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To evaluate the efficacy and safety of elobixibat in patients with diabetes and concomitant chronic constipation.This was a single-center, single-arm study. Thirty-three patients with diabetes and chronic constipation, as defined by the Rome IV criteria, were treated with elobixibat (10 mg/day) for 8 weeks. Patients recorded stool properties, including spontaneous bowel movements (SBMs) and stool consistency, according to the Bristol Stool Form Scale (BSFS). Quality of life for constipation was evaluated with the Japanese version of the Patient Assessment of Constipation Quality of Life (JPAC-QOL).Of the 33 eligible patients, 30 completed the study. Elobixibat significantly increased the median (interquartile range) frequency of SBMs per week, from 5.0 (3.0-7.0) at baseline to 6.0 (4.0-7.0] at week 8 (p = 0.030). After 8 weeks, the BSFS score approached 4; the score for normal stool consistency and the JPAC-QOL score significantly improved from 1.05 ± 0.40 at baseline to 0.94 ± 0.53 (p = 0.048); and glycated albumin and serum lipid profiles significantly improved. Stratified analysis revealed that SBMs increased especially in patients with low SBM frequency, in particular in women, older adults, patients without overweight, patients with a long duration of constipation, and patients with diabetic neuropathy. No serious adverse events occurred.Among patients with diabetes who met the Rome IV criteria for constipation, elobixibat was effective, especially in those with few SBMs at baseline. Improvements in lipid profiles could be an advantage of elobixibat compared with other laxatives.Japan Registry of Clinical Trials registration number: jRCTs031190092.

Breath acetone (BrAce) has been reported to be useful for monitoring the pathophysiology of patients with diabetes. However, devices that measure BrAce are expensive, complex and uncommon. The FM-001, originally designed to monitor a marker of weight loss in healthy people, is a device for measuring BrAce. The FM-001 is a loading semiconducting gas sensor that is a simple and reusable device. The aim of this study was to evaluate the correlation between blood total ketone bodies (TKB) and BrAce measured with the FM-001 in patients with diabetes. Furthermore, through evaluation of that correlation, we sought to detect patients at high risk of developing diabetic ketoacidosis (DKA). Thirty-five participants (age 52 [40–57], T2DM 32, T1DM 3) were enrolled. Scatter plots and linear regression lines relating BrAce to TKB and the correlation coefficients were calculated. Receiver-operating characteristic analysis was performed to determine the cut-off for predicting patients prone to DKA. The results showed that BrAce strongly correlates with TKB (R = 0.828), and the correlation was stronger in patients whose serum C-peptide was not low. The optimal BrAce cut-off for predicting risk of developing DKA was 3400 ppb (AUC 0.924, sensitivity 73.3%, specificity 100%), which corresponds to a TKB ⩾ 1000 µmol l−1. BrAce also weakly correlated with free fatty acid. Thus, BrAce levels measured with the FM-001 strongly correlate with TKB, even in patients with diabetes. This suggests the FM-001 is a simple and potentially useful method for detecting diabetic ketosis. (UMIN-ID: UMIN000038086)

Introduction Patients with type 2 diabetes (T2D) in Japan are prescribed a lower dose of metformin that their counterparts in Western countries due to concerns for the risk of lactic acidosis incidence. Here we report our study on the association between high-dose metformin administration and the incidence of lactic acidosis in Japanese patients with T2D. Methods A Japanese claims database (April 2008–November 2018) was analyzed. Factors associated with the incidence of lactic acidosis were first identified from the database records by conducting a case–control study, and these were then used as confounding factors in subsequent analyses. The association between high-dose metformin administration (≥ 1000 mg/day) and the incidence of lactic acidosis was compared with that between low-dose metformin (

Introduction Metformin has dose-dependent hypoglycemic effects on patients with type 2 diabetes (T2D). In Japan, metformin has been prescribed at lower doses than in Western countries. We analyzed the effect of increasing the metformin dose on glycemic control and compared it to a combination therapy with dipeptidyl peptidase-4 inhibitors (DPP-4i) and a replacement therapy with DPP-4i. Methods This is a cohort study using a Japanese claims database. Patients with T2D who had been initially treated with low-dose metformin (≥ 500 mg/day and

The aim of this study is to investigate the renoprotective effect of the GLP-1 receptor agonist, liraglutide, in early-phase diabetic kidney disease (DKD) using an animal model of type 2 diabetes with several metabolic disorders. Male 8-week-old spontaneously diabetic Torii (SDT) fatty rats (n = 19) were randomly assigned to three groups. The liraglutide group (n = 6) was injected subcutaneously with liraglutide. Another treatment group (n = 6) received subcutaneous insulin against hyperglycemia and hydralazine against hypertension for matching blood glucose levels and blood pressure with the liraglutide group. The control groups of SDT fatty (n = 7) and non-diabetic Sprague–Dawley rats (n = 7) were injected only with a vehicle. The control group of SDT fatty rats exhibited hyperglycemia, obesity, hypertension, hyperlipidemia, glomerular sclerosis, and tubulointerstitial injury with high urinary albumin and L-FABP levels. Liraglutide treatment reduced body weight, food intake, blood glucose and blood pressure levels, as well as ameliorated renal pathologic findings with lower urinary albumin and L-FABP levels. Liraglutide increased expressions of phosphorylated (p)-eNOS and p-AMPK in glomeruli, downregulated renal expression of p-mTOR, and increased renal expressions of LC3B-II, suggesting activation of autophagy. However, these effects were not caused by the treatments with insulin and hydralazine, despite comparable levels of hyperglycemia and hypertension to those achieved with liraglutide treatment. Liraglutide may exert a renoprotective effect via prevention of glomerular endothelial abnormality and preservation of autophagy in early-phase DKD, independent of blood glucose, and blood pressure levels.

