Research Paper Volume 12, Issue 18 pp 18033—18051

Insulin sensitivity in long-lived growth hormone-releasing hormone knockout mice

Fang Zhang1, , Mert Icyuz1, , Zhenghui Liu2, , Michael Fitch1, , Liou Y. Sun1, ,

  • 1 Department of Biology, University of Alabama at Birmingham, Birmingham, AL 35254, USA
  • 2 Department of Obstetrics and Gynecology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA

Received: April 3, 2020       Accepted: June 5, 2020       Published: July 8, 2020
How to Cite

Copyright: © 2020 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


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.


GH: growth hormone; GHRH: growth hormone-releasing hormone; WAT: white adipose tissue; vWAT: visceral white adipose tissue; sWAT: subcutaneous white adipose tissue; BAT: brown adipose tissue; FFA: free fatty acid; GIR: glucose infusion rate; GSK3: glycogen synthesis kinase; IRS: insulin receptor substrate; GHRKO: GH receptor/binding protein-deficient; i.p. injection: intraperitoneal injection; HOMA-IR: homeostasis model for assessment of insulin resistance; GTT: glucose tolerance tests; ITT: insulin tolerance test; B.W.: body weight; DXA: dual-energy X-ray absorptiometry; IGF-1: Insulin growth factor-1.