Alterations in insulin action and contraction-mediated metabolism in myotubes derived from Roux-en-Y gastric bypass patients
Hinkley, J. Matthew
Roux-en-Y gastric bypass (RYGB) surgery induces various metabolic benefits in severely obese (BMI> 40 kg/m2) individuals, including improved insulin action in peripheral tissues, most notably skeletal muscle, and remission of type 2 diabetes. Despite these improvements, the mechanism in which RYGB improves metabolism is unclear. To examine this, primary human skeletal muscle cells were isolated from muscle biopsies obtained from individuals prior to, 1-month, and 7-months following RYGB. Insulin-stimulated glycogen synthesis, an index of insulin action, improved in myotubes derived from subjects at 1-month following RYGB, which was sustained at 7-months post-surgery. The cellular mechanisms involved appear to consist of distinct acute and chronic components, with the acute response consisting of reduced muscle glycogen content and increased phosphorylation of ACC, and the chronic response associated with a physiological increase in PGC1[alpha] protein abundance. To further examine the combined role of RYGB surgery and muscle contraction on skeletal muscle metabolism, fully differentiated myotubes from RYGB patients were electrically stimulated to contract for 24-hours. Prior to surgery, myotubes were unresponsive to the benefits of muscle contraction to subsequently increase insulin action, suggesting exercise resistance in these cells. However, only 1-month following RYGB surgery, myotubes became responsive to muscle contraction, as indicated by enhanced insulin-stimulated glycogen synthesis and AS160 phosphorylation, as well as increased basal glucose oxidation. To explore whether the improvements in insulin action were due to an improved ability of cells to switch fuel preference, we examined in vitro metabolic flexibility in cells derived from RYGB patients. Utilizing several methods to examine in vitro metabolic flexibility, we were unable to detect major differences amongst the groups, suggesting that alterations in metabolic flexibility at the whole-body level following RYGB surgery are not retained in primary myotubes. The results from this study suggest RYGB surgery alters the inherent characteristics of skeletal muscle that invoke improved insulin action and exercise-responsiveness. While previous research suggest insulin action in skeletal muscle is improved once substantial weight loss is achieved, we show that, when utilizing a muscle-specific model, improvements in insulin action occur as early as 1-month following RYGB surgery. Furthermore, it appears that acute adaptations in skeletal muscle following RYGB surgery invoke a cellular environment that is more responsive to the additional benefits of muscle contraction. Collectively, the results of this study provide valuable mechanisms in which RYGB surgery and muscle contraction can improve insulin action in skeletal muscle.
Hinkley, J. Matthew. (January 0005). Alterations in insulin action and contraction-mediated metabolism in myotubes derived from Roux-en-Y gastric bypass patients (Doctoral Dissertation, East Carolina University). Retrieved from the Scholarship. (http://hdl.handle.net/10342/6068.)
Hinkley, J. Matthew. Alterations in insulin action and contraction-mediated metabolism in myotubes derived from Roux-en-Y gastric bypass patients. Doctoral Dissertation. East Carolina University, January 0005. The Scholarship. http://hdl.handle.net/10342/6068. April 23, 2018.
Hinkley, J. Matthew, “Alterations in insulin action and contraction-mediated metabolism in myotubes derived from Roux-en-Y gastric bypass patients” (Doctoral Dissertation., East Carolina University, January 0005).
Hinkley, J. Matthew. Alterations in insulin action and contraction-mediated metabolism in myotubes derived from Roux-en-Y gastric bypass patients [Doctoral Dissertation]. Greenville, NC: East Carolina University; January 0005.