Type 2 diabetes is associated with sarcopenia. Resistance training and appropriate nutritional therapy are reported to be effective for muscle strength and mass. This study aimed to evaluate the effect of resistance training using elastic bands at home combined with a leucine-rich amino acid supplement on muscle strength, physical function, and muscle mass in elderly type 2 diabetes. We conducted a 48-week prospective single-center randomized controlled trial in 60 patients who were randomly allocated to one of three groups: control (C), resistance exercise (R), and resistance exercise plus supplement (RL). R and RL groups performed daily bodyweight resistance training with elastic bands exercises at home, and the RL group also took 6 g of a leucine-rich amino acid supplement daily. Knee extension strength (muscle strength), grip strength, usual gait speed (physical function), muscle mass, and cognitive function were assessed at 0 and 48 weeks. Although the change in knee extension strength from baseline was significantly increased by 6.4 Nm (95% CI 1.0, 11.7) in the RL group (p = 0.036), no significant difference was observed among the three groups (p = 0.090). Physical function, muscle mass, and cognitive function also had no changes during the study period among the three groups. No additive effect of a leucine-rich amino acid supplement on muscle strength or mass was observed. Although a post hoc analysis comparing with or without resistance training (C group vs. R + RL group) found that knee extension strength was significantly increased (p = 0.028), and cognitive decline was less (p = 0.046) than in the C group.

Background: We previously reported the effect of sitagliptin or glimepiride treatment for 24 weeks on body composition in Japanese overweight and obese patients with type 2 diabetes. Although the degree of HbA1c reduction was similar between the two groups, significant reduction of intrahepatic lipid (IHL), determined by proton magnetic resonance spectroscopy ( 1 H-MRCP), and fat mass (FM), determined by dual-energy X-ray absorptiometry (DXA), was observed in the sitagliptin group but not in the glimepiride group. As both IHL and FM are known as associating factors of insulin resistance, these reductions may lead to improvement of insulin sensitivity, which in turn may contribute to sitagliptin-induced amelioration of glycemic control. On the other hand, muscle and muscle/fat ratio were also reported to be positively correlated with insulin sensitivity, but we did not evaluate these factors. Methods: DXA separates the whole body into three major components, bone mass (BM), FM and fat and bone-free mass (FBFM), and measures the weight of each component. FBFM is normally used as a good marker of muscle mass; therefore, in this post-hoc analysis, we investigated whether sitagliptin treatment for 24 weeks influenced the FBFM and FBFM/FM ratio. Results: After 24 weeks, the FBFM and FBFM/FM ratio significantly increased in the sitagliptin group (47.6 ± 10.3 to 48.8 ± 11.0 kg, P < 0.05 and 2.0 ± 0.8 to 2.1 ± 0.8, P < 0.05), but not in the glimepiride group (49.7 ± 10.6 to 49.3 ± 9.9, P = 0.655 and 2.1 ± 0.9 to 2.0 ± 0.7, P = 0.855). The mean change of FBFM and FBFM/FM ratio from baseline to 24 weeks in the sitagliptin and glimepiride groups was 1.24 ± 2.01 (sitagliptin group) vs. -0.34 ± 2.63 kg (glimepiride group) (P = 0.074) and 0.13 ± 0.17 (sitagliptin group) vs. -0.11 ± 0.30 (glimepiride group) (P < 0.05), respectively. Conclusions: Sitagliptin 24-week treatment demonstrated not only reduction of body fat and liver fat but also an increase of muscle and muscle/fat ratio. These changes may partly explain the mechanism underlining sitagliptin-induced improvement of glycemic control. J Clin Med Res. 2020;12(2):122-126 doi: https://doi.org/10.14740/jocmr4078

Background: Renal hypoxia is an aggravating factor for tubulointerstitial damage, which is strongly associated with renal prognosis in diabetic kidney disease (DKD). Therefore, urinary markers that can detect renal hypoxia are useful for monitoring DKD. Objective: To determine the correlation between urinary liver-type fatty acid-binding protein (L-FABP) and renal hypoxia using a novel animal model of type 2 diabetes. Methods: Male spontaneously diabetic Torii (SDT) fatty rats (n = 6) were used as an animal model of type 2 diabetes. Age- and sex-matched Sprague-Dawley (SD) rats (n = 8) were used as controls. Body weight, systolic blood pressure, and blood glucose levels were measured at 8, 12, 16, and 24 weeks of age. Urine samples and serum and kidney tissues were collected at 24 weeks of age. Microvascular blood flow index (BFI) was measured using diffuse correlation spectroscopy before sampling both the serum and kidneys for the evaluation of renal microcirculation at the corticomedullary junction. Results: Obesity, hyperglycemia, and hypertension were observed in the SDT fatty rats. Focal glomerular sclerosis, moderate interstitial inflammation, and fibrosis were significantly more frequent in SDT fatty rats than in SD rats. While the frequency of peritubular endothelial cells and phosphoendothelial nitric oxide synthase levels were similar in both types of rats, the degree of renal hypoxia-inducible factor-1α (HIF-1α) expression was significantly higher (and with no change in renal vascular endothelial growth factor expression levels) in the SDT fatty rats. Urinary L-FABP levels were significantly higher and renal microvascular BFI was significantly lower in the SDT fatty rats than in the SD rats. Urinary L-FABP levels exhibited a significant positive correlation with renal HIF-1α expression and a significant negative correlation with renal microvascular BFI. Conclusions: Urinary L-FABP levels reflect the degree of renal hypoxia in DKD in a type 2 diabetic animal model. Urinary L-FABP may thus prove useful as a renal hypoxia marker for monitoring DKD in patients with type 2 diabetes in clinical practice.

This study investigated the effect of liraglutide, a glucagon-like peptide-1 receptor agonist, on skeletal muscles in rats with type 2 diabetes. Male SDT fatty rats (8-week-old) were provided liraglutide, or insulin-hydralazine for 8 weeks; control SDT fatty rats and SD rats were administered a vehicle. At 16 weeks of age, muscle strength of limbs was significantly lower in all SDT fatty rats compared to SD rats. While cross-sectional areas of type IIb muscle fibers in extensor digitorum longus muscle were significantly lower in SDT fatty rats than in SD rats, those of type I muscle fibers in soleus were similar in all rats. In the soleus of SDT fatty rats, liraglutide led to greater citrate synthase activity and cytochrome c oxidase subunit 5 B protein expression, independently of blood glucose and blood pressure levels. Liraglutide may contribute to preservation of mitochondrial content on soleus muscle in type 2 diabetes.

