Concentrations of various tryptophan metabolites are higher in patients with diabetes mellitus than in healthy aged male adults.

Tryptophan metabolites in plasma samples from 20 male subjects with type 2 diabetes mellitus (T2DM) and 20 nondiabetic reference males were analyzed by ultra high performance liquid chromatography. Tryptophan levels in the diabetic subjects were significantly lower than those in nondiabetic subjects. The concentrations of 5-hydroxytryptophan, 5-hydroxyindoleacetic acid, kynurenic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid, and xanthurenic acid were found to be higher in the diabetic patients. When the diabetic patients were divided into higher- and lower-tryptophan groups, the concentrations of 5-hydroxytryptophan, indole-3-acetic acid, kynurenine, 5-hydroxykynurenine, and kynurenic acid were found to be higher in the diabetic patients with higher tryptophan levels. However, diabetic patients with lower plasma tryptophan levels had higher levels of 5-hydroxyindoleacetic acid than the patients with higher tryptophan levels. These results suggest that tryptophan was metabolized more in T2DM patients than in nondiabetic subjects. In the kynurenine pathway, the degradation of tryptophan seems to be accelerated in patients with higher plasma levels of tryptophan than in patients with lower levels of tryptophan. In the serotonin pathway, when the level of tryptophan is low, the conversion of serotonin to 5-hydroxyindoleacetic acid appears to be accelerated. In conclusion, our results suggest that T2DM patients may be exposed to stress constantly.

Diabetic Microangiopathy Is an Independent Predictor of Incident Diabetic Foot Ulcer.

AIM: To determine the diabetic foot ulcer incidence and examine its association with microangiopathy complications, including diabetic retinopathy (DR) and albuminuria (Alb), in type 2 diabetes patients. METHODS: This was a retrospective cohort study of 1,305 patients with type 2 diabetes who were assigned to the following groups: Category 1, normoalbuminuria without DR (n = 712); Category 2, Alb without DR (n = 195); Category 3, normoalbuminuria with DR (n = 185); and Category 4, Alb with DR (n = 213). Cox proportional hazard models were used to compare the risks of developing diabetic foot ulcers across the categories. RESULTS: During 14,249 person-years of follow-up, 50 subjects developed diabetic foot ulcers, with incidence rates of 1.6/1,000, 1.5/1,000, 3.4/1,000, and 12.5/1,000 person-years in Categories 1, 2, 3, and 4, respectively. After adjusting for the presence of diabetic neuropathy and macroangiopathy, the hazard ratios and 95% confidence intervals (CIs) for the risk of diabetic foot ulcer development were 0.66 (95% CI, 0.18-2.36), 1.72 (95% CI, 0.67-4.42), and 3.17 (95% CI, 1.52-6.61) in Categories 2, 3, and 4, respectively, compared with Category 1. CONCLUSION: The presence of DR and Alb significantly increases the risk of diabetic foot ulcer development.

Benefit of cilostazol in patients with high risk of bleeding: subanalysis of cilostazol stroke prevention study 2.

BACKGROUND: The Cilostazol Stroke Prevention Study 2 (CSPS 2) showed that cilostazol significantly reduced the risk of stroke by 25.7% relative to aspirin, with significantly fewer hemorrhagic events, in patients with prior ischemic stroke, excluding cardioembolic stroke. However, whether the benefit of cilostazol is sustained in patients with a high risk of bleeding has not been examined. METHODS: We conducted a subanalysis of CSPS 2 to examine whether known risk factors for hemorrhagic stroke, such as stroke subtype and systolic blood pressure (SBP), influence the efficacy of the study drugs on hemorrhagic stroke. The relative risk reduction of hemorrhagic stroke was determined from the incidences calculated by the person-year method. The cumulative incidence rates of ischemic stroke and hemorrhagic stroke were estimated and plotted using the Kaplan-Meier method. Incidences of serious hemorrhage and hemorrhage requiring hospital admission were also evaluated in the two treatment groups. Hazard ratios (HR) and 95% confidence intervals (95% CI) calculated by the Cox proportion hazard model for cilostazol versus aspirin were assessed, and a log-rank test was used for the comparison between treatments. RESULTS: The incidence of hemorrhagic stroke was significantly lower in the cilostazol group than in the aspirin group among patients with prior lacunar stroke (0.36 vs. 1.20% in person-year, HR 0.35, 95% CI 0.18-0.70, p < 0.01), but not among those with prior atherothrombotic stroke (0.31 vs. 0.59% in person-year, HR 0.53, 95% CI 0.14-2.0, p = 0.34). The incidence of hemorrhagic stroke was significantly lower in the cilostazol group than in the aspirin group throughout all SBP categories (Poisson regression model including time-dependent covariates, p < 0.01) including SBP above 140 mm Hg (cilostazol 0.45% vs. aspirin 1.44% in person-year; Poisson regression model including time-dependent covariates, p = 0.02). Cilostazol, compared with aspirin, significantly reduced the incidence of cerebral hemorrhage (HR 0.36, 95% CI 0.19-0.70, p < 0.01), overall hemorrhage requiring hospital admission (HR 0.53, 95% CI 0.29-0.97, p = 0.04), and gastrointestinal (GI) bleeding requiring hospital admission (HR 0.44, 95% CI 0.21-0.90, p = 0.03). CONCLUSIONS: Hemorrhagic stroke was less frequent in the cilostazol group than in the aspirin group among patients with lacunar stroke as well as those with increased blood pressure levels. As for extracranial hemorrhage requiring hospitalization, GI bleeding was also less frequent in the cilostazol than in the aspirin group. Cilostazol is supposed to be a therapeutic option to replace aspirin for secondary stroke prevention, especially in these subgroups with high risks for hemorrhagic events.

Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin-controlled, double-blind, randomised non-inferiority trial.

BACKGROUND: The antiplatelet drug cilostazol is efficacious for prevention of stroke recurrence compared with placebo. We designed the second Cilostazol Stroke Prevention Study (CSPS 2) to establish non-inferiority of cilostazol versus aspirin for prevention of stroke, and to compare the efficacy and safety of cilostazol and aspirin in patients with non-cardioembolic ischaemic stroke. METHODS: Patients aged 20-79 years who had had a cerebral infarction within the previous 26 weeks were enrolled at 278 sites in Japan and allocated to receive 100 mg cilostazol twice daily or 81 mg aspirin once daily for 1-5 years. Patients were allocated according to a computer-generated randomisation sequence by means of a dynamic balancing method using patient information obtained at registration. All patients, study personnel, investigators, and the sponsor were masked to treatment allocation. The primary endpoint was the first occurrence of stroke (cerebral infarction, cerebral haemorrhage, or subarachnoid haemorrhage). The predefined margin of non-inferiority was an upper 95% CI limit for the hazard ratio of 1·33. Analyses were by full-analysis set. This trial is registered with ClinicalTrials.gov, number NCT00234065. FINDINGS: Between December, 2003, and October, 2006, 2757 patients were enrolled and randomly allocated to receive cilostazol (n=1379) or aspirin (n=1378), of whom 1337 on cilostazol and 1335 on aspirin were included in analyses; mean follow-up was 29 months (SD 16). The primary endpoint occurred at yearly rates of 2·76% (n=82) in the cilostazol group and 3·71% (n=119) in the aspirin group (hazard ratio 0·743, 95% CI 0·564-0·981; p=0·0357). Haemorrhagic events (cerebral haemorrhage, subarachnoid haemorrhage, or haemorrhage requiring hospital admission) occurred in fewer patients on cilostazol (0·77%, n=23) than on aspirin (1·78%, n=57; 0·458, 0·296-0·711; p=0·0004), but headache, diarrhoea, palpitation, dizziness, and tachycardia were more frequent in the cilostazol group than in the aspirin group. INTERPRETATION: Cilostazol seems to be non-inferior, and might be superior, to aspirin for prevention of stroke after an ischaemic stroke, and was associated with fewer haemorrhagic events. Therefore, cilostazol could be used for prevention of stroke in patients with non-cardioembolic stroke. FUNDING: Otsuka Pharmaceutical.

A long-term effect of epalrestat on motor conduction velocity of diabetic patients: ARI-Diabetes Complications Trial (ADCT).

In order to study a long-term effect along with adverse action of epalrestat, an aldose reductase inhibitor, a randomized, prospective study was conducted over the period of 3 years at 112 facilities. Six hundred and three diabetic patients with median motor conduction velocity (MCV)>40 m/s, HbA1c<9% were randomly allocated to epalrestat (50 mg/day p.o. ac, t.i.d.) group (E group: n=289, age: 61+/-9.8 y.o.) and a control group (C group: n=305, age: 61+/-9.1 y.o.). MCV was measured once a year for 3 years. MCV (m/s, M+/-S.D.) on baseline, 1 year and 3 years, was 52.0+/-4.5, 52.2+/-4.9, 52.1+/-4.6 in E group and 53.3+/-4.4, 52.4+/-4.2, 52.0+/-4.6 in C group, respectively. After 3 years, difference from the baseline was significant (p<0.0001, E versus C). Among the subjects with HbA1c<7.0%, C group showed marked deterioration of MCV while in E group, there was no significant deterioration (p<0.001). Although, the subjects with pre-proliferative or proliferative retinopathy, there was no difference between E and C groups for 3 years, in subjects with background retinopathy or without retinopathy, deterioration rate of E group was significantly less than that of C group (p<0.0001). Epalrestat was found to prevent deterioration of MCV especially in well-controlled patients without advanced complications. No remarkable side effects serious enough to discontinue the study was observed.

