[D-Leu-4]-OB3, an orally bioavailable leptin-related synthetic peptide insulin sensitizer: A study comparing the efficacies of [D-Leu-4]-OB3 and metformin on energy balance and glycemic regulation in insulin-deficient male Swiss Webster mice

• Published in: Peptides (New York, N.Y. : 1980) Vol. 43; pp. 167 - 173
• Main Authors: Novakovic, Zachary M., Leinung, Matthew C., Grasso, Patricia
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2013
• Subjects: acetates; Administration, Oral; animal models; Animals; Biological Availability; blood glucose; Blood Glucose - metabolism; blood serum; body weight changes; c-peptide; Diabetes; Disease Models, Animal; energy balance; Energy Metabolism - drug effects; enzyme-linked immunosorbent assay; fasting; glycemic control; glycemic effect; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - pharmacology; Insulin - deficiency; Insulin - metabolism; insulin replacement therapy; insulin resistance; Insulin sensitizer; Leptin - administration & dosage; Leptin - pharmacology; Leptin-related peptide; Male; males; Metformin; Metformin - administration & dosage; Metformin - pharmacology; Mice; Obesity; Peptide Fragments - administration & dosage; Peptide Fragments - pharmacology; streptozotocin; synthetic peptides; weight gain; Leptin-related peptide; Obesity; Diabetes; Metformin; Insulin sensitizer
• ISSN: 0196-9781; 1873-5169
• DOI: 10.1016/j.peptides.2013.02.023

•Oral [D-Leu-4]-OB3 prevents insulin-related weight gain in insulin-deficient mice.•Oral [D-Leu-4]-OB3 regulates blood glucose levels in insulin-deficient mice.•Oral [D-Leu-4]-OB3 enhances insulin sensitivity in insulin-deficient mice.•On a molar basis, the efficacy of oral [D-leu-4]-OB3 surpasses that of metformin. The effects of oral delivery of exenatide or pramlintide acetate in dodecyl maltoside (DDM) on energy balance and glycemic control in insulin-resistant obese db/db mice are enhanced when given in combination with [D-Leu-4]-OB3. To examine the anti-hyperglycemic influence of [D-Leu-4]-OB3 in a non-obese insulin-deficient animal model, we compared the effects of metformin (200mg/kg) and [D-Leu-4]-OB3 (40mg/kg) on energy balance and glycemic control in streptozotocin (STZ)-induced diabetic male Swiss Webster (SW) mice. Diabetic mice were given insulin (Levemir®, sc) alone, or in combination with metformin or [D-Leu-4]-OB3 orally in DDM, for 14 days. Body weight and food and water intake were measured daily. Fasting blood glucose levels were determined every other day. Serum C-peptide was measured by ELISA. Diabetic mice receiving insulin alone for 14 days gained significantly more weight than DDM-treated control mice, or mice given insulin in combination with metformin or [D-Leu-4]-OB3. The weight gain seen in mice given insulin alone was accompanied by significant increases in both food and water intake. Mice treated with insulin in combination with metformin or [D-Leu-4]-OB3, consumed significantly less food and water. Blood glucose levels in STZ-treated mice receiving insulin alone were reduced to 65.3% of initial levels, while mice receiving insulin with metformin or [D-Leu-4]-OB3 were reduced to 44.5% and 38.9%, respectively. Our results indicate that [D-Leu-4]-OB3 is as effective as metformin in preventing the body weight gain associated with insulin therapy, and on a molar basis, that the efficacy of [D-Leu-4]-OB3 as an insulin sensitizer may equal or surpass that of metformin.