Kai Zou1,2,3,4, J Matthew Hinkley5,6,7,8, Sanghee Park5,6,7, Donghai Zheng5,6,7, Terry E Jones9, Walter J Pories7,10, Pamela J Hornby11, James Lenhard11, G Lynis Dohm7,12, Joseph A Houmard5,6,7. 1. Department of Exercise and Health Sciences, University of Massachusetts Boston, Boston, MA, USA. kai.zou@umb.edu. 2. Department of Kinesiology, East Carolina University, Greenville, NC, USA. kai.zou@umb.edu. 3. Human Performance Laboratory, East Carolina University, Greenville, NC, USA. kai.zou@umb.edu. 4. East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, USA. kai.zou@umb.edu. 5. Department of Kinesiology, East Carolina University, Greenville, NC, USA. 6. Human Performance Laboratory, East Carolina University, Greenville, NC, USA. 7. East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, USA. 8. Translational Research Institute for Metabolism and Diabetes, Florida Hospital, Orlando, FL, USA. 9. Department of Physical Therapy, East Carolina University, Greenville, NC, USA. 10. Department of Surgery, East Carolina University, Greenville, NC, USA. 11. Janssen Research & Development LLC, Spring House, PA, USA. 12. Department of Physiology, East Carolina University, Greenville, NC, USA.
Abstract
BACKGROUND/ OBJECTIVE: The partitioning of glucose toward glycolytic end products rather than glucose oxidation and glycogen storage is evident in skeletal muscle with severe obesity and type 2 diabetes. The purpose of the present study was to determine the possible mechanism by which severe obesity alters insulin-mediated glucose partitioning in human skeletal muscle. SUBJECTS/ METHODS: Primary human skeletal muscle cells (HSkMC) were isolated from lean (BMI = 23.6 ± 2.6 kg/m2, n = 9) and severely obese (BMI = 48.8 ± 1.9 kg/m2, n = 8) female subjects. Glucose oxidation, glycogen synthesis, non-oxidized glycolysis, pyruvate oxidation, and targeted TCA cycle metabolomics were examined in differentiated myotubes under basal and insulin-stimulated conditions. RESULTS: Myotubes derived from severely obese subjects exhibited attenuated response of glycogen synthesis (20.3%; 95% CI [4.7, 28.8]; P = 0.017) and glucose oxidation (5.6%; 95% CI [0.3, 8.6]; P = 0.046) with a concomitant greater increase (23.8%; 95% CI [5.7, 47.8]; P = 0.004) in non-oxidized glycolytic end products with insulin stimulation in comparison to the lean group (34.2% [24.9, 45.1]; 13.1% [8.6, 16.4], and 2.9% [-4.1, 12.2], respectively). These obesity-related alterations in glucose partitioning appeared to be linked with reduced TCA cycle flux, as 2-[14C]-pyruvate oxidation (358.4 pmol/mg protein/min [303.7, 432.9] vs. lean 439.2 pmol/mg protein/min [393.6, 463.1]; P = 0.013) along with several TCA cycle intermediates, were suppressed in the skeletal muscle of severely obese individuals. CONCLUSIONS: These data suggest that with severe obesity the partitioning of glucose toward anaerobic glycolysis in response to insulin is a resilient characteristic of human skeletal muscle. This altered glucose partitioning appeared to be due, at least in part, to a reduction in TCA cycle flux.
BACKGROUND/ OBJECTIVE: The partitioning of glucose toward glycolytic end products rather than glucose oxidation and glycogen storage is evident in skeletal muscle with severe obesity and type 2 diabetes. The purpose of the present study was to determine the possible mechanism by which severe obesity alters insulin-mediated glucose partitioning in human skeletal muscle. SUBJECTS/ METHODS: Primary human skeletal muscle cells (HSkMC) were isolated from lean (BMI = 23.6 ± 2.6 kg/m2, n = 9) and severely obese (BMI = 48.8 ± 1.9 kg/m2, n = 8) female subjects. Glucose oxidation, glycogen synthesis, non-oxidized glycolysis, pyruvate oxidation, and targeted TCA cycle metabolomics were examined in differentiated myotubes under basal and insulin-stimulated conditions. RESULTS: Myotubes derived from severely obese subjects exhibited attenuated response of glycogen synthesis (20.3%; 95% CI [4.7, 28.8]; P = 0.017) and glucose oxidation (5.6%; 95% CI [0.3, 8.6]; P = 0.046) with a concomitant greater increase (23.8%; 95% CI [5.7, 47.8]; P = 0.004) in non-oxidized glycolytic end products with insulin stimulation in comparison to the lean group (34.2% [24.9, 45.1]; 13.1% [8.6, 16.4], and 2.9% [-4.1, 12.2], respectively). These obesity-related alterations in glucose partitioning appeared to be linked with reduced TCA cycle flux, as 2-[14C]-pyruvate oxidation (358.4 pmol/mg protein/min [303.7, 432.9] vs. lean 439.2 pmol/mg protein/min [393.6, 463.1]; P = 0.013) along with several TCA cycle intermediates, were suppressed in the skeletal muscle of severely obese individuals. CONCLUSIONS: These data suggest that with severe obesity the partitioning of glucose toward anaerobic glycolysis in response to insulin is a resilient characteristic of human skeletal muscle. This altered glucose partitioning appeared to be due, at least in part, to a reduction in TCA cycle flux.
Authors: Sanghee Park; Kristen D Turner; Donghai Zheng; Jeffrey J Brault; Kai Zou; Alec B Chaves; Thomas S Nielsen; Charles J Tanner; Jonas T Treebak; Joseph A Houmard Journal: J Physiol Date: 2018-12-02 Impact factor: 5.182
Authors: Mary-Margaret E Remchak; Emily M Heiston; Anna Ballantyne; Brielle L Dotson; Nathan R Stewart; Andrea M Spaeth; Steven K Malin Journal: J Clin Endocrinol Metab Date: 2022-07-14 Impact factor: 6.134
Authors: Nicholas T Broskey; Walter J Pories; Terry E Jones; Charles J Tanner; Donghai Zheng; Ronald N Cortright; Zhen W Yang; Nkaujyi Khang; Josh Yang; Joseph A Houmard; G Lynis Dohm Journal: Physiol Rep Date: 2021-02
Authors: Luke C McIlvenna; Rhiannon K Patten; Andrew J McAinch; Raymond J Rodgers; Nigel K Stepto; Alba Moreno-Asso Journal: Front Endocrinol (Lausanne) Date: 2021-10-11 Impact factor: 5.555
Authors: Benjamin A Kugler; Anders E Gundersen; Junhan Li; Wenqian Deng; Nancy Eugene; Philimon N Gona; Joseph A Houmard; Kai Zou Journal: Int J Obes (Lond) Date: 2019-10-17 Impact factor: 5.095