Knockout mouse models of insulin signaling: Relevance past and future

Table 1 Knockout mouse reproducibility

Model	Ref.	Genetic background	Observed discrepancy
IRS1 knockout	Tamemoto et al[19]	C57BL/6 × CBA	Growth defect twice as severe in Araki 1994
	Araki et al[18]	C57BL/6
IRS2 knockout	Withers et al[60]	C57BL6 × 129Sv	Growth defect observed only in Withers et al[60]. Much more severe glucose dysregulation in Withers et al[60]
	Kubota et al[61]	C57BL/6 × CBA mixed
IR and IRS1 double heterozygous knockout	Kulkarni et al[62]	C57BL/6 129/Sv DBA/2	Diabetes not observed in 129/Sv mice, observed in 85% of C57BL/6 mice and 64% of DBA/2 mice. Glucose intolerance only in C57BL/6 strain
AKT2 knockout	Cho et al[64]	C57BL/6	More severe hyperglycemia and hyperinsulinemia in Garofalo et al[63]. Growth defect only in Garofalo et al[63]
	Garofalo et al[63]	DBA/1lacJ
AKT1 knockout	Chen et al[65]	C57BL/6 × 129R1	High neonatal mortality only in Cho et al[64]. Improved glucose tolerance and insulin sensitivity only in Buzzi et al[68]
	Cho et al[66]	C57BL/6
	Buzzi et al[68]	129/Ola, C57BL/6 mixed
Pik3r1 heterozygote	Mauvais-Jarvis et al[72]	129Sv, C57BL/6 mixed	Improved glucose tolerance and insulin sensitivity and low glucose and insulin levels on normal diet only in Mauvais-Jarvis et al[72]
	McCurdy et al[73]	C57BL/6SVJ
Liver-specific Pik3ca	Sopasakis et al[74]	129Sv, C57BL/6, FVB mixed	Insulin resistance and glucose intolerance on normal diet in Sopasakis et al[74] only
	Chattopadhyay et al[75]	129, C57BL/6J mixed
GLUT4 heterozygous knockout	Stenbit et al[76]	CD1, C57BL/6 mixed	Unexpected more severe phenotype in heterozygous knockout than homozygous
PKCλ heterozygous knockout	Farese et al[79]	C57BL/6, 129P2/Sv, FVB mixed	Unexpected more severe hepatic steatosis in heterozygous knockout than homozygous
PKCδ knockout	Leitges et al[81]	129/SV × Ola	High neonatal mortality observed only in Bezy et al[82]
	Bezy et al[82]	C57BL6/J
PPARγ	He et al[86]	C57BL/6J	Resistance to diet-induced insulin resistance only in Jones et al[85] study
	Jones et al[85]	C57BL/6J, FVB mixed
Muscle-specific PPARγ	Norris et al[87]	129/sv, C57BL/6, FVB mixed	Insulin resistance and glucose intolerance on normal diet in Hevener et al[88] only. Improvement with rosiglitazone in Norris et al[87] only
	Hevener et al[88]	C57BL6/J

Reproducibility problems in knockout mouse studies. Some variant results can be explained by differences in genetic background. IRS: Insulin receptor substrate 1; IR: Insulin receptor; AKT2: Protein kinase B isoform 2; GLUT4: Glucose transporter isoform 4; PKCλ: Protein kinase C λ; PPARγ: Peroxisome proliferator-activated receptor γ.