Background: We previously reported changes of body composition determined by dual-energy X-ray absorptiometry after treatment with ipragliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor. In that study, mean body weight was decreased by 3.5 kg (4.3% of the baseline value) after ipragliflozin treatment at 50 mg/day, with fat mass and lean mass showing similar reductions of 1.7 and 1.8 kg, respectively. A long-term decrease of lean mass in patients treated with SGLT2 inhibitors may be associated with loss of skeletal muscle, which could potentially have an impact on quality of life. Methods: In this post hoc analysis, we investigated whether changes of body composition were influenced by other medications for diabetes in 20 patients (11 men and nine women) who received ipragliflozin for 24 weeks. Results: When we divided the patients into two subgroups with or without metformin treatment, fat mass showed a significant decrease in the ipragliflozin + metformin subgroup and a significantly greater decrease compared to the ipragliflozin subgroup (2.0 kg; 95% confidence interval (CI): 0.1 - 3.9; P = 0.038). Lean mass was significantly decreased in the ipragliflozin subgroup, but the decrease showed no significant difference from that in the ipragliflozin + metformin subgroup (1.9 kg; 95% CI: -4.1 - 0.3; P = 0.087). No significant differences of body composition changes were observed with other antidiabetic agents. Conclusions: More desirable weight reduction due to preferential fat loss and less muscle loss may be achieved by combining an SGLT2 inhibitor with metformin. J Clin Med Res. 2019;11(4):297-300 doi: https://doi.org/10.14740/jocmr3785

We have previously demonstrated that eating glutinous brown rice (GBR) for 1 day or 8 weeks was well accepted and improved glycemic control in patients with type 2 diabetes. The present study evaluated whether eating GBR could also improve glucose metabolism in subjects without diabetes. A prospective 6-week, single-center, randomized, open-label, parallel-group study was carried out in subjects receiving annual medical checkup at our hospital. A total of 42 subjects were randomly assigned to continue their regular diet (RD group) or to switch GBR twice a day (GBR group). The primary outcome was the change in the serum concentration of 1,5-anhydroglucitol (1,5-AG) from baseline after the 6-week dietary intervention. One subject was excluded from the analysis because of a traffic accident. After 6 weeks, the serum 1,5-AG was significantly increased in the GBR group and the mean treatment difference (GBR group − RD group) was 1.1 µg/mL (95% CI: 0.6 to 1.6, p = 0.022 ). Body mass index decreased significantly in both groups, with no significant difference between them ( p = 0.210 ). There were no changes in fasting plasma glucose, fasting insulin, or eating behavior. Intake of GBR for 6 weeks significantly increased serum 1,5-AG in Japanese subjects without diabetes. The increase of 1,5-AG may have been due to the alleviation of postprandial hyperglycemia, which could be effective for the primary prevention of diabetes.

Background. Type 2 diabetes (T2D) is a known risk factor for diabetic kidney disease (DKD) and sarcopenia in older patients. Because there may be an interaction between DKD and sarcopenia, the aim of the present study is to investigate the relationship between urinary levels of liver-type fatty acid-binding protein (L-FABP) and sarcopenia using a novel rat model of T2D. Methods. Male spontaneously diabetic Torii (SDT) fatty rats (n=5) at 16 weeks of age were used as an animal model of T2D. Age- and sex-matched Sprague-Dawley (SD) rats (n=7) were used as controls. Urine samples were obtained from the rats, and muscle strength was evaluated with the use of the forelimb grip test at 16, 20, and 24 weeks of age. Serum, kidney, soleus, and extensor digitorum longus (EDL) muscle samples were collected at 24 weeks of age. Urinary L-FABP levels were measured using dedicated enzyme-linked immunosorbent assays. Results. Increased urinary L-FABP levels, focal glomerular sclerosis, moderate interstitial inflammation and fibrosis, and accumulation of renal oxidative proteins were significantly observed in the SDT fatty rats, compared to the SD rats. Muscle weight, muscle strength, cross-sectional areas of both type I and type IIb muscle fibers, and increasing rate of muscle strength were significantly decreased in the SDT fatty rats compared to the SD rats at 24 weeks. Urinary L-FABP levels at 20 and 24 weeks were significantly negatively correlated with muscle strength. Urinary L-FABP levels at 16 weeks were significantly negatively correlated with the increasing rate of muscle strength. Conclusions. Urinary L-FABP reflects the degree of muscle strength and weight, as well as cross-sectional areas of muscle fibers. Although further clinical study is needed, urinary L-FABP may be useful to monitor the progression of sarcopenia and DKD in T2D patients.

The impact of tofogliflozin, a sodium‐glucose co‐transporter‐2 inhibitor, on peripheral glucose uptake in patients with type 2 diabetes mellitus (T2DM) was investigated using the hyperinsulinaemic‐euglycaemic clamp method in a single‐arm, open‐label study. The following variables were compared between before and after tofogliflozin administration for 12 weeks in 16 patients with T2DM who were receiving dipeptidyl peptidase‐4 inhibitor treatment: body weight (BW); blood pressure; glucose metabolism; liver function; lipid profile; and body composition. Peripheral glucose uptake (M value and M/I ratio) was examined by the hyperinsulinaemic‐euglycaemic clamp method. After 12 weeks, there was a significant decrease (P < .001) in glycated haemoglobin, BW, body fat mass and lean body mass. Peripheral glucose uptake, which indicates insulin sensitivity, increased significantly (M value by 0.90 and M/I ratio by 0.49; both P < .05). The change in the M value after 12 weeks of tofogliflozin therapy was correlated with the change in body fat mass (P < .05). Tofogliflozin significantly improved insulin sensitivity and peripheral glucose uptake in patients with T2DM. These improvements were significantly correlated with reduction in body fat mass.

