Fuki Ikeda

Gut Dysbiosis and Detection of “Live Gut Bacteria” in Blood of Japanese Patients With Type 2 Diabetes

OBJECTIVE Mounting evidence indicates that the gut microbiota are an important modifier of obesity and diabetes. However, so far there is no information on gut microbiota and “live gut bacteria” in the systemic circulation of Japanese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Using a sensitive reverse transcription–quantitative PCR (RT-qPCR) method, we determined the composition of fecal gut microbiota in 50 Japanese patients with type 2 diabetes and 50 control subjects, and its association with various clinical parameters, including inflammatory markers. We also analyzed the presence of gut bacteria in blood samples. RESULTS The counts of the Clostridium coccoides group, Atopobium cluster, and Prevotella (obligate anaerobes) were significantly lower (P < 0.05), while the counts of total Lactobacillus (facultative anaerobes) were significantly higher (P < 0.05) in fecal samples of diabetic patients than in those of control subjects. Especially, the counts of Lactobacillus reuteri and Lactobacillus plantarum subgroups were significantly higher (P < 0.05). Gut bacteria were detected in blood at a significantly higher rate in diabetic patients than in control subjects (28% vs. 4%, P < 0.01), and most of these bacteria were Gram-positive. CONCLUSIONS This is the first report of gut dysbiosis in Japanese patients with type 2 diabetes as assessed by RT-qPCR. The high rate of gut bacteria in the circulation suggests translocation of bacteria from the gut to the bloodstream.

Comparison of effects of olmesartan and telmisartan on blood pressure and metabolic parameters in Japanese early-stage type-2 diabetics with hypertension.

Angiotensin II type-1 receptor blockers (ARBs) are regarded as first-line treatments for type-2 diabetes with hypertension. Despite the availability of various types of ARBs, there are no comparative studies of their effects on patients with diabetes. In this open-label prospective crossover study, we compared the effects of olmesartan (20 mg/day) and telmisartan (40 mg/day). Twenty Japanese early-stage type-2 diabetes patients with hypertension treated with valsartan (80 mg/day) for at least 8 weeks were recruited to this study. At study entry, valsartan was changed to olmesartan (20 mg/day) or telmisartan (40 mg/day) and administered for 8 weeks. The drugs were then switched and treatment was continued for another 8 weeks. We analyzed the blood pressure lowering effects of each drug by 24-h ambulatory blood pressure monitoring at 0, 8, and 16 weeks. Simultaneously, we measured metabolic parameters and inflammation markers. Olmesartan lowered mean systolic and diastolic blood pressure more significantly than did telmisartan. While there were no differences between the groups in metabolic parameters, including HbA1c and adiponectin, the decreases in serum interleukin-6 and highly sensitive C-reactive protein were more significant by olmesartan treatment. Our results indicate that olmesartan has more potent arterial blood pressure lowering and anti-inflammatory effects than telmisartan. (Hypertens Res 2008; 31: 7−13)

Combination of the Framingham Risk Score and Carotid Intima-Media Thickness Improves the Prediction of Cardiovascular Events in Patients With Type 2 Diabetes

OBJECTIVE The aim of this study was to investigate whether carotid intima-media thickness (IMT) and brachial-ankle pulse wave velocity (baPWV) add value to the Framingham risk score (FRS) in predicting the development of cardiovascular diseases (CVDs) in type 2 diabetic patients with a negative history of CVD. RESEARCH DESIGN AND METHODS Type 2 diabetic patients (n = 783) were retrospectively recruited and followed for CVD. RESULTS During a 5.4-year follow-up period, 85 incidences of CVD were recorded (10.9%). After adjustment for conventional arterial risk factors, multivariate analysis with the Cox proportional hazards model identified IMT, but not baPWV, as a significant determinant of CVD. In addition, the combination of FRS with IMT, but not with baPWV, improved the prediction of CVD. CONCLUSIONS Carotid IMT is a significant predictor of CVD in asymptomatic type 2 diabetic patients, and the combination of FRS and IMT improves the prediction of CVD in these patients.

