Bistable insulin response: The win-win solution for glycemic control

Javed Akhtar; Yukun Han; Shangchen Han; Weiping Lin; Chenyu Cao; Ruowen Ge; Isaac Adeyemi Babarinde; Qingzhao Jia; Yueyang Yuan; Guangming Chen; Yajie Zhao; Richard Ye; Guozhen Liu; Luonan Chen; Guanyu Wang

doi:10.1016/j.isci.2022.105561

Bistable insulin response: The win-win solution for glycemic control

iScience. 2022 Nov 13;25(12):105561. doi: 10.1016/j.isci.2022.105561. eCollection 2022 Dec 22.

Authors

Javed Akhtar^{1

2

3

4}, Yukun Han^{3

4}, Shangchen Han⁴, Weiping Lin⁴, Chenyu Cao^{4

5}, Ruowen Ge⁵, Isaac Adeyemi Babarinde^{4

6}, Qingzhao Jia⁴, Yueyang Yuan⁴, Guangming Chen⁴, Yajie Zhao⁴, Richard Ye¹, Guozhen Liu^{1

2

7}, Luonan Chen^{8

9

10}, Guanyu Wang^{1

2

3

4}

Affiliations

¹ School of Medicine|Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen 518172, China.
² Center for Endocrinology and Metabolic Diseases, Second Affiliated Hospital, The Chinese University of Hong Kong, Shenzhen 518172, China.
³ Guangdong Provincial Key Laboratory of Computational Science and Material Design, Shenzhen 518055, China.
⁴ Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, China.
⁵ Department of Biological Sciences, National University of Singapore, Singapore 117558, Singapore.
⁶ Shenzhen Key Laboratory of Gene Regulation and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, China.
⁷ Bio-Sens Tech Pty Ltd, Sydney, NSW 2052, Australia.
⁸ Key Laboratory of Systems Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China.
⁹ Key Laboratory of Systems Health Science of Zhejiang, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou 310024, China.
¹⁰ West China Biomedical Big Data Center, Med-X Center for Informatics, West China Hospital, Sichuan University, Chengdu 610041, China.

Abstract

To satisfy both the safety and rapidity of glycemic control, muscles' insulin response must be bistable, as theoretically predicted. Here, we test the bistability hypothesis by combining cellular experiments (to measure the threshold values in vitro) with mathematical modeling (to test the relevance of bistability in vivo). We examine bistability in C2C12 myotubes by both single-cell analysis (Fӧrster resonance energy transfer) and cultured cells analysis (immunoblot). These technologies demonstrate bistable insulin response, with typical switch-on and switch-off thresholds of approximately 300 and 100 pM, respectively. Our mathematical model demonstrates the indispensability of bistability in interpreting experimental data, reveals fine details of plasma glucose-insulin dynamics, and explains unclear phenomena. These results suggest that the body's ability to simultaneously avoid both hypoglycemia and hyperglycemia is mediated by bistability. The switch-on threshold is a promising biomarker for metabolic complications due to its deep quantitative connection with body composition, which is easy to measure.

Keywords: Human metabolism; mathematical biosciences.