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.

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.

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.

Statin inhibits the expression of secretory phospholipase A2 and subsequent monocyte chemoattractant protein-1 in human endothelial cells.

Phospholipase A2 (PLA2) changes the phosphatidylcholine contained in low-density lipoprotein (LDL) to lysophosphatidylcholine (LPC), which has various proatherogenic properties. We reported that tumor necrosis factor-alpha (TNFα) enhanced the expression of group V PLA2 (sPLA2-V) in human umbilical vein endothelial cells (HUVECs), and the LPC content in LDL and the monocyte chemoattractant protein-1 (MCP-1) expression were augmented when TNFα-stimulated HUVECs were incubated with LDL. Here, we observed that an HMG-CoA reductase inhibitor, pitavastatin, at the concentration of >1 µM administered 12 hours before TNFα stimulation suppressed the enhancement of sPLA2-V mRNA and protein. Pitavastatin also prevented the enhancement of the LPC content in LDL and the expression of MCP-1 mRNA when TNFα-stimulated HUVECs were incubated with LDL. The administration of geranylgeranyl pyrophosphate restored the expression of sPLA2-V mRNA and protein. The administration of the Rho kinase inhibitor Y-27632 and the transfection of small interfering RNA (siRNA) against sPLA2-V before TNFα stimulation both diminished the TNFα-induced sPLA2-V mRNA expression. Therefore, Y-27632 and siRNA against sPLA2-V also prevented the enhancement of MCP-1 mRNA expression when TNFα-stimulated HUVECs were incubated with LDL. Pitavastatin's inhibitory effect on the expression of sPLA2-V induced by TNFα may be useful to prevent the proatherogenic modification of LDL.

Sleep duration and its association with constipation in patients with diabetes: The fukuoka diabetes registry.

AIMS: Shorter and longer sleep durations are associated with adverse health consequences. However, available evidence on the association of sleep duration with constipation is limited, especially in patients with diabetes, who are at a high risk of both conditions. This study aimed to examine the association between sleep duration and constipation in patients with type 2 diabetes. METHODS: A total of 4,826 patients with type 2 diabetes were classified into six groups according to sleep duration: <4.5, 4.5-5.4, 5.5-6.4, 6.5-7.4, 7.5-8.4, and ≥8.5 hours/day. The odds ratios for the presence of constipation, defined as a defecation frequency <3 times/week and/or laxative use, were calculated using a logistic regression model. RESULTS: Shorter and longer sleep durations were associated with a higher likelihood of constipation than an intermediate duration (6.5-7.4 hours/day). This U-shaped association persisted after adjusting for confounding factors, including lifestyle behavior, measures of obesity and glycemic control, and comorbidities. Broadly identical findings were observed when decreased defecation frequency and laxative use were individually assessed. CONCLUSIONS: This study shows a U-shaped association between sleep duration and constipation in patients with type 2 diabetes, and highlights the importance of assessing sleep duration in daily clinical practice.

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.

Effects of thirty-times chewing per bite on secretion of glucagon-like peptide-1 in healthy volunteers and type 2 diabetic patients.

Glucagon-like peptide 1 (GLP-1) is secreted from the small intestine to the blood in response to glucose intake during a meal; however, it is not known whether mastication affects GLP-1 secretion. Here, we examined the relationship between mastication and GLP-1 secretion, along with postprandial blood glucose and insulin concentrations. We compared the levels of blood glucose, serum insulin, and plasma active GLP-1 concentrations after young healthy volunteers ate a test meal either by usual eating (control) or in one of three specified ways: 1. unilateral chewing, 2. quick eating, 3. 30-times chewing per bite. Ten volunteers participated in each of the three groups. Plasma active GLP-1 concentrations did not change by unilateral chewing or quick eating, but did increase by the third method, without affecting the concentrations of blood glucose or serum insulin. Next, we tested whether 30-times chewing per bite increased plasma active GLP-1 concentrations in 15 patients with type 2 diabetes mellitus, but there was no difference in results between usual eating and 30-times chewing per bite. This is a pilot trial with a small number of subjects, but is the first study to investigate the relationships between various styles of mastication and the GLP-1 secretion in young healthy volunteers and type 2 diabetic patients.

Sex differences in cardiovascular risk, lifestyle, and psychological factors in patients with type 2 diabetes: the Fukuoka Diabetes Registry.

