*Human*

Although the significance of GLUT4 for insulin-stimulated glucose uptake in muscle and adipose tissue is well understood, thus far, no polymorphisms within the GLUT4 gene have been identified that would robustly be associated with impaired glucose homeostasis in humans under circumstances such as type 2 diabetes, increased fasting blood glucose levels, or obesity.

#### *Mouse Models of GLUT4 deficiency*

#### *Conventional Knockout*

GLUT4 knockout mice, surprisingly, are normoglycemic with insulin resistance and hyperinsulinemia in the fed state. The mice are growth-retarded, with markedly reduced fat mass, cardiomegaly, and shortened lifespan, but no diabetes. In contrast, heterozy‐ gous GLUT4-null mice develop hyperglycemia and hyperinsulinemia associated with reduced muscle glucose uptake, hypertension and morphological alterations in heart and liver. Rather unexpectedly, about 50% of heterozygous GLUT4 knockout mice develop diabetes before the age of 6 months, a phenotype that can be reversed by selective overexpression of GLUT4 in skeletal muscle.
