Table 2.

Animal models of targets of insulin signaling

Insulin target	Phenotype of (liver-specific) KO mice	Potential mechanism of action	Reference
IRS1, IRS2	Hyperglycemia, hyperinsulinemia	Induction of gluconeogenic genes	29–31
PI3K (p110-α and p110-β subunits)	Diet-induced liver steatosis ↓ Glucose intolerance (p110-α) ↑	Insulin-induced Akt phosphorylation at Ser473 ↓	135
PDK1	Glucose tolerance ↓ Pyruvate tolerance ↓ Insulin sensitivity ↑	Disruption of acute AKT-dependent insulin signaling	34
Akt2	Insulin resistance ↑ Hepatic glucose production ↑	Increased expression of FOXO1 target genes	20, 38, 39
p38 MAPK	Glycemia ↓ Gluconeogenesis ↓	Decreased transcription of Pparg, Ppargc1a	46
FoxO1	Fasting glucose ↓ Gluconeogenic gene expression ↓	Direct regulation of G6pc and Pck1 transcription	67–70
PGC-1α	Gluconeogenic gene expression ↑ Loss of feeding-induced regulation	Regulation of G6pc and Pck1 transcription	96