Pancreatic cancer is a highly lethal malignancy. CA19-9 is a well-known marker for diagnosis of pancreatic cancer, but the serum CA19-9 level is reported to be elevated in patients with poorly controlled diabetes. This study evaluated the sensitivity, specificity, and cut-off value of serum CA19-9 for detection of pancreatic cancer in patients with diabetes. A case-control study of 236 patients was performed. The case group was selected from diabetic patients with pancreatic cancer, while one control was selected for each case from among diabetic patients without pancreatic cancer during the same period. The case group (n = 118) and the control group (n = 118) were matched for age, sex, and pancreatic cancer risk factors. Receiver operating characteristic (ROC) curves were plotted to determine the serum CA19-9 level that predicted pancreatic cancer. Then the sensitivity and specificity of CA19-9 were calculated for the threshold value. There were no significant differences of age, sex, BMI, smoking, alcohol intake, and HbA1c between the case and control groups. According to ROC analysis, a serum CA19-9 level of 75 U/mL had the maximum sensitivity and specificity for separating diabetic patients with or without pancreatic cancer. Using this cut-off value, the sensitivity and specificity of CA19-9 for pancreatic cancer was 69.5% and 98.2%, respectively, while the area under the ROC curve was 0.875 [95%CI: 0.826-0.924]. We propose that a serum CA19-9 level of 75 U/mL should be used as the cut-off value when screening patients with diabetes for pancreatic cancer.

Aims/Introduction A prospective, 4-week, single-center, randomized, open-label, parallel-group, treat-to-target study was carried out to develop an algorithm for safe and effective switching from basal insulin to once-daily insulin degludec/insulin aspart (IDegAsp) in patients with inadequately controlled type 2 diabetes. Materials and Methods Patients were randomly assigned to continue their current basal insulin therapy (n = 10) or to switch to IDegAsp on a 1:1 unit basis (n = 10). The insulin dose could be titrated once weekly, targeting a self-measured blood glucose of 80–100 mg/dL before breakfast. A mixed meal test was carried out at baseline and after 4 weeks. Results After 4 weeks, the mean daily dose of insulin was similarly increased by 60% in both groups, and there was a significant decrease of mean plasma glucose and glucose area under the glucose concentration vs time curve for 2 h in the meal test. The mean estimated treatment difference (IDegAsp group − basal insulin group) of the mean plasma glucose level was −28 mg/dL (95% confidence interval −47 to −8, P = 0.008) after 4 weeks and that of the area under the glucose concentration vs time curve for 2 h was −2,800 mg/min/dL (95% confidence interval −5,300 to −350, P = 0.028), confirming the superiority of IDegAsp to basal insulin. In the IDegAsp group, the 2-h postprandial plasma glucose level was significantly decreased to the fasting plasma glucose range. There were no confirmed hypoglycemic episodes in either group during the 4-week study period. Conclusions After switching from basal insulin, the IDegAsp dose can be uptitrated by 60% based on fasting plasma glucose data. However, monitoring of postprandial glucose should be considered before further uptitration of IDegAsp.

Background: The aim of this study was to evaluate effect of ezetimibe monotherapy on serum low-density lipoprotein cholesterol (LDL-C) in Japanese patients and to investigate the association between changes of LDL-C and changes of markers for cholesterol synthesis and absorption. Methods: Seventy-six hypercholesterolemic patients without statin therapy were enrolled and randomized to two groups, which were an ezetimibe group (group E, n = 44) and a control group without ezetimibe treatment that received diet therapy alone (group C, n = 32). The study period was 12 weeks. In group E, 10 mg of ezetimibe was administered daily after breakfast. Serum lipids were measured every 4 weeks, while lathosterol (a cholesterol synthesis marker) and campesterol and sitosterol (cholesterol absorption markers) were examined at baseline and at 12 weeks. Results: A significant reduction of LDL-C was observed in group E at both 4 and 12 weeks (from 155 ± 3.9 to 128 ± 3.4 mg/dL and 132 ± 3.9 mg/dL, respectively, both P < 0.01), associated with an increase of high-density lipoprotein cholesterol (HDL-C)at 12 weeks (from 53 ± 1.3 to 55 ± 1.5 mg/dL, P < 0.05) and no change of triglycerides. In contrast, none of these lipids changed in group C. An increase of lathosterol and a decrease of campesterol and sitosterol were observed in group E, while none of these markers changed in group C. When group E was divided into two subgroups according to the reduction of LDL-C, which were a good response group (reduction ≥ 20 mg/dL, ΔLDL-C = -27.9 ± 1.3 mg/dL, n = 18) and a poor response group (reduction < 20 mg/dL, ΔLDL-C = -3.7 ± 2.5 mg/dL, n = 26), baseline levels of campesterol and sitosterol were higher in the good response group. Conclusion: Ezetimibe monotherapy reduced LDL-C and increased HDL-C, with the reduction of LDL-C being greater in patients with higher levels of cholesterol absorption markers. J Clin Med Res. 2017;9(6):476-481 doi: https://doi.org/10.14740/jocmr2782w

Aims Glucagon has an important role in glucose homeostasis. Recently, a new plasma glucagon assay based on liquid chromatography-high resolution mass spectrometry was developed. We evaluated the influence of a dipeptidyl peptidase-4 inhibitor (anagliptin) on plasma glucagon levels in Japanese patients with type 2 diabetes by using this new assay. Methods Twenty-four patients with type 2 diabetes were enrolled in a prospective, single-center, randomized, open-label study and were randomly allocated to 4 weeks of treatment with metformin (1000 mg/day) or anagliptin (200 mg/day). A liquid test meal labeled with sodium [13C] acetate was ingested before and after the treatment period. Samples of blood and expired air were collected over 3 h. Plasma levels of glucose, glucagon, C-peptide, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) were measured, and gastric emptying was also evaluated. Results Twenty-two patients completed the study (metformin group: n = 10; anagliptin group: n = 12). Glycemic control showed similar improvement in both groups. In the anagliptin group, there was a slight decrease of the incremental area under the plasma concentration versus time curve for glucagon after the test meal (P = 0.048). In addition, the plasma level of active GLP-1 and GIP was increased, and plasma C-peptide was also increased versus baseline. Neither anagliptin nor metformin delayed gastric emptying. Conclusions In patients with type 2 diabetes maintained endogenous insulin secretion, anagliptin increased the plasma level of active GLP-1 and GIP in association with a slight stimulation of insulin secretion and slight inhibition of glucagon secretion, but did not delay gastric emptying. Clinical Trial Registry: University hospital Medical Information Network UMIN000028293.

