Genetic engineering in mice: impact on insulin signalling and action

Abstract

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.

Counteraction of Type 1 Diabetic Alterations by Engineering Skeletal Muscle to Produce Insulin

“…The MLC1 promoter/enhancer directs the expression of foreign genes specifically to skeletal muscle (selective expression in fast-twitch muscle fibers), in a rostrocaudal gradient (39,40). The three lines of transgenic mice expressed insulin mRNA in skeletal muscle (quadriceps and gastrocnemius), while no insulin mRNA was noted in controls (Fig.…”

“…Furthermore, these transgenic mice did not show alterations of whole body glucose homeostasis and had normal lifespan and reproductive life. Because of the high insulin receptor levels in muscle fibers (40,41), insulin produced by skeletal muscle, acting in a paracrine/autocrine manner, may lead to increased disposal of glucose. However, fed transgenic mice were normoglycemic and normoinsulinemic, suggesting that skeletal muscle insulin production may have led to a compensatory decrease in pancreatic insulin secretion, thus maintaining normoglycemia and normoinsulinemia (42)(43)(44)(45)(46).…”

Les insulines des invertébrés sèment le trouble

“…Enfin, les défauts de croissance des différents mutants de la voie insuline chez la drosophile sont évocateurs des phénotypes observés en situation de carence nutritionnelle, ce qui suggère que la signalisation insuline puisse être utilisée pour coupler les conditions nutritionnelles à la croissance des tissus. Ce rôle de la voie insuline dans le contrôle de la croissance cellulaire est évidemment à rapprocher de celui des IGF de mammifères [3] et du fort retard de croissance associé à une mutation homozygote dans le domaine kinase du récepteur de l'insuline, retrouvé chez des patients atteints du syndrome de résistance insulinique aiguë [4]. En ce qui concerne le contrôle du métabolisme général, les mutations de l'IRS et du récepteur de l'insuline chez la drosophile provoquent également l'accumulation d'une grande quantité de lipides chez l'adulte [5,6].…”

Differential phosphorylation of IRS-1 by insulin and insulin-like growth factor I receptors in Chinese hamster ovary cells

“…Recent evidence suggests that the receptors for insulin and IGF-I have some common biological roles, and others that are distinct (Blakesley et al 1996, Lamothe et al 1998, Urso et al 1999. Evidence for distinct roles for the two receptors includes the study of IR-and IGF-IR-deficient mice, which have distinct phenotypes (Lamothe et al 1998).…”

“…Evidence for distinct roles for the two receptors includes the study of IR-and IGF-IR-deficient mice, which have distinct phenotypes (Lamothe et al 1998). Insulin is known to be a key regulator of physiological processes such as glucose transport and biosynthesis of glycogen and fat (Patti & Kahn 1998), but IGF-I has been shown to be more potent in stimulating cell growth by increasing DNA synthesis, and has a greater mitogenic potential than insulin (Lammers et al 1989, Blakesley et al 1996.…”