Genetic engineering in mice: impact on insulin signalling and action.
The expression of a number of genes encoding key players in insulin signalling and action, including insulin, insulin receptor (IR), downstream signalling molecules such as insulin receptor substrate-1 (IRS-1) and IRS-2, glucose transporters (GLUT4, GLUT2) and important metabolic enzymes such as glucokinase, has now been altered in transgenic or knockout mice. Such mice presented with phenotypes ranging from mild defects, revealing complementarity between key molecules or pathways, to severe diabetes with ketoacidosis and early postnatal death. Insulin action could also be improved by overproduction of proteins acting at regulatory steps. The development of diabetes by combining mutations, which alone do not lead to major metabolic alterations, validated the 'diabetogenes' concept of non-insulin-dependent diabetes mellitus. Genes encoding insulin-like growth factors (IGF-I and IGF-II) and their type I receptor (IGF-IR) have also been disrupted. It appears that although IR and IGF-IR are both capable of metabolic and mitogenic signalling, they are not fully redundant. However, IR could replace IGF-IR if efficiently activated by IGF-II. Studies with cell lines lacking IR or IGF-IR lend support to such conclusions. Concerning the issues of specificity and redundancy, studies with cell lines derived from IRS-1-deficient mice showed that IRS-1 and IRS-2 are also not completely interchangeable.
Institut Cochin de Génétique Moléculaire, INSERM U257, 24, rue du Faubourg Saint-Jacques, 75014 Paris, France.
B
B
Lamothe
A
A
Baudry
P
P
Desbois
L
L
Lamotte
D
D
Bucchini
P
P
De Meyts
R L
RL
Joshi
D000818:Animals; D005818:Genetic Engineering; D051273:Glucose Transporter Type 2; D051275:Glucose Transporter Type 4; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics*; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic / Q000235:genetics*; D009004:Monosaccharide Transport Proteins / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013002:Somatomedins / Q000235:genetics / Q000378:metabolism
D051273:Glucose Transporter Type 2; D051275:Glucose Transporter Type 4; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D010750:Phosphoproteins; C495693:Slc2a4 protein, mouse; D013002:Somatomedins; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin