Postnatal β2 adrenergic treatment improves insulin sensitivity in lambs with IUGR but not persistent defects in pancreatic islets or skeletal muscle

Authors

• Dustin T. Yates, University of Nebraska - LincolnFollow
• Leticia E. Camacho, University of Arizona
• Amy C. Kelly, University of Arizona
• Leah V. Steyn, University of Arizona
• Melissa A. Davis, University of Arizona
• Andrew T. Antolic, University of Arizona
• Miranda J. Anderson, University of Arizona
• Ravi Goyal, University of Arizona
• Ronald E. Allen, University of Arizona
• Klearchos K. Papas, University of Arizona
• William W. Hay Jr, University of Arizona
• Sean W. Limesand, University of ArizonaFollow

ORCID IDs

Amy C. Kelly

William W. Hay Jr

Sean W. Limesand

Document Type

Article

Date of this Version

2019

Citation

J Physiol 00.0 (2019) pp 1–24

Comments

© 2019 The Authors.

Open access

DOI: 10.1113/JP278726

Abstract

Placental insufficiency causes intrauterine growth restriction (IUGR) and disturbances in glucose homeostasis with associated β adrenergic receptor (ADRβ) desensitization. Our objectives were to measure insulin-sensitive glucose metabolism in neonatal lambs with IUGR and to determine whether daily treatment with ADRβ2 agonist and ADRβ1/β3 antagonists for 1 month normalizes their glucose metabolism. Growth, glucose-stimulated insulin secretion (GSIS) and glucose utilization rates (GURs) were measured in control lambs, IUGR lambs and IUGR lambs treated with adrenergic receptor modifiers: clenbuterol atenolol and SR59230A (IUGR-AR). In IUGR lambs, islet insulin content and GSIS were less than in controls; however, insulin sensitivity and whole-bodyGUR were not different from controls.Of importance, ADRβ2 stimulation with β1/β3 inhibition increases both insulin sensitivity and whole-body glucose utilization in IUGR lambs. In IUGR and IUGR-AR lambs, hindlimb GURs were greater but fractional glucose oxidation rates and ex vivo skeletal muscle glucose oxidation rates were lower than controls. Glucose transporter 4 (GLUT4) was lower in IUGR and IUGR-AR skeletal muscle than in controls but GLUT1 was greater in IUGR-AR. ADRβ2, insulin receptor, glycogen content and citrate synthase activity were similar among groups. In IUGR and IUGR-AR lambs heart rates were greater, which was independent of cardiac ADRβ1 activation. We conclude that targeted ADRβ2 stimulation improved whole-body insulin sensitivity but minimally affected defects in GSIS and skeletal muscle glucose oxidation. We show that risk factors for developing diabetes are independent of postnatal catch-up growth in IUGR lambs as early as 1 month of age and are inherent to the islets and myocytes.