FP02-1 [D-Leu-4]-OB3, a New Orally Bioavailable Leptin-Related Synthetic Peptide Amide Insulin Sensitizer: A Study Comparing the Efficacies of [D-Leu-4]-OB3 and Metformin On Energy Balance and Glycemic Control in Insulin-Deficient Male Swiss Webster Mice

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: FP02-Obesity and Diabetes: Drugs & Interventions
Saturday, June 15, 2013: 11:00 AM-11:30 AM
Presentation Start Time: 11:00 AM
Room 303 (Moscone Center)

Poster Board SAT-786
Zachary M Novakovic1, Matthew C Leinung2 and Patricia Grasso*1
1Albany Medical College, Albany, NY, 2Albany Med College, Albany, NY
Background:  We have recently shown that oral delivery of exenatide and pramlintide acetate in dodecyl maltoside (DDM), either alone or in combination with [D-Leu-4]-OB3 is feasible,  and that [D-Leu-4]-OB3, when given in combination with exenetide or pramlintide acetate, significantly augments their effects on energy balance and glycemic control in insulin-resistant male C57BLK/6-m db/db mice.  The observed synergism between [D-Leu-4]-OB3 and exenatide or pramlintide acetate appears be related to the ability of [D-Leu-4]-OB3 to reduce caloric intake, increase energy expenditure, and to enhance insulin sensitivity in this animal model.

Aim and methods:  To further explore the insulin sensitizing influence of [D-Leu-4]-OB3, we compared the effects of metformin and [D-Leu-4]-OB3 on energy balance and glycemic control in streptozotocin (STZ)-induced diabetic (insulin-deficient) male Swiss Webster (SW) mice.  Diabetic SW mice were given insulin (Levemir®, sc), either alone or in combination with metformin (200 mg/kg) or [D-Leu-4]-OB3 (40 mg/kg) orally in DDM, for 14 days.  Body weight gain, and food and water intake were measured daily.  Blood glucose levels were determined at the beginning of the study, and every other day thereafter.  Serum was prepared from whole blood on day 15, and C-peptide concentrations were determined by ELISA.

Results:  Insulin-deficient male SW mice given insulin alone for 14 days gained significantly (p < 0.001) more weight than DDM-treated control mice, or mice given insulin in combination with metformin or [D-Leu-4]-OB3.  Mice receiving metformin and [D-Leu-4]-OB3 together were two grams (p < 0.001) lighter.  The weight gain seen in mice given insulin alone was accompanied by significant increases in both food (p< 0.05) and water intake (p < 0.001).   Mice treated with insulin in combination with metformin or [D-Leu-4]-OB3, or with metformin and [D-Leu-4]-OB3, consumed significantly less food (p < 0.05) and water (p < 0.05).  Blood glucose levels in mice receiving insulin alone were reduced to 65.3% (p < 0.05) of initial levels, while mice receiving insulin with metformin or [D-Leu-4]-OB3 were reduced to 44.5% (p < 0.001) and 38.9% (p < 0.001) of initial levels, respectively.

Conclusions:   Our results indicate that [D-Leu-4]-OB3 is as effective as metformin in preventing the body weight gain associated with insulin therapy, and in reducing blood glucose levels.  They further indicate that [D-Leu-4]-OB3, on a molar basis, may be as efficient or surpass metformin as an insulin sensitizer, and suggest the possibility that this peptide may have potential application to the management of both T1DM and T2DM in humans.

Leinung MC, Grasso P.  [D-Leu-4]-OB3, a synthetic peptide amide with leptin-like activity, augments the effects of orally delivered exenatide (Byetta®) and pramlintide acetate (Symlin®) on energy balance and glycemic control in insulin-resistant C57BLK/6-m db/db mice. Regulatory Pept. 179: 33-38. 2012. Novakovic ZM, Leinung MC, Lee DW, Grasso P.  Oral delivery of mouse [D-Leu-4]-OB3, a synthetic peptide amide with leptin-like activity, in male C57BL/6J wild type and ob/ob mice:  effects on energy balance, glycemic control, and serum osteocalcin levels.  Diabetes, Obesity and Metabolism 12: 532-539, 2010. Grasso P.  Novel approaches to the treatment of obesity and type 2 diabetes mellitus:  bioactive leptin-related synthetic peptide analogs.  Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 5:163-175, 2011.

Nothing to Disclose: ZMN, MCL, PG

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: This research was supported by a grant from the Willard B. and LuLah Warring Memorial Fund.
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