Innovative submucosal injection solution for endoscopic resection with phosphorylated pullulan: a preclinical study.

BACKGROUND AND AIMS: A submucosal injection solution is used to assist in endoscopic surgery. The high viscosity of current solutions makes them difficult to inject. In the present study, we developed an extremely low-viscosity, easy-to-use submucosal injection solution using phosphorylated pullulan (PPL). METHODS: The PPL solutions were prepared at different concentrations, and their viscosities were measured. The mucosal elevation capacity was evaluated using excised porcine stomachs. Controls included 0.4% sodium hyaluronate (SH), 0.6% sodium alginate (SA), and saline. To evaluate the practicality, the catheter injectability of 0.7% PPL was measured, and EMR and endoscopic submucosal dissection (ESD) were performed using the stomach and colorectum of live pigs. As controls, 0.4% SH and saline were used. RESULTS: The PPL solutions were of extremely low viscosity compared to the solutions of 0.4% SH and 0.6% SA. Nevertheless, the mucosal elevation capacity of PPL solutions for up to 0.7% concentration was similar to that of 0.4% SH, and 0.7% PPL was less resistant to catheter infusion than 0.4% SH and 0.6% SA. In live pig experiments with endoscopic mucosal resection and ESD, snaring after submucosal injection of 0.7% PPL was easier than with 0.4% SH, ESD with 0.7% PPL produced less bubble formation than with 0.4% SH, and the procedure time tended to be shorter with 0.7% PPL than with 0.4% SH because of the shorter injection time. CONCLUSIONS: The PPL solution is an innovative and easy-to-use submucosal injection solution.

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.

Expression of kinesin family member C1 in pancreatic ductal adenocarcinoma affects tumor progression and stemness.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer and the third leading cause of cancer-related deaths. Therefore, there is an urgent need for a novel molecular target for the treatment of PDAC. Kinesin family member C1 (KIFC1) belongs to the kinesin superfamily proteins and has been reported to be involved in the pathogenesis of a wide variety of carcinomas. However, the role of KIFC1 in PDAC remains unknown. This study aimed to analyze the expression and biological function of KIFC1 in PDAC. Immunohistochemically, KIFC1 was found in 37 of 81 PDAC cases (46%). A high expression of KIFC1 was significantly related to tumor size (p = 0.023) and poor overall survival (p = 0.011). Univariate and multivariate analysis indicated that KIFC1 expression was a prognostic factor in PDAC cases. As for cancer stem cell markers, KIFC1 expression tended to co-express significantly with CD44 (p < 0.01). The growth and spheroid colony formation of KIFC1 small interfering RNA (siRNA)-transfected PDAC cells were significantly lower than those of negative control siRNA-transfected cells. Therefore, our findings suggest that KIFC1 is an independent prognostic factor in PDAC and may represent a new promising therapeutic target in PDAC.

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.

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.

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.

[Anti-nuclear matrix protein 2 antibody-positive dermatomyositis with the preferential involvement of neck extensors: a case report].

A 68-year-old man with a 2-month history of progressive weakness and spontaneous pain in proximal limb muscles presented to our hospital with a dropped head. He started experiencing progressive dysphagia several days before admission. On admission, he had muscle weakness of the limbs and neck extensors with edema and induration in distal extremities. Laboratory tests showed elevation of muscle enzymes. FDG-PET/CT demonstrated multiple hypermetabolic lymph nodes, but the primary site was not identified; thus, metastatic carcinoma of unknown primary origin was considered. The patient was diagnosed with anti-nuclear matrix protein 2 antibody-positive paraneoplastic myopathy based on serum tests. Histological findings of the left biceps brachii muscle biopsy revealed severe variation in fiber size and perifascicular myofiber atrophy. Myofibers exhibited myxovirus resistance protein A expression predominantly in the perifascicular region. Following intravenous methylprednisolone pulse therapy and intravenous immunoglobulin, the patient's muscle strength improved with normalization of muscle enzyme levels. The dropped head was considered to have resulted from the preferential involvement of neck extensors based on the observed FDG-PET/CT uptake in neck extensors.

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.

Up-regulation of cytosolic prostaglandin E synthase in fetal-membrane and amniotic prostaglandin E2 accumulation in labor.

Prostaglandin E2 (PGE2) is known to have important roles in labor, but the detailed mechanism underlying the spontaneous human labor remains unknown. Here, we examined the involvement of prostaglandin biosynthetic enzymes and transporter in the accumulation of PGE2 in amniotic fluid in human labor. PGE2 and its metabolites were abundant in amniotic fluid in deliveries at term in labor (TLB), but not at term not in labor (TNL). In fetal-membrane Transwell assays, levels of PGE2 production in both maternal and fetal compartments were significantly higher in the TLB group than the TNL group. In fetal-membrane, the mRNA level of PTGES3, which encodes cytosolic prostaglandin E synthase (cPGES), was significantly higher in TLB than in TNL, but the mRNA levels of the other PGE2-synthase genes were not affected by labor. Moreover, the mRNA level of PTGS2, which encodes cyclooxygenase-2 (COX-2) in the amnion was significantly higher in TLB than in TNL. Western blot analyses revealed that the levels of COX-1 and COX-2 were comparable between the two groups, however, the level of cPGES was relatively higher in TLB than in TNL. COXs, cPGES, and prostaglandin transporter (SLCO2A1) proteins were all expressed in both chorionic trophoblasts and amniotic epithelium. These findings suggest that COXs, cPGES and SLCO2A1 contribute to PGE2 production from fetal-membrane in labor.

