leptin and ipragliflozin

We investigated whether peripheral combination treatment of a sodium-glucose cotransporter 2 (SGLT2) inhibitor and leptin improves glucose metabolism in insulin-dependent diabetes mellitus (IDDM) model mice. Twelve-week-old male C57BL6 mice were intraperitoneally administered a high dose of streptozotocin to produce IDDM. IDDM mice were then divided into five groups: SGLT2 inhibitor treatment alone, leptin treatment alone, leptin and SGLT2 inhibitor co-treatment, untreated IDDM mice, and healthy mice groups. The blood glucose (BG) level at the end of the dark cycle was measured, and a glucose tolerance test (GTT) was performed and compared between the five groups. Leptin was peripherally administered at 20 μg/day using an osmotic pump, and an SGLT2 inhibitor, ipragliflozin, was orally administered at 3 mg/kg/day. Monotherapy with SGLT2 inhibitor or leptin significantly improved glucose metabolism in mice as evaluated by BG and GTT compared with the untreated group, whereas the co-treatment group with SGLT2 inhibitor and leptin further improved glucose metabolism as compared with the monotherapy group. Notably, glucose metabolism in the co-treatment group improved to the same level as that in the healthy mice group. Thus, peripheral combination treatment with leptin and SGLT2 inhibitor improved glucose metabolism in IDDM mice without the use of insulin.

Topics: Administration, Oral; Animals; Diabetes Mellitus, Type 1; Disease Models, Animal; Drug Therapy, Combination; Glucose; Glucosides; Infusions, Intravenous; Leptin; Male; Mice, Inbred C57BL; Sodium-Glucose Transporter 2 Inhibitors; Thiophenes

Sodium-glucose cotransporter 2 (SGLT-2) inhibitors improve blood glucose control, as well as reducing bodyweight by promoting urinary glucose excretion. The weight loss is less than expected from urinary glucose loss, however, likely because of an increase in food intake. To investigate whether SGLT-2 inhibitors might increase appetite by affecting related hormones, we examined the effects of the SGLT-2 inhibitor, ipragliflozin, including those on appetite-regulating hormones, in individuals with suboptimally controlled type 2 diabetes.. Both glycated hemoglobin level (from 7.9 ± 0.8 to 7.1 ± 0.7%) and bodyweight (from 75.2 ± 12.6 to 72.6 ± 12.4 kg) were significantly decreased after treatment for 16 weeks. The fasting serum leptin level was significantly decreased after 2 weeks (from 19.5 ± 13.1 to 18.1 ± 12.4 ng/mL) and remained decreased up to 16 weeks, even after adjustment for bodyweight, whereas the plasma active ghrelin level showed no significant change. The visual analog scale score for hunger was significantly increased at 2 and 8 weeks.. The present results suggest that ipragliflozin improved glycemic control and reduced bodyweight, but also reduced serum leptin levels and might thereby have increased appetite.

Topics: Appetite; Biomarkers; Blood Glucose; Body Mass Index; Body Weight; Diabetes Mellitus, Type 2; Eating; Female; Follow-Up Studies; Ghrelin; Glucosides; Glycated Hemoglobin; Glycemic Index; Humans; Leptin; Male; Middle Aged; Prognosis; Prospective Studies; Sodium-Glucose Transporter 2 Inhibitors; Thiophenes; Weight Loss

Type 2 diabetes mellitus (T2DM) is associated with a high incidence of non-alcoholic fatty liver disease (NAFLD) related to obesity and insulin resistance. Currently, medical interventions for NAFLD have focused on diet control and exercise to reduce body weight, and there is a requirement for effective pharmacological therapies. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are oral antidiabetic drugs that promote the urinary excretion of glucose by blocking its reabsorption in renal proximal tubules. SGLT2 inhibitors lower blood glucose independent of insulin action and are expected to reduce body weight because of urinary calorie loss. Here we show that an SGLT2 inhibitor ipragliflozin improves hepatic steatosis in high-fat diet-induced and leptin-deficient (ob/ob) obese mice irrespective of body weight reduction. In the obese mice, ipragliflozin-induced hyperphagia occurred to increase energy intake, attenuating body weight reduction with increased epididymal fat mass. There is an inverse correlation between weights of liver and epididymal fat in ipragliflozin-treated obese mice, suggesting that ipragliflozin treatment promotes normotopic fat accumulation in the epididymal fat and prevents ectopic fat accumulation in the liver. Despite increased adiposity, ipragliflozin ameliorates obesity-associated inflammation and insulin resistance in epididymal fat. Clinically, ipragliflozin improves liver dysfunction in patients with T2DM irrespective of body weight reduction. These findings provide new insight into the effects of SGLT2 inhibitors on energy homeostasis and fat accumulation and indicate their potential therapeutic efficacy in T2DM-associated hepatic steatosis.

Topics: Adipose Tissue; Adult; Animals; Body Weight; Diabetes Mellitus, Type 2; Diet, High-Fat; Drug Evaluation, Preclinical; Energy Intake; Epididymis; Glucose; Glucosides; Humans; Hyperphagia; Hypoglycemic Agents; Insulin Resistance; Leptin; Lipids; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Non-alcoholic Fatty Liver Disease; Obesity; Organ Size; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Thiophenes; Weight Loss