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Mouse Models of Type 2 Diabetes Mellitus in Drug Discovery

  • Helene BaribaultEmail author
Protocol
Part of the Methods in Molecular Biology book series (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.

Key words

Type 2 diabetes mellitus Drug discovery Glucose tolerance test Insulin tolerance test Insulin secretion Insulin sensitivity Diet-induced obesity Leptin Insulin NEFA 

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

Notes

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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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Ardelyx Inc.FremontUSA

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