Long-term clinical effects of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy: the 3-year, multicenter, comparative Aldose Reductase Inhibitor-Diabetes Complications Trial.

OBJECTIVE: We sought to evaluate the long-term efficacy and safety of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy. RESEARCH DESIGN AND METHODS: Subjects with diabetic neuropathy, median motor nerve conduction velocity (MNCV) >or=40 m/s, and HbA(1c)

[Role of the diabetes educator for elderly patients].

Diabetes is a heterogeneous disorder characterized by a genetic predisposition and interaction between insulin resistance and decreased pancreatic beta cell function. Elderly patients are often accompanied by other chronic conditions as well as additional risk factors for atherosclerosis and cardiovascular disease. In recent years in Japan, with extension of life expectancy, preventive measure both primary and secondary for senior citizens is increasingly important. Diabetes education for elderly patients is fundamentally the same as for much young group. The social background of the elderly is tremendously diversified. Therefore, the clinical decision-making has to be started with educational model, and complete primary care setting is necessary with exclusively individualized program understanding the ability of a key person in a support group.

Change of components of the metabolic syndrome in a workers' health checkup after five years--relation with elevated liver enzymes, gene polymorphisms for ALDH 2, beta3-AR and lifestyle.

We previously reported that the prevalence of elevated alanine aminotransferase (ALT) increases with accumulation of metabolic syndrome components, and a greater degree of involvement of aldehyde dehydrogenase 2 (ALDH2) than beta3-adrenergic receptor gene (beta3-AR) polymorphisms. The present study was designed to clarify the effect of aging, lifestyle and the two gene polymorphisms on the relationship between 4 components of the metabolic syndrome (obesity, hypertension, dyslipidemia and impaired glucose tolerance) and elevated ALT values in a subset of 73 out of 148 male workers who were 35 years of age in the baseline study and 40 years old in the present study. Study subjects completed questionnaires about drinking and smoking habits, and underwent urinalysis, physical examination and peripheral blood tests, blood chemistry, electrocardiogram and chest X-rays each year as required by Japanese law. Information from the questionnaires and physical examinations, including liver function tests, were compared with previously reported ALDH2 and beta3-AR genotypes for the 73 workers. Of the 73 workers studied, 14 (19%) demonstrated decrease in metabolic syndrome components, 39 (53%) demonstrated no change, and 20 (27%) demonstrated an increase. Ten workers (14%) showed liver dysfunction at age 35 and 20 workers (27%) at age 40. Fourteen workers were newly diagnosed as having liver dysfunction at their 40-year checkup, thus being associated with the BMI and an active ALDH2 genotype. Accumulation of components of the metabolic syndrome were associated with the presence of liver dysfunction at 35 years. In conclusion, these findings indicate that ALDH2 genotyping as well as lifestyle habits may be important factors in causing metabolic syndrome with liver dysfunction.

ALDH2/ADH2 polymorphism associated with vasculopathy and neuropathy in type 2 diabetes.

In the history of diabetes, chlorpropamide alcohol flushing test (CPAF) was a big topic in the 1970s to 1980s. Alcohol tolerance after chlorpropamide has prognostic significance, with the intolerant group (CPAF-positive group) being less prone to develop vascular complication than the tolerant group (CPAF-negative group). A mechanism of CPAF has been regarded as the inhibition of aldehyde dehydrogenase 2 (ALDH2) by an N-alkyl-substituted derivative of chlorpropamide, and the expression of these mutations of ALDH2 and alcohol dehydrogenase 2 (ADH2) could determine the alcohol tolerance among the Japanese population. Therefore, we hypothesized that expression of different ALDH2 and ADH2 polymorphisms may induce differences in vascular complications in diabetes and conducted two studies. The first study (study 1) was to determine the association of ALDH2/AHD2 polymorphism with diabetic complications. To know the association of ALDH2/AHD2 polymorphism with diabetic vasculopathy and neuropathy, a total of 158 patients with type 2 diabetes were divided into four groups on the basis of ALDH2 "activity" and ADH2 "superactivity." The frequency of proteinuria and the percentage of proliferative retinopathy among the patients with retinopathy was higher in those with active ALDH2 and superactive ADH2. We speculated that protein kinase C isoforms up-regulated by 4-hydroxynonenal that was detoxified by ALDH2 and ADH2 may account for the long-term development of diabetic nephropathy and severe retinopathy. As for neuropathy, the frequency of symptomatic neuropathy was higher in patients with inactive ALDH2 and usual ADH2. We speculate that increased tissue levels of toxic aldehyde could result from inactive ALDH2 and usual ADH2 expression, which results in the increased level of reactive aldehyde in sensory neuron pathway, thereby causing symptomatic polyneuropathy.