BACKGROUND: The excess risk of cardiovascular diseases associated with diabetes is greater in women than in men. The present study aimed to examine sex differences in the control of cardiovascular risk factors, as well as lifestyle and psychological factors, in patients with type 2 diabetes. METHODS: A total of 4923 Japanese patients with type 2 diabetes were included in this cross-sectional study. Female/male differences in cardiovascular risk factor levels, and corresponding odds ratios for achieving recommended ranges for preventing cardiovascular diseases and having unhealthy lifestyle and psychological factors were computed by linear and logistic regression models. RESULTS: Women were less likely than men to achieve recommended ranges for glycated hemoglobin, low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and obesity-related anthropometric indices such as body mass index and waist circumference, but were more likely than men to be on target for high-density lipoprotein cholesterol and triglycerides. Women were also more likely than men to have an unhealthy lifestyle and psychological factors, including less dietary fiber intake, less leisure-time physical activity, shorter sleep duration, more constipation, and more depressive symptoms. Similar findings were observed when the participants were subgrouped by age (< 65 and ≥ 65 years) and past history of cardiovascular disease. CONCLUSIONS: We observed significant sex differences for a range of cardiovascular risk factors, as well as lifestyle and psychological factors, suggesting the importance of adopting a sex-specific approach for the daily clinical management of diabetes.

Diabetes increases the risk of cardiovascular diseases, and growing evidence suggests that the risk increases more in women than men. Differences between the sexes in terms of the control of risk factors have been proposed to explain this association. Although ethnic and regional differences in the management of cardiovascular risk factors have been reported, most evidence has come from Western countries, and evidence from Asia is limited. Given the differences in health care systems, as well as cultural and sociological backgrounds, it is important to clarify the sex differences in the management of cardiovascular risk factors, lifestyle, and psychological factors in order to incorporate appropriate sex-specific approaches into public health policies.The present study comprehensively assessed sex differences in a wide range of cardiovascular risk factors, as well as lifestyle and psychological factors in Japanese patients with type 2 diabetes. The results showed that women were less likely than men to achieve recommended ranges for glycemic control, low-density lipoprotein-cholesterol and non-high-density lipoprotein-cholesterol, as well as obesity-related anthropometric indices, but were more likely to be on target for high-density lipoprotein-cholesterol and triglycerides. In addition, women were more likely to have unhealthy lifestyle and psychological factors, such as less dietary fiber intake, less physical activity, shorter sleep duration, and more constipation, and depressive symptoms. These results suggest the need for a comprehensive and sex-specific approach for the management of cardiovascular risk factors, as well as lifestyle and psychological factors, to reduce the risk of cardiovascular diseases in patients with diabetes.

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.

Association between glucose tolerance level and cancer death in a general Japanese population: the Hisayama Study.

The authors examined the associations of glucose tolerance status and fasting and 2-hour postload glucose levels with the risk of cancer death in a 19-year follow-up study of 2,438 Japanese subjects aged 40-79 years who underwent a 75-g oral glucose tolerance test (1988-2007). During follow-up, 229 subjects died of cancer. The risk of cancer death was significantly higher in subjects with fasting plasma glucose levels of ≥5.6 mmol/L or 2-hour postload glucose levels of ≥11.1 mmol/L than in those with the lowest fasting or 2-hour postload glucose levels, after adjustment for potentially confounding factors. According to glucose tolerance status, not only diabetes but also impaired fasting glycemia and impaired glucose tolerance were significant risk factors for cancer death (for impaired fasting glycemia, multivariable-adjusted hazard ratio (HR) = 1.49 (95% confidence interval (CI): 1.05, 2.11); for impaired glucose tolerance, HR = 1.52 (95% CI: 1.05, 2.22); and for diabetes, HR = 2.10 (95% CI: 1.41, 3.12)). With regard to site-specific cancers, elevated fasting or 2-hour postload glucose levels were associated with the risks of death from stomach, liver, and lung cancer. These findings suggest that both prediabetic hyperglycemia and diabetes are significant risk factors for cancer death in the general Japanese population.

N-terminal pro-brain natriuretic peptide and risk of cardiovascular events in a Japanese community: the Hisayama study.

