An insulin signaling pathway couples feeding and nutritional status in mammals to the rate and mode of metabolism in most tissues of the animal. We have shown that an insulin-like signaling pathway regulates longevity and metabolism in C. elegans. This is reminiscent and may be mechanistically related to the longevity increase caused by caloric restriction in mammals. Thus the genetic components of the C. elegans insulin signaling pathway may be key components of a mammalian longevity determining pathway. Our genetic analysis has also revealed that the key output of C. elegans insulin-like signaling is the activity of the transcription factor DAF-16. Much of this proposal focuses on how DAF-2 insulin-like receptor signals are transduced to the DAF-16 transcription factor, and how those modulations of DAF-16 activity in turn regulate metabolism and longevity. Three human homologues of DAF-16 are excellent candidates for transducing insulin-like signaling in humans to also regulate longevity and metabolism. We will test whether these human proteins can function in the C. elegans insulin-like signaling pathway, that is, are functional homologues. In addition to their possible roles in longevity control, the insulin signaling genes we have identified by C. elegans genetics may reveal components of insulin signaling in mammals that are important for the understanding and eventual treatment of diabetes. Diabetes is a common diseases that affects the production or response to insulin, causing devastating metabolic dysregulations. The molecular basis of the defective insulin response in the adult onset or type II diabetes is unknown. It is clear that it is at least in part a genetic disease. The C. elegans genetics strongly argues that inhibition of human DAF-16 activity by drugs may bypass the need for upstream insulin signaling. Thus human DAF-16 may become a major target for pharmaceutical development of diabetes therapies.
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