A mitochondrial DNA variant associated with left ventricular hypertrophy in diabetes.

Diabetes was reported to be associated with a mitochondrial (mt) DNA mutation at 3243 and variants at 1310, 1438, 3290, 3316, 3394, 12,026, 15,927, and 16,189. Among these mtDNA abnormalities, those at 3243, 3316, 15,927, and 16,189 were also suggested to cause cardiomyopathies. We investigated the prevalence of such mtDNA abnormalities in 68 diabetic patients with LV hypertrophy (LVH), 100 without LVH, and 100 controls. Among the 9 mtDNA abnormalities, those at 3243, 3316, and 15,927 tended to be more prevalent in diabetic patients with LVH than in those without LVH (1%, 1%, and 4% vs. 0%, 0%, and 0%). Notably, the variant at 16,189 was more prevalent in diabetic patients with LVH than without LVH (46% vs. 24%, [Formula: see text] ). The odds ratio for LVH was 3.0 (95% CI, 1.5-6.1) for the 16,189 variant. A common mtDNA variant at 16,189 was found to be associated with LVH in diabetic patients.

Aldehyde dehydrogenase 2 and beta3-adrenergic receptor gene polymorphisms: their association with elevated liver enzymes and metabolic syndrome.

Recent studies indicate that some patients with nonalcoholic fatty liver have ongoing liver injury that may progress from steatosis to steatohepatitis or fibrosis. The present study was designed to clarify the clinical features of liver dysfunction observed in the course of workplace physical check-ups in relation to multiple risk factor syndrome including obesity, hyperlipidemia, hypertension, and impaired glucose tolerance, and to clarify the involvement of aldehyde dehydrogenase 2 (ALDH2) and beta(3)-adrenergic receptor (beta3-AR) gene polymorphisms in elevation of liver enzymes. One hundred forty-eight male workers 35 years of age were enrolled. They were requested to answer questionnaires about drinking and smoking habits, and underwent urinalysis, physical and peripheral blood examinations, blood chemistry, electrocardiogram and chest x-rays. The genotypes of ALDH2 and beta3-AR were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The subjects were divided into active ALDH2 or inactive ALDH2 groups. They were also divided into 2 groups according to the beta3-AR genotype. The relationships between ALDH2 and beta3-AR gene polymorphism and the results of the physical examination including liver function tests were analyzed. The subjects were also divided according to the number of components of metabolic syndrome. The prevalence of elevated alanine aminotransferase (ALT) level increased with the accumulation of components of metabolic syndrome. Active ALDH2 was associated with elevated ALT level to a greater degree than beta3-AR polymorphism. Among those with normal body mass index (BMI), the genotypes of ALDH2 and beta3-AR were strongly associated with elevated ALT level. Logistic regression analysis revealed that BMI, triglyceride level, and ALDH2 genotype were associated with ALT elevation. In conclusion, evaluating the genotype of ALDH2 and beta3-AR may assist in predicting and preventing the development of fatty liver which may be related to multiple risk factor syndrome.

Cardiac autonomic nervous dysfunction in diabetic patients with a mitochondrial DNA mutation: assessment by heart rate variability.

OBJECTIVE: To elucidate the degree and characteristics of cardiac autonomic nervous dysfunction in diabetic patients associated with a mitochondrial DNA mutation at base pair 3243. RESEARCH DESIGN AND METHODS: We investigated heart rate variability using 24-h Holter monitoring in 10 diabetic patients with the mutation compared with 55 ordinary diabetic patients and 45 nondiabetic control subjects. RESULTS: Age and sex were similar in the three groups. Between patients with the mutation and ordinary diabetic patients, the duration of diabetes and blood glycemic levels were not different. In the time domain analysis of heart rate variability, patients with the mutation and ordinary diabetic patients had significantly smaller SDNN index and pNN50 than control subjects. Compared with ordinary diabetic patients, patients with the mutation had smaller SDNN index (P < 0.02), but rMSSD and pNN50 were not different. In the frequency domain analysis, total, low frequency (LF), and high frequency (HF) spectra were significantly smaller in patients with the mutation and ordinary diabetic patients than in control subjects. Compared with ordinary diabetic patients, patients with the mutation had smaller total and LF spectra (P < 0.02). However, HF spectra were not significantly different. Notably, the LF/HF spectra ratio was lower in patients with the mutation than in ordinary diabetic patients and control subjects (P < 0.05), but this ratio was similar in ordinary diabetic patients and control subjects. CONCLUSIONS: Our results suggest that diabetic patients with the mitochondrial DNA mutation have more severely impaired cardiac autonomic nervous function with sympathovagal imbalance, as compared with ordinary diabetic patients.