Masked Hypertension, Endothelial Dysfunction, and Arterial Stiffness in Type 2 Diabetes Mellitus: A Pilot Study

BACKGROUND The aim of this study was to assess the relationship between masked hypertension (MHT) and vascular damage in patients with type 2 diabetes. METHODS The study subjects were patients with type 2 diabetes who were normotensive based on blood pressure (BP) measurement in the clinic (n = 80) without antihypertensive drugs and free of retinopathy, macroalbuminuria, overt cardiovascular disease. Subjects underwent 24-h ambulatory blood pressure monitoring (ABPM), measurement of flow-mediated dilatation (FMD), and brachial-ankle pulse wave velocity (baPWV). Based on the results of ABPM, subjects with mean daytime systolic BP ≥135 and/or 85 mm Hg were defined as MHT and their clinical data were compared with those of normotensive patients (NT). The data were also compared with those of type 2 diabetic patients with hypertension (HT) as measured in the clinic (n = 32). RESULTS MHT was detected in 47.5% of the study subjects with normotension at clinic (n = 38). Impaired FMD (5.65 ± 2.00% for NT, 4.26 ± 1.88% for MHT, 3.90 ± 1.71% for HT, P < 0.001) and higher baPWV (1,514.2 ± 212.7 cm/s for NT, 1,749.9 ± 339.7 cm/s for MHT, and 1,768.6 ± 302.8 cm/s for HT, P < 0.001) were similarly noted in patients with MHT and HT compared with NT. Multivariate regression analysis indicated that daytime systolic BP measured by ABPM, the estimated duration of diabetes and serum triglycerides were significantly associated with FMD and daytime systolic BP measured by ABPM, not systolic BP at clinic, age, and HbA(1c) were significantly associated with baPWV. CONCLUSIONS Given that patients with impaired FMD and higher baPWV are known to be at higher risk of cardiovascular disease, our data suggest that type 2 diabetic patients with MHT could be also at increased risk of cardiovascular disease.

Amelioration of glucose tolerance by hepatic inhibition of nuclear factor κB in db/db mice

Aims/hypothesisRecent studies have identified the involvement of inhibitor IκB kinase (IKK) in the pathogenesis of insulin resistance. To investigate the mechanism involved, we examined the role of nuclear factor κB (NF-κB), the distal target of IKK, in hepatic glucose metabolism.MethodsTo inhibit NF-κB activity, db/db mice were infected with adenovirus expressing the IκBα super-repressor.ResultsThe IκBα super-repressor adenovirus infection caused a moderate reduction of NF-κB activity in liver. The treatment was associated with improved glucose tolerance, reduction in the serum insulin level, and increased hepatic triacylglycerol and glycogen contents, but had no effect on insulin-stimulated phosphorylation of Akt. On the other hand, quantification of mRNA in the liver revealed marked reduction of expression of gluconeogenic genes, such as those encoding phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase, concurrent with reduced expression of gene encoding peroxisome proliferator-activated receptor gamma coactivator-1α (PPARGC1A, also known as PGC-1α). Furthermore, the production of super-repressor IκBα suppressed the increase in blood glucose level after pyruvate injection.Conclusions/interpretationOur results indicate that moderate inhibition of NF-κB improved glucose tolerance through decreased gluconeogenesis associated with reduced PGC-1α gene expression in db/db mice, and suggest that inhibition of NF-κB activity in liver is a potentially suitable strategy for the normalisation of blood glucose concentration in type 2 diabetes.

Dose-dependent requirement of patched homologue 1 in mouse pancreatic beta cell mass

Aims/hypothesisEctopic activation of hedgehog (HH) signalling in pancreas induces various abnormal morphogenetic events in the pancreas. This study analysed the dose-dependent requirement of patched homologue 1 (PTCH1), a negative regulator of HH signalling on pancreatic development.MethodsWe used a recessive spontaneous mutant mouse denoted as mes which carries a mutated Ptch1 resulting in deletion of the most carboxy-terminal cytoplasmic domain of the PTCH1 protein. In this study, we analysed pancreatic morphology in Ptch1+/+, Ptch1+/mes, Ptch1+/−, Ptch1mes/mes and Ptch1−/mes mouse embryos, as well as the islet mass in adult Ptch1+/+, Ptch1+/mes and Ptch1+/− mice.ResultsUntil embryonic day (E) 12.5, no obvious abnormality of pancreas was observed in any of the Ptch1 mutants. The levels of PDX1 and glucagon were also not evidently different among the mice genotypes studied. Thereafter, morphological abnormalities appeared in the Ptch1 mutant mice. The beta, alpha and exocrine cell masses decreased at E18.5 in parallel with increased HH signalling, with beta cell mass showing the highest sensitivity to HH signalling with a significant decrease even in Ptch1+/mes mice. Adult Ptch1+/− mice also showed a significant decrease in beta cell mass compared with wild-type mice.Conclusions/interpretationOur findings indicate that the carboxy-terminal domain of Ptch1 is essential for pancreatic development. In addition, the loss of Ptch1 function decreases both the endocrine and exocrine cell mass in a dose-dependent manner, with beta cells particularly sensitive to changes in HH signalling.

