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The Sweet Pee model for Sglt2 mutation.

Joseph P Ly¹, Tuncer Onay, Karen Sison

¹The Samuel Lunenfeld Research Institute, TCP Building, Room 5-1015-2, 25 Orde Street, Toronto, Ontario M5T 3H7, Canada.

Journal of the American Society of Nephrology : JASN

|January 7, 2011

Summary

This summary is machine-generated.

A new mouse model, Sweet Pee, mimics human SGLT2 gene mutations. This model shows improved glucose control but increased risks of infection and mortality, aiding diabetes drug development.

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Area of Science:

Nephrology
Endocrinology
Pharmacology

Background:

Inhibiting renal glucose transport via sodium-glucose transporter 2 (SGLT2) is a therapeutic strategy for diabetes.
SGLT2 reabsorbs 90% of filtered glucose; understanding its long-term inhibition effects is crucial.

Purpose of the Study:

To develop and characterize a mouse model (Sweet Pee) with SGLT2 dysfunction to study long-term SGLT2 inhibition effects.
To assess the safety and efficacy of SGLT2 inhibition in a preclinical setting.

Main Methods:

Generation of the Sweet Pee mouse model with a nonsense mutation in the Slc5a2 gene, leading to loss of SGLT2 function.
Phenotypic analysis, including glucose tolerance tests, renal physiology studies, and assessment of injury markers (KIM-1, NGAL).
Induction of diabetes in Sweet Pee mice and wild-type controls to evaluate glycemic control, infection risk, and mortality.

Main Results:

Sweet Pee mutants exhibited improved glucose tolerance, increased urinary calcium and magnesium excretion, and growth retardation.
Renal studies showed osmotic diuresis without enhanced natriuresis; no signs of acute tubular injury were observed.
Diabetic Sweet Pee mice had better glycemic control but a significantly higher mortality rate (70%) and increased infection risk compared to controls (10%).

Conclusions:

The Sweet Pee mouse model accurately reflects human SGLT2 mutations and is valuable for studying long-term SGLT2 inhibition.
SGLT2 inhibition improves glycemic control but may increase risks of infection, malnutrition, volume contraction, and mortality.