Abstract
IntroductionGH induces acute insulin resistance in skeletal muscle in vivo, which in rodent models has been attributed to crosstalk between GH and insulin signaling pathways. Our objective was to characterize time course changes in signaling pathways for GH and insulin in human skeletal muscle in vivo following GH exposure in the presence and absence of an oral glucose load.MethodsEight young men were studied in a single-blinded randomized crossover design on 3 occasions: 1) after an intravenous GH bolus 2) after an intravenous GH bolus plus an oral glucose load (OGTT), and 3) after intravenous saline plus OGTT. Muscle biopsies were taken at t = 0, 30, 60, and 120. Blood was sampled at frequent intervals for assessment of GH, insulin, glucose, and free fatty acids (FFA).ResultsGH increased AUCglucose after an OGTT (p<0.05) without significant changes in serum insulin levels. GH induced phosphorylation of STAT5 independently of the OGTT. Conversely, the OGTT induced acute phosphorylation of the insulin signaling proteins Akt (ser473 and thr308), and AS160.The combination of OGTT and GH suppressed Akt activation, whereas the downstream expression of AS160 was amplified by GH.We Concluded the Following1) A physiological GH bolus activates STAT5 signaling pathways in skeletal muscle irrespective of ambient glucose and insulin levels 2) Insulin resistance induced by GH occurs without a distinct suppression of insulin signaling proteins 3) The accentuation of the glucose-stimulated activation of AS 160 by GH does however indicate a potential crosstalk between insulin and GH.Trial RegistrationClinicalTrials.gov NCT00477997
Highlights
Growth hormone (GH) induces acute insulin resistance in skeletal muscle in vivo, which in rodent models has been attributed to crosstalk between GH and insulin signaling pathways
Any step in this cascade is a potential target for GH, and could involve direct crosstalk between signaling proteins, or indirect effects via free fatty acids (FFA), a known inhibitor of insulin receptor signaling in human skeletal muscle [10]
A significant difference between the plasma glucose curves obtained from OGTT+GH vs. OGTT alone was recorded (ANOVA, p = 0.04) (Figure 2a)
Summary
GH induces acute insulin resistance in skeletal muscle in vivo, which in rodent models has been attributed to crosstalk between GH and insulin signaling pathways. In the post-absorptive phase, where endogenous GH secretion is stimulated, GH promotes lipolysis and oxidation of fatty acids at the expense of glucose [2,3] This insulin-antagonistic effect is accentuated during more prolonged fasting and may constitute a favorable protein-saving mechanism due to impeded demand for gluconeogenesis from amino acids [4,5,6]. It is well known that insulin signaling promotes translocation of the glucose transporter GLUT4 to the cell surface Any step in this cascade is a potential target for GH, and could involve direct crosstalk between signaling proteins, or indirect effects via free fatty acids (FFA), a known inhibitor of insulin receptor signaling in human skeletal muscle [10]
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