| Nearly eighty years since the discovery of insulin, the intracellular signal transduction cascade responsible for the hormone action critical to organismal fuel and energy homeostasis remains incompletely defined. Proximal signaling proteins, including the insulin receptor, insulin receptor substrate (IRS) and phosphoinositide 3-kinase (PI-3K) have recently been proven to transduce the signal necessary for insulin's metabolic action. While the contemporary concept of signal transduction has been shaped by the elucidation of phosphorvlation cascades in various growth factor signaling systems, no protein kinase downstream of the cognate receptor has been definitively connected to insulin action until this study. Utilizing targeted mutagenesis in mice, this study establishes that insulin critically depends on one of three members of a highly related family of Akt kinases, also referred as protein kinase B (PKB), for its metabolic action. Mice harboring null mutation in the Akt2 gene were impaired in their ability to lower circulating glucose levels in response to insulin. Thus, Akt2 is the first serine-threonine kinase demonstrated to be an obligate intermediate in insulin signal transduction critical to normal glucose homeostasis. The monogenic alteration of Akt2 in mice results in multiple defects in peripheral insulin sensitivity, closely mimicking those observed in the pathogenesis of insulin resistance and Type 2 diabetes in humans. Surprisingly, in mice, null mutations in either Akt1 or Akt3 genes did not produce the insulin resistance phenotype as elicited by the disruption in the Akt2 locus. Marked growth retardation phenotype, reminiscent of insulin-like growth factor (IGF) mutation in mice, was unique to the mutation in the Akt1 gene in comparison to Akt2 or Akt3 mutations. These data evoke the notion that the evolution of insulin and IGF regulated physiology may be intricately connected with the diversification of Akt family of kinases. Evolutionary argument for gene diversification and resulting phenotypic complexity is substantiated in uncovering the segregation of distinct phenotypes, midst overlapping functions, resulting from null mutations in each Akt family member. |
