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Mouse Models of Type 2 Diabetes Mellitus in Drug Discovery

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Book cover Mouse Models for Drug Discovery

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1438))

Abstract

Type 2 diabetes is a fast-growing epidemic in industrialized countries, associated with obesity, lack of physical exercise, aging, family history, and ethnic background. Diagnostic criteria are elevated fasting or postprandial blood glucose levels, a consequence of insulin resistance. Early intervention can help patients to revert the progression of the disease together with lifestyle changes or monotherapy. Systemic glucose toxicity can have devastating effects leading to pancreatic beta cell failure, blindness, nephropathy, and neuropathy, progressing to limb ulceration or even amputation. Existing treatments have numerous side effects and demonstrate variability in individual patient responsiveness. However, several emerging areas of discovery research are showing promises with the development of novel classes of antidiabetic drugs.

The mouse has proven to be a reliable model for discovering and validating new treatments for type 2 diabetes mellitus. We review here commonly used methods to measure endpoints relevant to glucose metabolism which show good translatability to the diagnostic of type 2 diabetes in humans: baseline fasting glucose and insulin, glucose tolerance test, insulin sensitivity index, and body type composition. Improvements on these clinical values are essential for the progression of a novel potential therapeutic molecule through a preclinical and clinical pipeline.

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Abbreviations

DEXA:

Dual energy X-ray absorptiometry

DIO:

Diet-induced obesity

D-PBS:

Dulbecco’s Phosphate Buffered Saline

ED50 :

Dose providing 50 % efficacy

GSIS:

Glucose-stimulated insulin secretion

GTT:

Glucose tolerance test

i.p.:

Intraperitoneal

i.v.:

Intravenous

ITT:

Insulin tolerance test

MRI:

Magnetic Resonance Imaging

NEFA:

Nonesterified fatty acid

p.o.:

per oral gavage

PD:

Pharmacodynamics

PK:

Pharmacokinetics

s.c.:

Subcutaneous

STZ:

Streptozotocin

T2DM:

Type 2 diabetes mellitus

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Acknowledgements

I am grateful to Jonitha Gardner, Laura Hoffman, Cheryl Loughery, Drs. Jiangwen Majeti, Alykhan Motani, and Wen-Chen Yeh for scientific discussions and critical review of the manuscript.

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Authors and Affiliations

  1. Ardelyx Inc., 34175 Ardenwood Blvd, Suite 200, Fremont, CA, 94555, USA

    Helene Baribault

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  1. Helene Baribault
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Correspondence to Helene Baribault .

Editor information

Editors and Affiliations

  1. Takeda Pharmaceutical Company, Cambridge, Massachusetts, USA

    Gabriele Proetzel

  2. The Jackson Laboratory, Bar Harbor, Maine, USA

    Michael V. Wiles

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Baribault, H. (2016). Mouse Models of Type 2 Diabetes Mellitus in Drug Discovery. In: Proetzel, G., Wiles, M. (eds) Mouse Models for Drug Discovery. Methods in Molecular Biology, vol 1438. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-3661-8_10

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  • DOI: https://doi.org/10.1007/978-1-4939-3661-8_10

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  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-3659-5

  • Online ISBN: 978-1-4939-3661-8

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