Objective: Luseogliflozin -a novel, orally bioavailable, 1-thio-D-glucitol derivative and a selective sodium glucose cotransporter 2 inhibitor -has shown efficacy and tolerability in previous phase 2 studies. This phase 3, randomized, double-blind, placebo-controlled, comparative study aimed to confirm the superiority of 24 week luseogliflozin 2.5 mg monotherapy over placebo in reducing hemoglobin A1c (HbA1c) levels in Japanese patients with type 2 diabetes mellitus (T2DM). Methods:Patients with HbA1c levels of 6.9%-10.5% were randomized to receive luseogliflozin 2.5 mg or placebo once daily for 24 weeks (n ¼ 79 in each group). The primary endpoint was change from baseline in HbA1c at end of treatment. Secondary endpoints included change from baseline in fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) following a meal tolerance test, body weight, and abdominal circumference. Safety assessments included adverse events (AEs), clinical laboratory tests, and vital signs.

Fall in skin temperature during initial muscular work was investigated in ten healthy men. Bicycle exercise was performed at workloads of 50-150 W in a climatic chamber at ambient temperatures of 10-40'C (relative humidity 45-55%). Skin temperatures at seven or eight points over the body surface were measured using thermography and thermocouple recording systems. Sweat rates were significantly higher at 400C than at 30'C, whereas the fall in skin temperature was almost equal. The reduction of skin temperature during exercise was the same throughout the year, although sweat rate was significantly higher in summer than in winter. In coloured thermographics of the skin temperature distribution during exercise of both 50 and 150 W at 10 or 20'C, the skin temperature began to dedine immediately at the onset of the exercise. Increased work intensities reduced skin temperature. The results suggest that fall in skin temperature during initial exercise was not due to increased evaporative cooling but to vasoconstriction, probably caused by non-thermal factors.

We have previously shown that cAMP-binding protein cAMP-guanidine nucleotide exchange factor II (GEFII) (or Epac2) interacting with Rim2 is involved in cAMPdependent, protein kinase A-independent exocytosis in pancreatic ␤-cells. The action of the cAMP-GEFII⅐Rim2 complex requires both intracellular cAMP and Ca 2؉ . Although Rim2 has C 2 domains, its role as a Ca 2؉ sensor has remained unclear. In the present investigation, we have discovered that Piccolo, a CAZ (cytoskeletal matrix associated with the active zone) protein in neurons that is structurally related to Rim2, also binds to cAMP-GE-FII and that it forms both homodimer and heterodimer with Rim2 in a Ca 2؉ -dependent manner, whereas Rim2 alone does not form the homodimer. The association of Piccolo⅐Rim2 heterodimerization is stronger than Piccolo⅐Piccolo homodimerization. Treatment of pancreatic islets with antisense oligodeoxynucleotides against Piccolo inhibits insulin secretion induced by cAMP analog 8-bromo-cyclic AMP plus high glucose stimulation. These results suggest that Piccolo serves as a Ca 2؉ sensor in exocytosis in pancreatic ␤-cells and that the formation of a cAMP-GEFII⅐Rim2⅐Piccolo complex is important in cAMP-induced insulin secretion. In addition, this study suggests that CAZ proteins similar to those in neurons are also function in pancreatic ␤-cells.

Luseogliflozin improved glycemic control and reduced body weight in all eGFR groups, and its efficacy on HbA1c lowering was reduced in those with moderate renal impairment. Luseogliflozin was well tolerated and safe, with no significant safety issues identified, regardless of baseline eGFR. The study is registered with Clinical Trials Information/JapicCTI of the Japan Pharmaceutical Information Center, and the study registry identification numbers are JapicCTI-111507, JapicCTI-111508, JapicCTI-111509, and JapicCTI-111543.

Luseogliflozin treatment brought about favorable changes in body composition and metabolism of moderately obese Japanese type 2 diabetes patients, accompanied by body fat reduction, and minimal muscle and BMC reduction.

