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Bariatric Surgery

Roux-en-Y gastric bypass surgery restores insulin-mediated glucose partitioning and mitochondrial dynamics in primary myotubes from severely obese humans

Abstract

Background/objectives

Impaired insulin-mediated glucose partitioning is an intrinsic metabolic defect in skeletal muscle from severely obese humans (BMI ≥ 40 kg/m2). Roux-en-Y gastric bypass (RYGB) surgery has been shown to improve glucose metabolism in severely obese humans. The purpose of the study was to determine the effects of RYGB surgery on glucose partitioning, mitochondrial network morphology, and the markers of mitochondrial dynamics skeletal muscle from severely obese humans.

Subject/methods

Human skeletal muscle cells were isolated from muscle biopsies obtained from RYGB patients (BMI = 48.0 ± 2.1, n = 7) prior to, 1 month and 7 months following surgery and lean control subjects (BMI = 22.4 ± 1.1, n = 7). Complete glucose oxidation, non-oxidized glycolysis rates, mitochondrial respiratory capacity, mitochondrial network morphology, and the regulatory proteins of mitochondrial dynamics were determined in differentiated human myotubes.

Results

Myotubes derived from severely obese humans exhibited enhanced glucose oxidation (13.5%; 95% CI [7.6, 19.4], P = 0.043) and reduced non-oxidized glycolysis (−1.3%; 95% CI [−11.1, 8.6]) in response to insulin stimulation at 7 months after RYGB when compared with the presurgery state (−0.6%; 95% CI [−5.2, 4.0] and 19.5%; 95% CI [4.0, 35.0], P = 0.006), and were not different from the lean controls (16.7%; 95% CI [11.8, 21.5] and 1.9%; 95% CI [−1.6, 5.4], respectively). Further, the number of fragmented mitochondria and Drp1(Ser616) phosphorylation were trended to reduce/reduced (0.0104, 95% CI [0.0085, 0.0126], P = 0.091 and 0.0085, 95% CI [0.0068, 0.0102], P = 0.05) in myotubes derived from severely obese humans at 7 months after RYGB surgery in comparison with the presurgery state. Finally, Drp1(Ser616) phosphorylation was negatively correlated with insulin-stimulated glucose oxidation (r = −0.49, P = 0.037).

Conclusion/interpretation

These data indicate that an intrinsic metabolic defect of glucose partitioning in skeletal muscle from severely obese humans is restored by RYGB surgery. The restoration of glucose partitioning may be regulated through reduced mitochondrial fission protein Drp1 phosphorylation.

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Funding

This study was supported by the University of Massachusetts Boston (startup fund to KZ) and the National Institute of Diabetes and Digestive and Kidney Diseases (DK-56112 to JAH)

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BAK and KZ: initiated and designed the study; BAK, AEG, and WD performed experiments; BAK, PNG, and KZ analyzed data; BAK and KZ interpreted the results of experiments; BAK and KZ prepared figures and drafted manuscript; BAK, JAH, and KZ edited and revised manuscript; KZ is the guarantor of this work and takes responsibility for the integrity of the data and accuracy of data analysis and interpretation.

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Correspondence to Kai Zou.

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Kugler, B.A., Gundersen, A.E., Li, J. et al. Roux-en-Y gastric bypass surgery restores insulin-mediated glucose partitioning and mitochondrial dynamics in primary myotubes from severely obese humans. Int J Obes 44, 684–696 (2020). https://doi.org/10.1038/s41366-019-0469-y

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