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.

Aims/IntroductionPemafibrate is a novel selective peroxisome proliferator‐activated receptor‐α modulator with potent triglyceride‐lowering and high‐density lipoprotein cholesterol‐raising effects. We showed that pemafibrate decreased the homeostatic model assessment for insulin resistance in patients with dyslipidemia. To investigate how pemafibrate improves insulin sensitivity, we used a hyperinsulinemic‐euglycemic clamp technique to determine the splanchnic and peripheral glucose uptake in patients with hypertriglyceridemia and insulin resistance.Materials and MethodsA total of 27 patients with hypertriglyceridemia and insulin resistance were randomly assigned to receive pemafibrate (0.4 mg/day, b.i.d.) or placebo treatment for 12 weeks. The hyperinsulinemic‐euglycemic clamp test combined with oral glucose loading was carried out at weeks 0 and 12 to evaluate the splanchnic and peripheral glucose uptake.ResultsPemafibrate, but not the placebo, significantly increased the splanchnic glucose uptake rate from baseline (19.6 ± 5.9% with P = 0.005 and 2.1 ± 7.4% with P = 0.78, respectively), although no significant difference between the groups was observed (P = 0.084). Conversely, peripheral glucose uptake rate was not significantly altered. Pemafibrate, compared with the placebo, significantly decreased plasma triglycerides (−61.4 ± 16.4% vs −2.5 ± 41.4%, P = 0.001), free fatty acids (−24.8 ± 23.2% vs 2.0 ± 26.8%, P = 0.016) and gamma‐glutamyl transpeptidase (−30 ± 46 vs 10 ± 19 U/L, P = 0.009) levels, and significantly increased fibroblast growth factor 21 (457.7 ± 402.1 vs −41.7 ± 37.4 pg/mL, P = 0.007) levels.ConclusionsPemafibrate increased splanchnic glucose uptake from baseline in patients with hypertriglyceridemia.

Background Glucagon-like peptide-1 receptor agonists have been reported to reduce body fat as well as improving glycemic control in obese patients with type 2 diabetes. However, the maximum dose of liraglutide is limited to 0.9 mg in Japan, while the international dose is 1.8 mg; and the effect of this low dose on body composition has not been assessed in detail. Accordingly, this study was performed to evaluate the effect of liraglutide on body composition when administered at 0.9 mg once daily for 24 weeks. Methods Nine patients were enrolled and started liraglutide at 0.3 mg once daily, which was titrated to 0.9 mg once daily after 1 - 2 weeks and continued for 24 weeks. To comprehensively investigate changes of body composition, the body fat and muscle weight were determined by dual energy absorptiometry, visceral fat volume (VFV) and abdominal subcutaneous fat volume (SFV) were measured by abdominal computed tomography (CT), and the intrahepatic lipid content (IHL) was assessed by proton magnetic resonance spectroscopy. Measurements were obtained before starting liraglutide therapy and after 12 and 24 weeks of treatment. Results Fasting plasma glucose was significantly reduced from 127 ± 22 to 101 ± 14 mg/dL at 24 weeks and hemoglobin A1c (HbA1c) showed significant reduction from 6.4±0.9% to 5.2±0.5%. Body weight was reduced from 103.4 ± 14.7 to 97.0 ± 12.4 kg (mean reduction: 11.7%) and BMI decreased from 37.4 ± 6.4 to 35.0 ± 5.3 kg/m 2 (mean reduction: 5.8%). Furthermore, VFV and IHL decreased from 5,192 ± 1,730 to 4,513 ± 1,299 cm 3 (mean reduction: 11.9%) and 32.1±12.6% to 15.2±9.2% (mean reduction: 49.2%), respectively, but SFV did not change. Moreover, the fat index was reduced from 14.8 ± 4.4 to 12.9 ± 3.4 kg/m 2 (mean reduction: 10.9%), but the skeletal muscle index did not change. Conclusions In obese Japanese drug-naive patients who had type 2 diabetes, treatment with liraglutide (0.9 mg once daily for 24 weeks) reduced body fat, especially visceral fat and intrahepatic fat, while having no significant effect on skeletal muscle.

AimWe performed a replication study in a Japanese population to evaluate the association between type 2 diabetes and 7 susceptibility loci originally identified by European genome-wide association study (GWAS) in 2012: ZMIZ1, KLHDC5, TLE1, ANKRD55, CILP2, MC4R, and BCAR1. We also examined the association of 3 additional loci: CCND2 and GIPR, identified in sex-differentiated analyses, and LAMA1, which was shown to be associated with non-obese European type 2 diabetes.MethodsWe genotyped 6,972 Japanese participants (4,280 type 2 diabetes patients and 2,692 controls) for each of the 10 single nucleotide polymorphisms (SNPs): rs12571751 in ZMIZ1, rs10842994 near KLHDC5, rs2796441 near TLE1, rs459193 near ANKRD55, rs10401969 in CILP2, rs12970134 near MC4R, rs7202877 near BCAR1, rs11063069 near CCND2, rs8108269 near GIPR, and rs8090011 in LAMA1 using a multiplex polymerase chain reaction invader assay. The association of each SNP locus with the disease was evaluated using a logistic regression analysis.ResultsAll SNPs examined in this study had the same direction of effect (odds ratio > 1.0, p = 9.77 × 10-4, binomial test), as in the original reports. Among them, rs12571751 in ZMIZ1 was significantly associated with type 2 diabetes [p = 0.0041, odds ratio = 1.123, 95% confidence interval 1.037–1.215, adjusted for sex, age and body mass index (BMI)], but we did not observe significant association of the remaining 9 SNP loci with type 2 diabetes in the present Japanese population (p ≥ 0.005). A genetic risk score, constructed from the sum of risk alleles for the 7 SNP loci identified by un-stratified analyses in the European GWAS meta-analysis were associated with type 2 diabetes in the present Japanese population (p = 2.3 × 10-4, adjusted for sex, age and BMI).Conclusions ZMIZ1 locus has a significant effect on conferring susceptibility to type 2 diabetes also in the Japanese population.