Switching from Twice-Daily Basal Insulin Injections to Once-Daily Insulin Degludec Injection for Basal-Bolus Insulin Regimen in Japanese Patients with Type 1 Diabetes: A Pilot Study.

The aim of this study was to investigate the efficacy of insulin degludec used for basal-bolus insulin regimen after switching from twice-daily basal insulin in Japanese patients with type 1 diabetes mellitus. The subjects were 22 type 1 diabetes patients treated with basal-bolus insulin regimen with twice-daily basal insulin. Basal insulin was switched to once-daily injection of insulin degludec with 10% dose reduction. HbA1c and fasting plasma glucose (FPG) were measured before and 12 weeks after switching. The frequency of hypoglycemic episodes, standard deviation (SD) of blood glucose, and mean of daily difference (MODD) were evaluated by continuous glucose monitoring (CGM) before and 4 weeks after switching. HbA1c and FPG before and 12 weeks after switching were comparable (HbA1c 8.5 ± 1.4 versus 8.7 ± 1.6%, P = 0.28; FPG 203.2 ± 81.2 versus 206.5 ± 122.4 mg/dL, P = 0.91). The frequency of hypoglycemia during nighttime was not significantly different at 4 weeks after switching (14.4 ± 17.0 versus 11.1 ± 15.0%, P = 0.45). In addition, SD and MODD before and 4 weeks after switching were also comparable. In conclusion, glycemic control under once-daily insulin degludec injection was almost comparable to that under twice-daily basal insulin injections in Japanese type 1 diabetes patients. This study was registered with ID: UMIN000010474.

NEUROD1-deficient diabetes (MODY6): Identification of the first cases in Japanese and the clinical features

Only a few families with neuronal differentiation 1 (NEUROD1)‐deficient diabetes, currently designated as maturity‐onset diabetes of the young 6 (MODY6), have been reported, but mostly in Caucasian, and no mutation has been identified by family‐based screening in Japanese. Accordingly, the phenotypic details of the disease remain to be elucidated.

One year follow-up after a randomized controlled trial of a 130 g/day low-carbohydrate diet in patients with type 2 diabetes mellitus and poor glycemic control

Background & aims Recently, we conducted a prospective randomized controlled trial (RCT) showing that a 6-month 130g/day low-carbohydrate diet (LCD) reduced HbA1c and BMI more than a calorie restricted diet (CRD). [1] To assess whether the benefits of the LCD persisted after the intensive intervention, we compared HbA1c and BMI between the LCD and CRD groups at 1 year after the end of the 6-month RCT. Methods Following the end of the 6-month RCT, patients were allowed to manage their own diets with periodic outpatient visits. One year later, we analyzed clinical and nutrition data. Results Of the 66 participants in the original study, 27 in the CRD group and 22 in the LCD group completed this trial. One year after the end of the original RCT, the carbohydrate intake was comparable between the groups (215 [189–243]/day in the CRD group and 214 (176–262) g/day in the LCD group). Compared with the baseline data, HbA1c and BMI were decreased in both groups (CRD: HbA1c -0.4 [-0.9 to 0.3] % and BMI -0.63 [-1.20 to 0.18] kg/m2; LCD: HbA1c -0.35 [-1.0 to 0.35] % and BMI -0.77 [-1.15 to -0.12] kg/m2). There were no significant differences in HbA1c and BMI between the groups. Conclusions One year after the diet therapy intervention, the beneficial effect of the LCD on reduction of HbA1c and BMI did not persist in comparison with CRD. However, combining the data of both groups, significant improvements in HbA1c and BMI from baseline were observed. Although the superiority of the LCD disappeared 1 year after the intensive intervention, these data suggest that well-constructed nutrition therapy programs, both CRD and LCD, were equally effective in improving HbA1c for at least 1 year. Trial registration University Hospital Medical Information Network (UMIN) ID000010663

Comparison of sitagliptin with nateglinide on postprandial glucose and related hormones in drug-naïve Japanese patients with type 2 diabetes mellitus: A pilot study

Dipeptidyl peptidase‐4 inhibitors and glinides are effective in reducing postprandial hyperglycemia. However, little information is available on the comparative effects of the two drugs on the levels of postprandial glucose. The aim of the present study was to compare the effects of sitagliptin and nateglinide on meal tolerance tests in drug‐naïve patients with type 2 diabetes mellitus.