Objectives: Luseogliflozin is a selective sodium glucose cotransporter 2 inhibitor under development for the treatment of type 2 diabetes mellitus (T2DM). This phase II study was conducted to confirm the efficacy and safety of luseogliflozin monotherapy at doses of up to 10 mg in Japanese patients with T2DM.

AimsThe efficacy and safety of insulin degludec (IDeg) was compared with insulin detemir (IDet), both administered once daily (OD) as basal treatment in participants with type 1 diabetes mellitus (T1DM). The primary outcome was non-inferiority of IDeg to IDet in glycated haemoglobin (HbA1c) reduction after 26 weeks.MethodsThis multinational, 26-week, controlled, open-label, parallel-group trial randomized adults with T1DM to IDeg or IDet as OD basal insulin treatment combined with mealtime bolus insulin aspart (IAsp). Participants with T1DM treated with any basal–bolus insulin regimen for ≥12 months prior to the trial, a mean HbA1c ≤ 10.0% (85.8 mmol/mol) and body mass index (BMI) ≤35.0 kg/m2 at screening participated in the trial (IDeg: N = 302; IDet: N = 153).ResultsAfter 26 weeks, HbA1c decreased 0.73% (8.0 mmol/mol) (IDeg) and 0.65% (7.1 mmol/mol) (IDet) [estimated treatment difference (ETD) IDeg–IDet: −0.09% (−0.23; 0.05)95%CI (−10.0 mmol/mol [−2.6; 0.6]95% CI); confirming non-inferiority]. Mean fasting plasma glucose improved in both groups, and was lower with IDeg than IDet [ETD IDeg–IDet: −1.66 mmol/l (−2.37; −0.95)95% CI, p < 0.0001]. The rate of confirmed hypoglycaemia was similar with IDeg and IDet [45.83 vs. 45.69 episodes per patient-year of exposure (PYE); estimated rate ratio (RR) IDeg/IDet: 0.98 (0.80; 1.20)95% CI, p = 0.86]. The rate of nocturnal confirmed hypoglycaemia was lower with IDeg than IDet [4.14 vs. 5.93 episodes per PYE; RR IDeg/IDet: 0.66 (0.49; 0.88)95% CI, p = 0.0049]. Adverse event profiles were similar between groups.ConclusionIDeg administered OD in basal–bolus therapy effectively improved long-term glycaemic control in participants with T1DM with a lower risk of nocturnal confirmed hypoglycaemia than IDet.

Objective: Luseogliflozin is a novel sodium glucose cotransporter 2 inhibitor for type 2 diabetes mellitus (T2DM) treatment. An exploratory Phase II study was conducted to assess the efficacy and safety of several doses of luseogliflozin in Japanese T2DM patients. Patients and methods:Japanese T2DM patients aged 20-74 years with hemoglobin A1c (HbA1c) of 6.9-10.5%, fasting plasma glucose (FPG) !126 mg/dL and on diet therapy were randomized in a double-blind manner to receive luseogliflozin (0.5, 2.5, or 5 mg) or placebo once daily for 12 weeks (n ¼ 61, 61, 61, and 56, respectively). The primary endpoint was the change in HbA1c from baseline to end of treatment. Other endpoints included FPG, 2 h postprandial plasma glucose (PPG) in a meal tolerance test (MTT), and body weight. Drug safety was also assessed.Trial registration: Japan Pharmaceutical Information Center (identifier: JapicCTI-090908). Results:Changes in HbA1c from baseline to end of treatment were À0.36, À0.62, and À0.75% in the 0.5, 2.5, and 5 mg luseogliflozin groups, respectively, versus þ0.06% in the placebo group (all P50.001). The reductions in FPG and 2 h-PPG in the MTT were also significantly greater in the luseogliflozin groups (all P50.01) without increases in insulin levels from baseline. Luseogliflozin reduced body weight at all doses. There were no significant differences in the incidences of adverse events among groups. Most adverse events were mild in severity. There were no serious adverse events. Conclusions:Although this was a small-scale study with a short duration, all tested doses of luseogliflozin significantly improved glycemic control, reduced body weight, and were well tolerated in Japanese T2DM patients over the 12-week treatment period.