Background: This study was performed to clarify whether gut microbiota obtained from fecal samples could identify the type of diabetes in patients of each gender by using a combination of terminal restriction fragment length polymorphism (T-RFLP) analysis and data mining. Methods: A cross-sectional study was performed at three centers. Fecal samples were collected from 12 Japanese patients with type 1 diabetes mellitus (T1D), 18 patients with type 2 diabetes mellitus (T2D), and 31 subjects without diabetes mellitus (non-DM). Amplification of fecal 16S rRNA was carried out. After digestion of the amplification products with restriction enzymes ( Alu I, Bsl I, Hae III, and Msp I), terminal restriction fragments (T-RFs) of DNA were detected. A data mining algorithm (classification and regression tree (CART) modeling system) provides a decision tree that classifies subjects into various groups according to pre-assigned characteristics. Results: Among men, the error rate was 2.4% with Msp I, while error rates were 0.0% with other restriction enzymes. Among women, the error rate was 0.0% with all restriction enzymes. The operational taxonomic units (OTUs) incorporated into the decision tree differed between men and women. Conclusions: We were able to classify the 16SrRNA gene amplification products obtained from fecal samples of T1D patients, T2D patients, and non-DM subjects with a high level of precision by combining T-RFLP analysis and data mining. Specific gut microbiota patterns were found for T1D and T2D patients, as well as a sex difference of the patterns. J Clin Med Res. 2019;11(6):401-406 doi: https://doi.org/10.14740/jocmr3791

This study assessed the association of muscle mass with insulin resistance, evaluated from the insulin sensitivity index (ISI), in Japanese patients with gestational diabetes mellitus (GDM). Consecutive patients with GDM (n = 96) admitted to St. Marianna University Hospital between October 2015 and March 2018 for initial education and glycemic control were enrolled in a prospective observational study. Insulin resistance was evaluated by measuring the ISI and body composition was assessed by bioelectrical impedance analysis. The subjects were aged 34.4 ± 4.8 years (mean ± SD) and their body mass index (BMI) before pregnancy was 22.3 ± 4.0 kg/m2. Fifty-three patients (55.2%) had a history of diabetes in first-degree relatives. The ISI was 7.2 ± 3.3, appendicular skeletal muscle mass (ASM) was 17.0 ± 2.1 kg, and fat mass (FM) was 18.8 ± 8.2 kg. The ASM/FM ratio was 1.02 ± 0.34. There was a positive correlation between FM and ASM (r = 0.734, p < 0.001). To adjust for confounders when evaluating the association of ASM with ISI, multivariate analysis was conducted using age, family history of diabetes, and BMI as variables. In this analysis, the ASM/FM ratio showed a significant positive correlation with ISI (β = 0.303, p = 0.020). These findings suggest that inadequate ASM/FM ratio is important for the development of insulin resistance in Japanese patients with GDM. Excessive emphasis on dieting rather than health might increase the risk of GDM by reducing the muscle mass below the level that maintains normal glucose metabolism.

Aim/Introduction Waist circumference (WC) is the most important parameter for diagnosis of metabolic syndrome. The present study was carried out to obtain optimal WC cut‐off values for diagnosis of metabolic syndrome in a Japanese population based on the measurement of total intra‐abdominal visceral fat volume (VFV), which could be expected to reflect visceral obesity more precisely than visceral fat area. Materials and Methods A total of 405 Japanese persons undergoing health screening were investigated. visceral fat volume was calculated from the data in 700–800 computed tomography slices from the top of the liver to the floor of the pelvic cavity. Then, receiver operating characteristic analysis was used to determine the cut‐off value of the VFV/height ratio. Subsequently, the corresponding WC value was obtained by linear regression analysis. Results The cut‐off value of the VFV/height ratio was 2,317 cm3/m in men and 1,425 cm3/m in women. The sensitivity and specificity of the ratio were 52.9 and 86.4% in men vs 63.4 and 82.2% in women, respectively. The corresponding cut‐off value of WC was 86.0 cm in men and 80.9 cm in women. Conclusions The proposed cut‐off values of WC for metabolic syndrome are 85 cm in Japanese men and 80 cm in Japanese women.

We recently investigated the effect of ipragliflozin, a sodium glucose co-transporter-2 inhibitor (SGLT-2I), in Japanese patients with type 2 diabetes by a 24-week. SGLT-2Is also have an anti-obesity effect, and reduction of body fat has been demonstrated by indirect methods. However, evaluation of the effect on the total visceral fat volume and intrahepatic lipid content has not been performed.We measured the abdominal subcutaneous fat volume (SFV) and visceral fat volume (VFV) by whole abdominal CT scanning, the intrahepatic lipid (IHL) content by proton magnetic resonance spectroscopy (1H-MRS), and the fat mass index (FI) and appendicular skeletal mass index (ASMI) by dual X-ray absorptiometry (DXA) in 20 patients from our previous study.Administration of ipragliflozin at 50 mg/day for 24 weeks significantly reduced SFV, VFV, and IHL. FI and ASMI were also significantly decreased. Changes of VFV and IHL content at 12 weeks were significantly correlated with the change of HbA1c, but no correlation was observed at 24 weeks.These findings demonstrate that ipragliflozin decreases visceral and hepatic fat, with improvement of glycemic control possibly being attributable to these changes at least up to 12 weeks.

