GENETIC-ENGINEERING IN MICE - IMPACT ON INSULIN SIGNALING AND ACTION

The expression of a number of genes encoding key players in insulin si gnalling and action, including insulin, insulin receptor (IR), downstr eam 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 kn ockout mice. Such mice presented with phenotypes ranging from mild def ects, revealing complementarity between key molecules or pathways, to severe diabetes with ketoacidosis and early postnatal death. Insulin a ction could also be improved by overproduction of proteins acting at r egulatory steps. The development of diabetes by combining mutations, w hich alone do not lead to major metabolic alterations, validated the ' diabetogenes' concept of non-insulin-dependent diabetes mellitus. Gene s encoding insulin-like growth factors (IGF-I and IGF-II) and their ty pe I receptor (IGF-IR) have also been disrupted. It appears that altho ugh IR and IGF-IR are both capable of metabolic and mitogenic signalli ng, 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 spe cificity and redundancy, studies with cell lines derived from IRS-1-de ficient mice showed that IRS-1 and IRS-2 are also not completely inter changeable.