Johannes D. Veldhuis, MD


March 15, 2000

In This Article

Insulin Action in Aging

Biochemically, insulin activates receptor-dependent autophosphorylation as well as phosphorylation of tyrosine residues of multiple (as many as 10) insulin-receptor substrates (eg, IRS-1, IRS-2), and multiple isoforms of phosphatidylinositol-3 (PI-3) kinase. Further divergence of these signaling pathways imposes selective control of cellular glucose metabolism, protein and lipid turnover, cell replication and hypertrophy, and gene expression.

The use of transgenic mouse signaling gene-knockout models have identified a new multiplicity of possible molecular defects in type 2 diabetes mellitus as well as plausible loci of targeted drug interventions. For example, experimentally disabling the IRS-1 or IRS-2 genes promotes tissue insulin resistance and causes variable intrauterine growth retardation.[20] Albeit unproven, the pathogenetic sequence that culminates in type 2 diabetes could be driven by an ensemble of single-allele molecular polymorphisms, which cause progressive insulin resistance in muscle, liver, fat, and systemic hyperinsulinemia and eventual beta-cell failure.

The novel Cre-lox conditional gene knockout approach is being used to further explore some of these hypotheses. For example, tissue-specific disruption of the muscle insulin receptor promotes visceral fat accumulation and hypertriglyceridemia without producing overt type 2 diabetes mellitus; knockout of the liver insulin receptor promotes postprandial hyperglycemia and marked hyperinsulinemia; and disabling the beta-cell insulin receptor eliminates glucose (but not L-arginine)-stimulated insulin secretion, resulting in impaired glucose tolerance and type 2 diabetes mellitus.[21]