We investigated whether intake of non-glutinous brown rice (BR) or glutinous brown rice (GBR) for 1 day had an influence on the daily glucose profile measured by continuous glucose monitoring (CGM) when compared with intake of non-glutinous white rice (WR).A total of 37 inpatients with type 2 diabetes mellitus (T2DM) were recruited for a 3-day randomized triple cross-over trial in which they ate WR, BR, or GBR for 1 day each. One of the three types of rice was eaten at breakfast, lunch, and dinner on the first day, before switching to the other types on the second and third days. Each meal had the same energy content and the same side dishes. The main outcome measures were the blood glucose profile determined by continuous glucose monitoring (CGM) and the profile of serum C-peptide (CPR) for 3 hours after breakfast. A self-administered questionnaire was used to assess the palatability of each type of rice.According to the CGM data, the mean 24-hour glucose concentration was lowest with GBR (p0.01). Serum Cpeptide showed no significant differences among the three diets. Regarding palatability, BR was assigned significantly lower scores than WR and GBR (p0.05), while there was no difference between WR and GBR.GBR intake suppressed the whole-day glucose profile of patients with T2DM, mainly by reducing postprandial glucose excursion, and GBR was preferred over BR with respect to palatability. GBR may be worth adding to the diet of patients with T2DM.

Background: Basal insulin-supported oral therapy (BOT) is commonly used to initiate insulin therapy when oral hypoglycemic agents do not achieve adequate glycemic control in patients with Type 2 diabetes. While supplementing basal insulin is expected to reduce the fasting plasma glucose level, some patients still fail to achieve the target hemoglobin A1c (HbA1c), probably due to postprandial hyperglycemia. Elevated postprandial glucose levels make an important contribution to overall hyperglycemia in patients with diabetes, suggesting that treatment targeting postprandial glucose in addition to fasting plasma glucose may be able to improve glycemic control. Insulin degludec/insulin aspart (IDegAsp) is a novel combination drug [70% insulin degludec (IDeg) and 30% insulin aspart (IAsp)]. IDeg and IAsp exist separately in solution (Eur J Endocrinol; 167: 287, 2012), allowing formulation as a single injection. After subcutaneous injection, IDeg immediately forms stable multihexamers that create a tissue depot from which IDeg monomers slowly dissociate, while IAsp monomers are rapidly released into the circulation. Based on the pharmacokinetic and pharmacodynamic profile of IDegAsp, it may be a novel option for BOT that could improve postprandial plasma glucose (although only after one meal a day). However, IDegAsp has a 30% lower content of basal insulin, suggesting that the fasting plasma glucose level may increase after switching from basal insulin to IDegAsp on a 1: 1 unit basis.Aims: The present study was performed to develop an algorithm for safe and effective switching from basal insulin to once-daily insulin IDegAsp in patients with inadequately controlled type 2 diabetes.Methods: This was a prospective, 4-week, single-center, randomized, open-label, parallel-group, treat-to-target study. Between April 2016 and March 2017, patients with type 2 diabetes were recruited at the outpatient clinic of St. Marianna University Hospital (Kawasaki, Japan). Patients were randomly assigned to continue their current basal insulin therapy (n=10) or to switch to IDegAsp on a 1: 1 unit basis (n=10). The insulin dose was titrated weekly at hospital visits or via telephone. Based on the mean self-measured blood glucose (SMBG) level before breakfast during the preceding 7 days, the dose was increased by 2 units if SMBG was > 100 mg/dL or was reduced by 2 units if it was < 80 mg/dL. At baseline and after 4 weeks, a mixed meal test (total caloric content of 460 kcal, including 53% carbohydrate, 16% protein, and 31% fat) was performed to evaluate the plasma glucose profile (fasting and 30 min, 60 min, 90 min, and 120 min postprandially).Results: There were no differences between the two groups with regard to gender, age, duration of diabetes, body mass index, fasting plasma glucose, HbA1c, blood pressure, and serum lipid profile. After 4 weeks, the SMBG before breakfast was significantly decreased from baseline by 29 u00b1 8 mg/dL in the basal insulin group (P=0.007), and was decreased by 18 u00b1 9 mg/dL in the IDegAsp group (P=0.328). In both groups, the mean daily dose of insulin was significantly increased by 60%. In the meal test, the mean plasma glucose level showed a significant decrease of 22 u00b1 6 mg/dL in the basal insulin group (P=0.008 vs. baseline) and 49 u00b1 7 mg/dL in the IDegAsp group (P < 0.001 vs. baseline). The mean estimated treatment difference (IDegAsp group u2013 basal insulin group) was u201327.5 mg/dL (95% CI u201347, u20138, p=0.008). After 4 weeks, the AUC0-2h of glucose was 20,300 u00b1 4,500 mgu00b7min/dL in the basal insulin group (P = 0.004 vs. baseline) and 18,000 u00b1 4,100 mgu00b7min/dL in the IDegAsp group (P < 0.001 vs. baseline). The mean estimated treatment difference (IDegAsp group u2013 basal insulin group) was u20132,800 mgu00b7min/dL (95% CI u20135,300, u2013350, p=0.028), confirming that IDegAsp was superior to basal insulin. In the IDegAsp group, the 2-hour postprandial plasma glucose level was significantly decreased from 204 u00b1 36 mg/dL to 133 u00b1 40 mg/dL (p

Chronic hyperglycemia has an adverse influence on beta-cell function, which is known as 'glucotoxicity'. Sodium-glucose cotransporter-2 (SGLT2) inhibitors lower the blood glucose concentration by enhancing urinary glucose excretion. This study was performed to clarify the influence of the SGLT2 inhibitor ipragliflozin on beta-cell function assessed from the plasma intact proinsulin/C-peptide ratio in Japanese patients with type 2 diabetes.This was a 24-week, prospective, single-center, open-label, single-arm study. The subjects were 19 Japanese patients with type 2 diabetes. After a 4- to 8-week period of lifestyle modification, ipragliflozin (50 mg/d) was added to their existing treatment. At baseline and at 12 and 24 weeks after starting ipragliflozin treatment, a meal test was performed to evaluate the fasting and 2-hour proinsulin/C-peptide ratio.After 24 weeks, the body mass index, fasting plasma glucose, and hemoglobin A1c were all decreased significantly. Both the fasting and 2-hour proinsulin/C-peptide ratio decreased significantly from 25.0 ± 18.9 × 10These findings indicate that ipragliflozin might have a beneficial effect on beta-cells.