Prediction of early recurrence of hepatocellular carcinoma after resection using digital pathology images assessed by machine learning.

Hepatocellular carcinoma (HCC) is a representative primary liver cancer caused by long-term and repetitive liver injury. Surgical resection is generally selected as the radical cure treatment. Because the early recurrence of HCC after resection is associated with low overall survival, the prediction of recurrence after resection is clinically important. However, the pathological characteristics of the early recurrence of HCC have not yet been elucidated. We attempted to predict the early recurrence of HCC after resection based on digital pathologic images of hematoxylin and eosin-stained specimens and machine learning applying a support vector machine (SVM). The 158 HCC patients meeting the Milan criteria who underwent surgical resection were included in this study. The patients were categorized into three groups: Group I, patients with HCC recurrence within 1 year after resection (16 for training and 23 for test); Group II, patients with HCC recurrence between 1 and 2 years after resection (22 and 28); and Group III, patients with no HCC recurrence within 4 years after resection (31 and 38). The SVM-based prediction method separated the three groups with 89.9% (80/89) accuracy. Prediction of Groups I was consistent for all cases, while Group II was predicted to be Group III in one case, and Group III was predicted to be Group II in 8 cases. The use of digital pathology and machine learning could be used for highly accurate prediction of HCC recurrence after surgical resection, especially that for early recurrence. Currently, in most cases after HCC resection, regular blood tests and diagnostic imaging are used for follow-up observation; however, the use of digital pathology coupled with machine learning offers potential as a method for objective postoprative follow-up observation.

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.

Prospective study of cancer in Japanese patients with type 2 diabetes: the Fukuoka Diabetes Registry.

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.

The serum creatinine to cystatin C ratio predicts bone fracture in patients with type 2 diabetes: The Fukuoka Diabetes Registry.

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.

A case of anti-MOG antibody-positive unilaterally dominant meningoencephalitis followed by longitudinally extensive transverse myelitis.

BACKGROUND: There are few reports of anti-myelin oligodendrocyte glycoprotein (MOG) antibody-positive, unilaterally dominant cerebral cortical encephalitis onset with epilepsy. We present such a case in a young female patient with myelitis. CASE PRESENTATION: A 19-year-old female developed generalized tonic seizures lasting several minutes. She had a low-grade fever and headache without other clinical neurological abnormalities while at our hospital. Cerebrospinal fluid (CSF) showed mononuclear pleocytosis. Other laboratory tests indicated no apparent abnormalities. Unilateral meningeal hyperintensity was seen on T2 fluid-attenuated inversion recovery MRI with associated cortical swelling and gadolinium enhancement of the cortical layer. One thousand mg/day of levetiracetam and a 3-day course of intravenous methylprednisolone at 1000 mg/day were administered. Dysuria appeared on the twentieth day of illness, and spinal MRI revealed a longitudinally extensive cord lesion from C5 to L1 consistent with myelitis. Two cycles of a 3-day course of intravenous methylprednisolone at 1000 mg/day were administered, and all symptoms disappeared. We found the patient to be anti-MOG antibody-positive using serum and CSF (titer: serum 1:256; CSF 1:128). CONCLUSION: Our report illustrates a unique case of anti-MOG presenting as new onset epilepsy secondary to unilaterally dominant meningoencephalitis preceding the onset of longitudinally extensive transverse myelitis.

Incidence of diabetic foot ulcer in Japanese patients with type 2 diabetes mellitus: The Fukuoka diabetes registry.

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 <60 mL/min/1.73 m2), depressive symptoms, and poor glycemic control were significant risk factors for developing DFU. Survival was significantly lower in participants with DFU and/or history of DFU compared with those without (5-year survival rates: with DFU, 87.7%, without DFU, 95.3%; P < .0001). The hazard ratio for death was 1.80 (95% confidence interval, 1.13-2.73, P = .014) in those with DFU and/or history of DFU in a multi-adjusted model. The most common cause of death was cardiovascular disease among participants with DFU, whereas it was malignant neoplasm among those without. 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.

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.

Joint impact of modifiable lifestyle behaviors on glycemic control and insulin resistance in patients with type 2 diabetes: the Fukuoka Diabetes Registry.

