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Omeprazole and PGC-Formulated Heparin Binding Epidermal Growth Factor Normalizes Fasting Blood Glucose and Suppresses Insulitis in Multiple Low Dose Streptozotocin Diabetes Model

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ABSTRACT

Purpose

Our objective was to develop novel nanocarriers (protected graft copolymer, PGC) that improve the stability of heparin binding EGF (HBEGF) and gastrin and then to use PGC-formulated HBEGF (PGC-HBEGF) and Omeprazole (+/− PGC-gastrin) for normalizing fasting blood glucose (FBG) and improving islet function in diabetic mice.

Methods

HBEGF, PGC-HBEGF, Omeprazole, Omeprazole + PGC-HBEGF, Omeprazole + PGC-gastrin + PGC-HBEGF and epidermal growth factor (EGF) + gastrin were tested in multiple low dose streptozotocin diabetic mice.

Results

Omeprazole + PGC-HBEGF normalized FBG and is better than EGF + gastrin at improving islet function and decreasing insulitis. Groups treated with Omeprazole, Omeprazole + PGC-HBEGF, or EGF + gastrin have significantly improved islet function versus saline control. All animals that received PGC-HBEGF had significantly reduced islet insulitis versus saline control. Non-FBG was lower for Omeprazole + PGC-gastrin + PGC-HBEGF but Omeprazole + PGC-HBEGF alone showed better FBG and glucose tolerance.

Conclusions

Omeprazole + PGC-HBEGF provides a sustained exposure to both EGFRA and gastrin, improves islet function, and decreases insulitis in multiple low dose streptozotocin diabetic mice. Although HBEGF or EGF elevates non-FBG, it facilitates a reduction of insulitis and, in the presence of Omeprazole, provides normalization of FBG at the end of treatment. The study demonstrates Omeprazole and PGC-HBEGF is a viable treatment for diabetes.

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Abbreviations

EGFRA:

Epidermal growth factor receptor agonist

FBG:

Fasting blood glucose

HBEGF:

Heparin-binding EGF

Kd :

Dissociation constant

non-FBG:

Non-fasting blood glucose

PGC:

Protected graft copolymer

T1D:

Type 1 diabetes

T2D:

Type 2 diabetes

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ACKNOWLEDGMENTS AND DISCLOSURES

This work was supported by the SBIR Grant # DK084724 from National Institute of Diabetes and Digestive and Kidney diseases of the National Institute of Health. There has been no prior publication of the present study.

G.M.C. conceived the approach, designed the experiments, researched data, and wrote the manuscript. A.N.A. contributed to the design of the experiments, researched data, and reviewed/edited the manuscript. A.A.B.. and J.L.L. researched data and reviewed/edited the manuscript. A.V.L. reviewed/edited the manuscript. E.M.B. contributed to the design of the experiments and reviewed/edited the manuscript. The authors thank Ms. Cynthia Jones for help with preparing the manuscript, and Mr. ManShun Lai and Dr. Sandra Reichstetter for technical assistance. G.M.C., A.N.A., C.C.J., M.S.L., S.R., and E.M.B. are employees of PharmaIN Corp.; A.A.B.., J.A.L., and A.V.L. are employees of the University of Illinois.

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Authors and Affiliations

  1. PharmaIN Corporation, 19805 North Creek Parkway, Suite 200, Bothell, Washington, 98011, USA

    Gerardo M. Castillo, Akiko Nishimoto-Ashfield & Elijah M. Bolotin

  2. Toxicology Research Laboratory, Department of Pharmacology, The University of Illinois at Chicago, College of Medicine, Chicago, Illinois, USA

    Aryamitra A. Banerjee, Jennifer A. Landolfi & Alexander V. Lyubimov

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  1. Gerardo M. Castillo
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  2. Akiko Nishimoto-Ashfield
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Correspondence to Gerardo M. Castillo.

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Castillo, G.M., Nishimoto-Ashfield, A., Banerjee, A.A. et al. Omeprazole and PGC-Formulated Heparin Binding Epidermal Growth Factor Normalizes Fasting Blood Glucose and Suppresses Insulitis in Multiple Low Dose Streptozotocin Diabetes Model. Pharm Res 30, 2843–2854 (2013). https://doi.org/10.1007/s11095-013-1112-6

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