This study was performed to clarify the influence of liraglutide on gastric emptying in Japanese patients with type 2 diabetes. In 16 patients, the [ 13 C]-acetate breath test was performed to compare gastric emptying before and after liraglutide treatment. We found two patterns of response, with gastric emptying being delayed by liraglutide in seven patients (delayers) and not delayed in nine patients (non-delayers). The mean increase of the maximum gastric emptying time was 31 ± 4m in (p< 0.01 vs. baseline) in the delayers, while it was only 2 ± 3m in (p= 0.60 vs. baseline) in the non-delayers. The delayers showed a greater early decrease of AUC-PG from 0 to 60 min, despite no increase of the plasma insulin level compared with non-delayers. In conclusion, the effect of liraglutide treatment on gastric emptying shows heterogeneity, and patients can be classified as delayers or non-delayers.

Nonalcoholic fatty liver disease is the most frequent liver disease. Ezetimibe, an inhibitor of intestinal cholesterol absorption, has been reported to ameliorate hepatic steatosis in human and animal models. To explore how ezetimibe reduces hepatic steatosis, we investigated the effects of ezetimibe on the expression of lipogenic enzymes and intestinal lipid metabolism in mice fed a high-fat or a high-fructose diet. CBA/JN mice were fed a high-fat diet or a high-fructose diet for 8 wk with or without ezetimibe. High-fat diet induced hepatic steatosis accompanied by hyperinsulinemia. Treatment with ezetimibe reduced hepatic steatosis, insulin levels, and glucose production from pyruvate in mice fed the high-fat diet, suggesting a reduction of insulin resistance in the liver. In the intestinal analysis, ezetimibe reduced the expression of fatty acid transfer protein-4 and apoB-48 in mice fed the high-fat diet. However, treatment with ezetimibe did not prevent hepatic steatosis, hyperinsulinemia, and intestinal apoB-48 expression in mice fed the high-fructose diet. Ezetimibe decreased liver X receptor-α binding to the sterol regulatory element-binding protein-1c promoter but not expression of carbohydrate response element-binding protein and fatty acid synthase in mice fed the high-fructose diet, suggesting that ezetimibe did not reduce hepatic lipogenesis induced by the high-fructose diet. Elevation of hepatic and intestinal lipogenesis in mice fed a high-fructose diet may partly explain the differences in the effect of ezetimibe.

cAMP-responsive element-binding protein (CREB)-regulated transcription coactivator 2 (CRTC2) regulates transcription of gluconeogenic genes by specifying targets for the transcription factor CREB in response to glucagon. We used an antisense oligonucleotide directed against CRTC2 in both normal rodents and in rodent models of increased gluconeogenesis to better understand the role of CRTC2 in metabolic disease. In the context of severe hyperglycemia and elevated hepatic glucose production, CTRC2 knockdown (KD) improved glucose homeostasis by reducing endogenous glucose production. Interestingly, despite the known role of CRTC2 in coordinating gluconeogenic gene expression, CRTC2 KD in a rodent model of type 2 diabetes resulted in surprisingly little alteration of glucose production. However, CRTC2 KD animals had elevated circulating concentrations of glucagon and a ∼80% reduction in glucagon clearance. When this phenomenon was prevented with somatostatin or a glucagon-neutralizing antibody, endogenous glucose production was reduced by CRTC2 KD. Additionally, CRTC2 inhibition resulted in reduced expression of several glucagon-induced pyridoxal 5′-phosphate-dependent enzymes that convert amino acids to gluconeogenic intermediates, suggesting that it may control substrate availability as well as gluconeogenic gene expression. CRTC2 is an important regulator of gluconeogenesis with tremendous impact in models of elevated hepatic glucose production. Surprisingly, it is also part of a previously unidentified negative feedback loop that degrades glucagon and regulates amino acid metabolism to coordinately control glucose homeostasis in vivo. Background: CRTC2 translocates to the nucleus upon glucagon stimulation, yet its role in regulating blood glucose remains controversial. Results: CRTC2 promotes expression of enzymes that direct amino acids toward gluconeogenesis and is a key regulator of glucagon clearance. Conclusion: CRTC2 has antagonistic cell-autonomous and endocrine effects on glucose homeostasis. Significance: We present new insights into glucagon/CRTC2 physiology.

We report a 63-year-old obese ketosis-prone diabetic woman who was being treated with metformin and a low dose of insulin. We performed two hyperinsulinemic-euglycemic clamp studies followed by an oral glucose load (clamp-OGL) with and without administration of metformin. These clamp studies revealed that her splanchnic glucose uptake (SGU) was increased from 27.6 to 64.4% by metformin administration, though the glucose infusion rate (GIR) was not altered. Further investigation indicated that the intrahepatic lipid (IHL) content was low in this patient. After she stopped metformin, the fasting plasma glucose, free fatty acid, and ketone body levels were elevated, while these were decreased by re-administration of the drug. Our results suggest that metformin might not only act on the liver, but also on adipose tissue, and it could be an adjunctive treatment for obese patients with ketosis-prone type 2 diabetes.

