1753-P: Insulin Sensitivity in Long-Lived Growth Hormone–Releasing Hormone Knockout Mice

Disruption of growth hormone releasing hormone results in extended longevity with increased insulin sensitivity in mice. Yet, less is known about tissue-specific insulin action and insulin signaling pathway in growth hormone releasing hormone knock-out mice (GHRH^-/-). In this study, our hyperinsulinemic-euglycemic clamp data showed that glucose infusion rate to maintain euglycemia was dramatically elevated in GHRH^-/- mice. Insulin-mediated hepatic glucose production was suppressed whereas glucose uptake in skeletal muscle and brown adipose tissue were significantly increased in GHRH^-/- mice compared to WT littermates. Furthermore, growth hormone deficiency further enhanced insulin sensitivity in metabolically active tissues via activated PI3K-AKT and MAPK-ERK1/2 signaling cascades. Altered tissue-specific insulin response is likely to mediate the prolonged longevity and healthy-aging effects of growth hormone deficiency in mice.