoglycemic agents or insulin. The homeostasis model assessment insulin sensitivity and HDL cholesterol positively associated with dietary fiber intake. Dietary fiber intake was associated with reduced prevalence of abdominal obesity, hypertension and metabolic syndrome after multivariate adjustments including obesity. Furthermore, dietary fiber intake was associated with lower prevalence of albuminuria, low estimated glomerular filtration rate and chronic kidney disease after multivariate adjustments including protein intake. Additional adjustments for obesity, hypertension or metabolic syndrome did not change these associations. CONCLUSION: We demonstrated that increased dietary fiber intake was associated with better glycemic control and more favorable cardiovascular disease risk factors including chronic kidney disease in Japanese type 2 diabetic patients. Diabetic patients should be encouraged to consume more dietary fiber in daily life.

Incidence and risks of coronary heart disease and heart failure in Japanese patients with type 2 diabetes mellitus: The Fukuoka diabetes registry.

AIMS: We prospectively investigated the incidence of coronary heart disease (CHD) and heart failure (HF), risk factors and prognosis in Japanese patients with type 2 diabetes. METHODS: A total of 4,874 outpatients with type 2 diabetes (mean age 65 years, male 57%, previous CHD 14%) were registered at multicenter diabetes clinics of a prefecture in 2008-2010 and followed for the development of CHD and HF requiring hospitalization for a median of 5.3 years (follow-up rate 98%). Risk factors were evaluated using multivariable adjusted Cox proportional models. RESULTS: The incidence rates per 1,000 person-years were 12.3 for CHD (silent myocardial ischemia 5.8, angina pectoris 4.3, myocardial infarction 2.1) and 3.1 for hospitalized HF, respectively. New-onset CHD was significantly associated with higher serum adiponectin [the highest quartile vs. the lowest quartile HR 1.6 (95%CI 1.0-2.6)]. HF was significantly associated with higher serum adiponectin [the highest quartile vs. the lowest quartile HR 2.4 (95%CI 1.1-5.2)], and lower serum creatinine/cystatin C ratio, a surrogate marker for sarcopenia [lowest quartile vs. the highest quartile HR 4.6 (95%CI 1.9-11.1)]. CONCLUSIONS: The incidence of heart disease was low and circulating adiponectin and sarcopenia may predict the development of heart disease in Japanese patients with type 2 diabetes.

Usefulness of urinary tubule injury markers for predicting progression of renal dysfunction in patients with type 2 diabetes and albuminuria: The Fukuoka Diabetes Registry.

AIMS: We prospectively investigated the association of urinary tubule injury markers with estimated glomerular filtration rate (eGFR) decline in Japanese patients with type 2 diabetes. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Relationship of coffee consumption with a decline in kidney function among patients with type 2 diabetes: The Fukuoka Diabetes Registry.

AIMS/INTRODUCTION: The evidence regarding the effects of coffee consumption on incident chronic kidney disease is inconclusive, and no studies have investigated the relationship in patients with diabetes. We aimed to prospectively investigate the relationship between coffee consumption and the decline in estimated glomerular function rate (eGFR) in patients with type 2 diabetes. MATERIALS AND METHODS: A total of 3,805 patients (2,112 men, 1,693 women) with type 2 diabetes (mean age 64.2 years) and eGFR ≥60 mL/min/1.73 m2 were followed (completion of follow up, 97.6%; median 5.3 years). Coffee consumption was assessed at baseline. The end-point was a decline in eGFR to <60 mL/min/1.73 m2 during the follow-up period. RESULTS: During follow up, 840 participants experienced a decline in eGFR to <60 mL/min/1.73 m2 . Higher coffee consumption reduced the risk of decline in eGFR. Compared with no coffee consumption, the multivariate-adjusted hazard ratios (95% confidence intervals) were 0.77 (0.63-0.93) for less than one cup per day, 0.77 (0.62-0.95) for one cup per day and 0.75 (0.62-0.91) for two or more cups per day (P for trend 0.01). This trend was unaffected by further adjustment for baseline eGFR and albuminuria. The mean eGFR change per year was -2.16 mL/min/1.73 m2 with no coffee consumption, -1.89 mL/min/1.73 m2 with less than one cup per day, -1.80 mL/min/1.73 m2 with one cup per day and -1.78 mL/min/1.73 m2 with two or more cups per day (P for trend 0.03). CONCLUSIONS: Coffee consumption is significantly associated with a lower risk of decline in eGFR in patients with type 2 diabetes.

Polypharmacy and bone fracture risk in patients with type 2 diabetes: The Fukuoka Diabetes Registry.

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 < 0.001). Compared with 0-2 drugs, the multivariate-adjusted hazard ratios (HRs) (95% confidence intervals [CIs]) for fractures were 1.34 (1.07-1.68) for 3-5 drugs, 1.76 (1.37-2.26) for 6-8 drugs, and 1.71 (1.27-2.31) in ≥ 9 drugs. The multivariate-adjusted HR (95% CI) per increment in drugs was 1.05 (1.02-1.08) (p < 0.001). Similar tendencies were observed for fragility fractures. CONCLUSIONS: A greater number of prescribed drugs is associated with an increased bone fracture risk in patients with type 2 diabetes.

Incidence of stroke and its association with glycemic control and lifestyle in Japanese patients with type 2 diabetes mellitus: The Fukuoka diabetes registry.

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.

Defecation frequency and glycemic control in patients with diabetes: The Fukuoka Diabetes Registry.

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-<7 and <3 times/week. 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-<7 times/week and <3 times/week (p for trend <0.001). This association remained after multivariable adjustment for confounding factors. There was no evidence of heterogeneity in the association between defecation frequency and HbA1c level according to age, sex, type of diabetes, or laxative use. CONCLUSIONS: The present study suggests the importance of assessing defecation frequency in the management of diabetes.

Incidence of severe hypoglycemia and its association with serum adiponectin in Japanese patients with type 1 and insulin-treated type 2 diabetes: The Fukuoka Diabetes Registry.

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.

Additive effects of green tea and coffee on all-cause mortality in patients with type 2 diabetes mellitus: the Fukuoka Diabetes Registry.

INTRODUCTION: The 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 METHODS: In 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. RESULTS: During 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 <1 cup/day; 0.81 (0.58-1.13) for 1 cup/day; 0.59 (0.42-0.82) for ≥2 cups/day; P for trend, 0.002. With the combination they were 1.0 (referent) for no consumption of green tea and coffee; 0.49 (0.24-0.99) for 2-3 cups/day of green tea with ≥2 cups/day of coffee; 0.42 (0.20-0.88) for ≥4 cups/day of green tea with 1 cup/day of coffee; and 0.37 (0.18-0.77) for ≥4 cups/day of green tea with ≥2 cups/day of coffee. CONCLUSIONS: Higher 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.

Impact of hip fracture on all-cause mortality in Japanese patients with type 2 diabetes mellitus: The Fukuoka Diabetes Registry.

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.