Peptides.2013 May;43:167-173.

[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.

Novakovic ZM, Leinung MC, Grasso P.

Department of Medicine, Division of Endocrinology and Metabolism, Albany Medical College, Albany, NY 12208, USA.

 

Abstract

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 (40 mg/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.

PMID: 23500518

 

Supplement:

[D-Leu-4]-OB3, a leptin-related synthetic peptide amide, augments the effects of exenatide and pramlintide acetate on body weight gain and glycemic control in insulin-resistant, genetically obese db/db mice (1).  In that same study, we also showed that both exenatide and pramlintide acetate, commonly delivered by subcutaneous (sc) injection in the management of type 2 diabetes mellitus (T2DM) in humans, retains glucoregulatory activity when given orally by gavage in dodecyl maltoside (DDM, trade name Intravail®), a patented transmucosal absorption enhancing agent.  In the above study, and in earlier studies with ob/ob and db/db mice, the effects of [D-Leu-4]-OB3 on energy balance and glycemic regulation, when given by intraperitoneal (ip) injection, and by gavage or intranasal instillation in DDM, were related to its ability to reduce caloric intake, enhance energy expenditure, and to increase tissue sensitivity to insulin (2-4).  To further explore the insulin sensitizing effects of [D-Leu-4]-OB3, we compared its efficacy with that of another well-characterized insulin sensitizing drug, metformin, in a nonobese insulin-deficient mouse model, Swiss Webster (SW) mice rendered hyperglycemic with streptozotocin (STZ).   The results of our study indicate that, on a molar basis, the efficacy of [D-Leu-4]-OB3 is 40-fold greater than that of metformin in preventing the body weight gain associated with insulin therapy, and in regulating blood glucose levels. Although caution must always be taken in attempts to transfer outcomes in rodent models of disease states to human disease, the results our previous studies in ob/ob and db/db mice, and the present study in a non-obese model of diabetes, suggest that an application of [D-Leu-4]-OB3 to the treatment of human diabetes, in the presence or absence of obesity, may be possible.

Patricia Grasso-1Fig. 1. Effects of insulin (0.05U reduced to 0.025U on day 5, sc, once daily), in the absence or presence of metformin (100 mg/kg), gavage, twice daily) or [DLeu-4]-OB3 (20 mg/kg), gavage, twice daily) on body weight gain in STZ-induced hyperglycemic male SW mice. Each point represents mean ± SEM body weight, expressed as percent of initial (n = 6 mice per group).

 

Patricia Grasso-2Fig. 2. Effects of insulin (0.05U reduced to 0.025U on day 5, sc, once daily), in the absence or presence of metformin (100 mg/kg, gavage, twice daily) or [D-Leu-4]-OB3 (20 mg/kg, gavage, twice daily) on fasting blood glucose levels in STZ-induced hyperglycemic male SW mice. Each bar and vertical line represents mean ± SEM fasting blood glucose (n = 6 mice per group).

 

References

1.   Leinung MC, Grasso P.  2012.  [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.

2.  Waldrop MA, Leinung MC, Lee DW, Grasso P.  Intranasal delivery of mouse [D-Leu-4]-OB3, a synthetic peptide amide with leptin –like activity, improves energy balance, glycaemis control, insulin sensitivity and bone formation in leptin-resistant C57BLK/6-m db/db mice.  2010. Diabetes, Obesity and Metabolism 12:871-875.

3.  Novakovic ZM, Leinung MC, Lee DW, Grasso P.  2010.  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, glycaemic control and serum ostoecalcin levels.  Diabetes, Obesity and Metabolism 12: 532-539.

4.  Grasso P, Rozhavskaya-Arena M, Leinung MC, Lee DW.  2001.  [D-Leu-4]-OB3, a synthdtic leptin agonist, improves hyperglycemic control in C57BL/6J ob/ob mice.  Regulatory Pept. 101: 123-129.

 

Acknowledgments:  This research was supported by a grant from the Willard B. Warring Memorial Fund.  Aegis Therapeutics (San Diego, CA) graciously provided  the Intravail® reagent..

 

Contact:

Patricia Grasso, Ph.D.

Associate Professor of Medicine

Division of Endocrinology and Metabolism

AlbanyMedicalCollege

47 New Scotland Avenue  MC-141

Albany, New   York  12203, USA

Email:  GrassoP@mail.amc.edu

Patricia Grasso-3

Comments

There are currently no comments on this post, be the first by filling out the form below.

Speak Your Mind

*

Multiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier SchönmannMultiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier Schönmann