Int J Med Sci 2021; 18(5):1189-1197. doi:10.7150/ijms.52701

Research Paper

Prolonged preoperative fasting induces postoperative insulin resistance by ER-stress mediated Glut4 down-regulation in skeletal muscles

Ming-Wei Lin1,2,3✉, Chih-I Chen4, Tzu-Ting Cheng5, Chien-Chi Huang1, Jen-Wei Tsai6, Guan-Ming Feng7, Tzer-Zen Hwang8, Chen-Fuh Lam5,9✉

1. Department of Medical Research, E-Da Hospital/E-Da Cancer Hospital, Kaohsiung, Taiwan.
2. Department of Nursing, I-Shou University College of Medicine, Kaohsiung, Taiwan.
3. Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.
4. Colorectal Surgery, Department of Surgery, E-Da Hospital/E-Da Cancer Hospital, Kaohsiung, Taiwan.
5. Department of Anesthesiology, E-Da Hospital/E-Da Cancer Hospital, Kaohsiung, Taiwan.
6. Department of Pathology, E-Da Hospital, Kaohsiung, Taiwan.
7. Department of Plastic Surgery, E-Da Hospital, Kaohsiung, Taiwan.
8. Department of Otolaryngology, E-Da Hospital, Kaohsiung, Taiwan.
9. School of Medicine, I-Shou University College of Medicine, Kaohsiung, Taiwan.

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Citation:
Lin MW, Chen CI, Cheng TT, Huang CC, Tsai JW, Feng GM, Hwang TZ, Lam CF. Prolonged preoperative fasting induces postoperative insulin resistance by ER-stress mediated Glut4 down-regulation in skeletal muscles. Int J Med Sci 2021; 18(5):1189-1197. doi:10.7150/ijms.52701. Available from https://www.medsci.org/v18p1189.htm

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Abstract

Preoperative fasting aims to prevent pulmonary aspiration and improve bowel preparation, but it may induce profound systemic catabolic responses that lead to protein breakdown and insulin-resistant hyperglycemia after operation. However, the molecular mechanisms of catabolic reaction induced by prolonged preoperative fasting and surgical stress are undetermined. In this study, anesthetized rats were randomly assigned to receive a sham operation or laparotomy cecectomy. Fasting groups were restricted from food and water for 12 h before operation, while the feeding group had free access to food throughout the study period. Twenty-four hours after operation, the animals were sacrificed to collect blood samples and soleus muscles for analysis. Postoperative blood glucose level was significantly increased in the fasting group with elevated serum insulin and C-peptide. Continuous feeding reduced serum myoglobin and lactate dehydrogenase concentrations. Preoperative fasting activated inositol-requiring transmembrane kinase/endoribonuclease (IRE)-1α and c-Jun N-terminal kinase (JNK) mediated endoplasmic reticulum (ER)-stress, and reduced glucose transporter type 4 (Glut4) expression in the soleus muscle. Phospholamban phosphorylation was reduced and intracellular calcium levels were increased in the isolated skeletal muscle cells. Similar results were found in ER stress-induced C1C12 myoblasts. The expression of Glut4 was suppressed in the stressed C1C12, but was potentiated following inhibition of ER stress and chelation of intracellular free calcium. This study provides evidence demonstrating that prolonged preoperative fasting induces ER stress and generates insulin resistance in the skeletal muscle through suppression of Glut4 and inactivation of Ca2+-ATPase, leading to intracellular calcium homeostasis disruption and peripheral insulin resistance.

Keywords: endoplasmic reticulum stress, fasting, insulin resistance, protein catabolism, skeletal muscle