Our previous studies showed that loss-of-function mutation of
growth hormone releasing hormone (GHRH) results in increased longevity and enhanced
insulin sensitivity in mice. However, the details of improved
insulin action and tissue-specific
insulin signaling are largely unknown in this healthy-aging mouse model. We conducted hyperinsulinemic-euglycemic clamp to investigate mechanisms underlying enhanced
insulin sensitivity in
growth hormone (GH) deficient mice. Further, we assessed in vivo tissue-specific
insulin activity via activation of PI3K-AKT and MAPK-ERK1/2 cascades using western blot. Clamp results showed that the
glucose infusion rate required for maintaining euglycemia was much higher in GHRH-/- mice compared to WT controls.
Insulin-mediated
glucose production was largely suppressed, whereas
glucose uptake in skeletal muscle and brown adipose tissue were significant enhanced in GHRH-/- mice compared to WT controls. Enhanced capacity of
insulin-induced activation of the PI3K-AKT and MAPK-ERK1/2 signaling were observed in a tissue-specific manner in GHRH-/- mice. Enhanced systemic
insulin sensitivity in long-lived GHRH-/- mice is associated with differential activation of
insulin signaling cascades among various organs. Improved action of
insulin in the
insulin sensitive tissues is likely to mediate the prolonged longevity and healthy-aging effects of GH deficiency in mice.