AIMS: 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. PATIENTS AND METHODS: 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 ß-cell function (HOMA2-%B) were cross-sectionally analyzed. RESULTS: HbA1c increased progressively with increases in lifestyle score (p for trend <0.001). Mean HbA1c was 0.48% (95% confidence intervals 0.34-0.63) higher in patients with scores of four to five than in those with zero scores. HOMA2-IR and high-sensitivity C-reactive protein also revealed a similar tendency, but adiponectin showed an inverse association. However, these graded tendencies were not observed for HOMA2-%B. Additionally, lower HOMA2-%B levels enhanced the effects of lifestyle score on glycemia. Increases in HbA1c per point in the lifestyle score in patients with the lowest and highest quartiles of HOMA2-%B were 0.25% (0.18-0.32) and 0.10% (0.06-0.15), respectively (p for interaction <0.001). CONCLUSIONS: Accumulation of unhealthy lifestyle factors was dose-dependently associated with poor glycemic control, which may be modified by insulin secretory capacity.

Effects of smoking and its cessation on creatinine- and cystatin C-based estimated glomerular filtration rates and albuminuria in male patients with type 2 diabetes mellitus: the Fukuoka Diabetes Registry.

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.

Association of Genetically Determined Aldehyde Dehydrogenase 2 Activity with Diabetic Complications in Relation to Alcohol Consumption in Japanese Patients with Type 2 Diabetes Mellitus: The Fukuoka Diabetes Registry.

Aldehyde dehydrogenase 2 (ALDH2) detoxifies aldehyde produced during ethanol metabolism and oxidative stress. A genetic defect in this enzyme is common in East Asians and determines alcohol consumption behaviors. We investigated the impact of genetically determined ALDH2 activity on diabetic microvascular and macrovascular complications in relation to drinking habits in Japanese patients with type 2 diabetes mellitus. An ALDH2 single-nucleotide polymorphism (rs671) was genotyped in 4,400 patients. Additionally, the relationship of clinical characteristics with ALDH2 activity (ALDH2 *1/*1 active enzyme activity vs. *1/*2 or *2/*2 inactive enzyme activity) and drinking habits (lifetime abstainers vs. former or current drinkers) was investigated cross-sectionally (n = 691 in *1/*1 abstainers, n = 1,315 in abstainers with *2, n = 1,711 in *1/*1 drinkers, n = 683 in drinkers with *2). The multiple logistic regression analysis for diabetic complications was adjusted for age, sex, current smoking habits, leisure-time physical activity, depressive symptoms, diabetes duration, body mass index, hemoglobin A1c, insulin use, high-density lipoprotein cholesterol, systolic blood pressure and renin-angiotensin system inhibitors use. Albuminuria prevalence was significantly lower in the drinkers with *2 than that of other groups (odds ratio [95% confidence interval (CI)]: *1/*1 abstainers as the referent, 0.94 [0.76-1.16] in abstainers with *2, 1.00 [0.80-1.26] in *1/*1 drinkers, 0.71 [0.54-0.93] in drinkers with *2). Retinal photocoagulation prevalence was also lower in drinkers with ALDH2 *2 than that of other groups. In contrast, myocardial infarction was significantly increased in ALDH2 *2 carriers compared with that in ALDH2 *1/*1 abstainers (odds ratio [95% CI]: *1/*1 abstainers as the referent, 2.63 [1.28-6.13] in abstainers with *2, 1.89 [0.89-4.51] in *1/*1 drinkers, 2.35 [1.06-5.79] in drinkers with *2). In summary, patients with type 2 diabetes and ALDH2 *2 displayed a lower microvascular complication prevalence associated with alcohol consumption but a higher macrovascular complication prevalence irrespective of alcohol consumption.

Association of severe hypoglycemia with depressive symptoms in patients with type 2 diabetes: the Fukuoka Diabetes Registry.

OBJECTIVE: Although many studies have investigated the clinical characteristics of patients with diabetes with depression in Western populations, there is a lack of information regarding other ethnicities. We studied the association between clinical characteristics and depressive symptoms in Japanese patients with type 2 diabetes. METHODS: A total of 4218 Japanese patients with type 2 diabetes who were not taking antidepressants were divided into four groups according to the Center for Epidemiologic Studies Depression Scale (CES-D) score. The relationship between the severity of depressive symptoms and clinical parameters was examined cross-sectionally. RESULTS: After multivariate adjustments, the severity of depressive symptoms was significantly associated with body mass index, leisure-time physical activity, current smoking, sleep duration, sucrose intake, skipping breakfast, insulin use, severe hypoglycemia, dysesthesia of both feet, history of foot ulcer, photocoagulation, ischemic heart disease, and stroke. ORs for severe hypoglycemia increased significantly with the CES-D score in 2756 sulfonylurea and/or insulin-treated patients after multivariate adjustment including age, sex, duration of diabetes, glycated hemoglobin, insulin use, self-monitoring of blood glucose, leisure-time physical activity, skipping breakfast, dysesthesia of both feet, ischemic heart disease, and stroke (CES-D score ≤9, referent; 10-15, OR 1.64; 16-23, OR 2.09; ≥24, OR 3.66; p for trend <0.01). CONCLUSIONS: Severe hypoglycemia was positively associated with the severity of depressive symptoms in Japanese patients with type 2 diabetes independent of glycemic control, insulin therapy, lifestyle factors, and diabetic complications. As both severe hypoglycemia and depression are known risk factors for morbidity and mortality in patients with diabetes, clinicians should be aware of this association. UMIN CLINICAL TRIAL REGISTRY: 000002627.