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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 (

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.

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.

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

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

OBJECTIVE—Insulin resistance in skeletal muscle plays a critical role in the pathogenesis of type 2 diabetes, yet the cellular mechanisms responsible for insulin resistance are poorly understood. In this study, we examine the role of serine phosphorylation of insulin receptor substrate (IRS)-1 in mediating fat-induced insulin resistance in skeletal muscle in vivo. RESEARCH DESIGN AND METHODS—To directly assess the role of serine phosphorylation in mediating fat-induced insulin resistance in skeletal muscle, we generated muscle-specific IRS-1 Ser302, Ser307, and Ser612 mutated to alanine (Tg IRS-1 Ser→Ala) and IRS-1 wild-type (Tg IRS-1 WT) transgenic mice and examined insulin signaling and insulin action in skeletal muscle in vivo. RESULTS—Tg IRS-1 Ser→Ala mice were protected from fat-induced insulin resistance, as reflected by lower plasma glucose concentrations during a glucose tolerance test and increased insulin-stimulated muscle glucose uptake during a hyperinsulinemic-euglycemic clamp. In contrast, Tg IRS-1 WT mice exhibited no improvement in glucose tolerance after high-fat feeding. Furthermore, Tg IRS-1 Ser→Ala mice displayed a significant increase in insulin-stimulated IRS-1–associated phosphatidylinositol 3-kinase activity and Akt phosphorylation in skeletal muscle in vivo compared with WT control littermates. CONCLUSIONS—These data demonstrate that serine phosphorylation of IRS-1 plays an important role in mediating fat-induced insulin resistance in skeletal muscle in vivo.

In rodents a high-fructose diet induces metabolic derangements similar to those in metabolic syndrome. Previously we suggested that in mouse liver an unidentified nuclear protein binding to the sterol regulatory element (SRE)-binding protein-1c (SREBP-1c) promoter region plays a key role for the response to high-fructose diet. Here, using MALDI-TOF MASS technique, we identified an X-chromosome-linked RNA binding motif protein (RBMX) as a new candidate molecule. In electrophoretic mobility shift assay, anti-RBMX antibody displaced the bands induced by fructose-feeding. Overexpression or suppression of RBMX on rat hepatoma cells regulated the SREBP-1c promoter activity. RBMX may control SREBP-1c expression in mouse liver in response to high-fructose diet.

SummaryIn patients with poorly controlled type 2 diabetes mellitus (T2DM), hepatic insulin resistance and increased gluconeogenesis contribute to fasting and postprandial hyperglycemia. Since cAMP response element-binding protein (CREB) is a key regulator of gluconeogenic gene expression, we hypothesized that decreasing hepatic CREB expression would reduce fasting hyperglycemia in rodent models of T2DM. In order to test this hypothesis, we used a CREB-specific antisense oligonucleotide (ASO) to knock down CREB expression in liver. CREB ASO treatment dramatically reduced fasting plasma glucose concentrations in ZDF rats, ob/ob mice, and an STZ-treated, high-fat-fed rat model of T2DM. Surprisingly, CREB ASO treatment also decreased plasma cholesterol and triglyceride concentrations, as well as hepatic triglyceride content, due to decreases in hepatic lipogenesis. These results suggest that CREB is an attractive therapeutic target for correcting both hepatic insulin resistance and dyslipidemia associated with nonalcoholic fatty liver disease (NAFLD) and T2DM.

Background The carotid artery intima-media thickness (CIMT) has been used as a predictor of cardiovascular events, but it remains unclear whether CIMT can change over the short term. We evaluated changes of CIMT in patients with diabetes during admission to hospital for 2 weeks. Methods A total of 279 inpatients with diabetes aged 61 ± 14 years were recruited. They were on treatment with insulin and/or oral agents, excluding drugs that influence the fluid balance and hemodynamics. CIMT was measured on the day after admission and on the day before discharge, and the association of ΔCIMT (calculated by subtracting the baseline value from that on the day before discharge) with clinical factors was evaluated. Results Based on the reported annual increase of CIMT (0.04 mm/year), the patients were divided into three groups, in which CIMT increased [I: ΔCIMT ≥ 0.04 mm, n = 64, ΔCIMT = 0.077 ± 0.048 (mean ± SD)], CIMT decreased (D: ΔCIMT ≤ −0.04 mm, n = 51, ΔCIMT = −0.090 ± 0.086), or CIMT was unchanged (N: −0.04 mm