OBJECTIVE: Few studies have examined the association between natriuretic peptides and the incidence of cardiovascular disease (CVD) in Asian populations. METHODS AND RESULTS: A total of 3104 community-dwelling Japanese individuals aged ≥40 years without history of CVD were followed up for 5 years. A total of 127 CVD events were identified. The age- and sex-adjusted incidence of CVD increased with increasing N-terminal pro-brain natriuretic peptide (NT-proBNP) levels (<55, 55-124, 125-399, and ≥400 pg/mL) at baseline and was significantly higher even in subjects with a modest increase. This association remained robust even after adjustment for other potential risk factors (55-124 pg/mL: multivariate-adjusted hazard ratio=1.85 [95% CI 1.07-3.18], P=0.03; 125-399 pg/mL: 2.98 [95% CI 1.65-5.39], P<0.001; ≥400 pg/mL: 4.54 [95% CI 2.22-9.29], P<0.001). The multivariate-adjusted hazard ratios for the development of total CVD and its subtypes, coronary heart disease and stroke, were significantly increased by a 1 SD increment of the log NT-proBNP concentrations and were nearly equal among CVD subtypes. Similar findings were observed for stroke subtypes of ischemic stroke and intracerebral hemorrhage but not subarachnoid hemorrhage. The effects of the 1 SD increment in log NT-proBNP values were comparable in subjects with and without other cardiovascular risk factors, except for sex. The area under the receiver operating characteristic curve was significantly (P=0.006) increased by adding NT-proBNP values to the model including other potential risk factors. CONCLUSIONS: Elevated NT-proBNP levels were shown to be a significant risk factor for the development of CVD and its subtypes in a general Japanese population, independently of other cardiovascular risk factors.

Telmisartan and N-acetylcysteine suppress group V secretory phospholipase A2 expression in TNFα-stimulated human endothelial cells and reduce associated atherogenicity.

Group V secretory phospholipase A2 (sPLA2-V) hydrolyzes phosphatidylcholine in low-density lipoprotein (LDL) to increase lysophosphatidylcholine (LPC) content. Because in human umbilical vein endothelial cells (HUVEC), tumor necrosis factor alpha (TNFα)-induced sPLA2-V expression, and LPC content in LDL and monocyte chemoattractant protein-1 mRNA were enhanced by incubation of LDL with TNFα-stimulated HUVEC, we investigated whether an angiotensin II receptor type 1 blocker, telmisartan, or an antioxidant drug, N-acetylcysteine (NAC), suppressed TNFα-induced sPLA2-V expression. Telmisartan or NAC administered before and during TNFα stimulation diminished the increase of sPLA2-V mRNA in HUVEC and reduced TNFα-induced sPLA2-V protein at 3 days after TNFα stimulation. Angiotensin II did not induce sPLA2-V mRNA, and a peroxisome proliferator-activated receptor-γ antagonist, GW3335, did not influence the inhibitory effect of telmisartan on TNFα-induced sPLA2-V mRNA. At 3 days after TNFα stimulation, 30 µM telmisartan or 20 mM NAC administered before and during TNFα stimulation prevented the enhancement of LPC content in LDL and monocyte chemoattractant protein-1 mRNA by LDL incubation with TNFα-stimulated HUVEC. A 2-month treatment with telmisartan in 29 hypertensive type 2 diabetic patients significantly reduced LPC content in circulating LDL. Telmisartan's suppressive effect on TNFα-induced sPLA2-V expression may have beneficial effects in preventing proatherogenic changes of LDL.

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.

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 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.

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.

Impact of glucose tolerance status on development of ischemic stroke and coronary heart disease in a general Japanese population: the Hisayama study.

BACKGROUND AND PURPOSE: Few studies have shown the association between glucose tolerance status defined by a 75-g oral glucose tolerance test and the development of different types of cardiovascular disease. METHODS: A total of 2421 community-dwelling Japanese subjects aged 40 to 79 years who underwent the oral glucose tolerance test were followed up for 14 years. RESULTS: In multivariable analysis, the risks of ischemic stroke in both sexes and coronary heart disease (CHD) in women were significantly higher in subjects with diabetes determined by the World Health Organization criteria than in those with normal glucose tolerance even after adjustment for other confounding factors, but such association was not seen for CHD in men (ischemic stroke: adjusted hazard ratio [HR]=2.54, P=0.002 in men; adjusted HR=2.02, P=0.03 in women; CHD: adjusted HR=1.26, P=0.47 in men; adjusted HR=3.46, P=0.002 in women). Similar associations were observed for fasting plasma glucose levels of >or=7.0 mmol/L (ischemic stroke: adjusted HR=2.15, P=0.03 in men; adjusted HR=2.10, P=0.045 in women; CHD: adjusted HR=1.29, P=0.47 in men; adjusted HR=3.83, P=0.003 in women) and for 2-hour postload glucose levels of >or=11.1 mmol/L (ischemic stroke: adjusted HR=2.71, P=0.003 in men; adjusted HR=2.19, P=0.03 in women; CHD: adjusted HR=1.58, P=0.16 in men; adjusted HR=4.44, P<0.001 in women). The age-adjusted incidences of ischemic stroke and CHD did not significantly increase in subjects with impaired fasting glycemia or impaired glucose tolerance in either sex. CONCLUSIONS: Our findings suggest that diabetes is an independent risk factor for ischemic stroke in both sexes and CHD in women in the Japanese population.