Insulin glulisine (Glu) is a rapidly-acting insulin analog with a faster onset of action than the other insulin analogs of its class, which are insulin aspart (Asp) and insulin lispro (Lisp). While insulin Glu is usually injected just before meals, postprandial injection may help to avoid unexpected postprandial hypoglycemia or hyperglycemia by adjusting the insulin dosage according to food intake. However, the effect of postprandial insulin Glu on the glucose profile has not been evaluated. The aim of this study was to compare daily glucose excursion by continuous glucose monitoring (CGM) between multiple daily doses of preprandial insulin Asp or postprandial insulin Glu. In a randomized cross-over trial, we performed CGM to evaluate the 48-hour glucose profile during treatment with the same dosage of insulin Asp just before each meal in 12 hospitalized patients with type 2 diabetes. Patients also received the same dosage of long-acting insulin glargine at bedtime. The average glucose level, standard deviation of the glucose level, mean amplitude of glucose excursion, and daily glucose profile did not differ between preprandial Asp and postprandial Glu. The incidence of hypoglycemic episodes (glucose level

Aims To determine the threshold intrahepatic lipid (IHL) content separating metabolically normal from abnormal in a Japanese population based on proton magnetic resonance spectroscopy ( 1 H-MRS). Methods A total of 305 Japanese subjects aged 20–69 years were investigated. The subjects underwent general examination, blood tests, and 1 H-MRS of the liver after an overnight fast. They completed a questionnaire about daily drinking habits and their daily alcohol intake was calculated. Results The median IHL content was 4.7% in men and 1.7% in women, and it increased along with the number of features of metabolic syndrome (MetS). The optimum IHL cut-off value for separating normal subjects from those with at least one feature of MetS was 6.5% in men (AUC of ROC: 0.727, 95%-CI: 0.649–0.804) and 1.8% in women (0.765, 0.685–0.844). Alcohol intake was not correlated with the IHL content according to multiple logistic regression analysis. Conclusion This study demonstrated a close association of IHL with features of MetS and identified IHL content cut-off values for metabolic normality in Japanese subjects.

We previously designed and reported a simple new method (the cold-loaded pain sensation test) for quantitative evaluation of the function of small nerve fibers. In the study reported here, we investigated the clinical usefulness of this test to evaluate diabetic neuropathy by comparison with a device for quantitative measurement of the neuroselective current perception threshold (CPT). We evaluated 68 diabetic patients without cerebrovascular disease. After cooling the test site, the recovery time (RT) required for pain sensation to return to an equivalent level to that on the noncooled side was evaluated. The rapid screening mode was employed to measure CPT. RT measured at the great toe (77.8 ± 43.2 s) was significantly longer than that measured at the medial malleolus (53.8 ± 30.0 s) (p

A variation of the response to Sodium glucose co-transporter 2 (SGLT2) inhibitors with age has not been investigated in patients with diabetes. The aim of this study was to assess renal threshold of glucose (RTg) before and after administration of an SGLT2 inhibitor in young adult patients (≤40 years) and older adult patients (40 years) with type 2 diabetes (T2DM).Twenty Japanese patients with T2DM were enrolled. Baseline data were obtained on the first day and dapagliflozin (5 mg) was administered at 6:00 on the second day. Glucose excursions were assessed by continuous glucose monitoring and urine samples were collected every hour during the daytime (7:00 to 15:00) on both days. RTg was estimated from the regression line of the scatter plot of the hourly mean glucose concentrations.After a single dose of dapagliflozin, RTg decreased from 121.5 to 6.1 mg/dl in the young adult group and from 151.0 mg/dl to -15.8 mg/dl in the older group. After dapagliflozin, the slope of the regression line was significantly steeper in the young adult group.Dapagliflozin was more effective in young patients because they showed a larger response of urinary glucose excretion.

A 30-year-old woman at 37 weeks of gestation died during labor induction with oxytocin shortly after an episode of abrupt drop of fetal heart rate. Autopsy showed extensive microvascular plugging of the pulmonary capillaries by massive platelet aggregations. Aside from platelet aggregations, the keratinized substances and granulocytes were also shown in the capillary of pulmonary arterioles. These findings were not observed in other systemic organs (heart, liver, spleen, kidney, adrenal, alimentary canal and pancreas). In general, the postmortem histological diagnosis of amniotic fluid embolism consisted of demonstrating mucus, leukocytes, squamous, amorphous, and fatty cells in the arteries of the lung. To our knowledge, there have not been any reports regarding massive platelet aggregations shown at pulmonary capillaries in case of acute amniotic fluid embolism except for an experimental model. This is a rare case of amniotic fluid embolism in which massive platelet aggregations were confirmed in pulmonary capillaries by autopsy.

Although varieties of organic rubber chemicals are used in the rubber industry, some of them are potentially harmful for human society and environment. In order to reduce such an environmental load caused by the release of chemical substances into the atmosphere, Japanese government has been establishing a series of laws and regulations concerning the manufacture, import, use and disposal of harmful chemical substances. These laws and regulations make the user of rubber chemicals easy to access the important information provided by the manufacturer concerning the hazards of the chemicals. As a result, users can make appropriate action for themselves and the environmental safety according to the individual circumstances.

The influence of temperature and leaf wetness duration on infection of spring onion (Japanese bunching onion) leaves by Puccinia allii was examined in controlled-environment experiments. Leaves of potted spring onion plants (Allium fistulosum cv. Yoshikura) were inoculated with urediniospores and exposed to 6.5, 10, 15, 22, or 27 h of wetness at 5, 10, 15, 20, or 25°C. The lesion that developed increased in density with increasing wetness duration. Relative infection was modeled as a function of both temperature and wetness duration using the modified version of Weibull's cumulative distribution function (R2 = 0.9369). Infection occurred between 6.5 and 27 h of leaf wetness duration at 10, 15, 20, and 25°C and between 10 and 27 h at 5°C, and increased rapidly between 6.5 and 15 h of wetness at 10, 15, and 20°C. At 25°C, few uredinia developed regardless of the wetness duration. Parameter H, one of eight parameters used in the equation and which controls the asymmetry in the response curve, varied markedly according to the temperature, so that the model could be improved by representing H as a function of wetness duration (R2 = 0.9501).