Not loss of stability but steady-state shift: A systems biology explanation for elevated fasting blood glucose in type 2 diabetes
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Guanyu Wang
Laboratory of Biocomplexity and Engineering Biology, Department of Biomedical Engineering, School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China; CUHKSZ-STEM Joint Laboratory of Precision Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China; Ciechanover Institute of Precision and Regenerative Medicine, School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China
Abstract
Elevated fasting blood glucose is a hallmark clinical feature of prediabetes and type 2 diabetes, reflecting underlying pathological alterations in the body’s glucose-insulin regulatory system. This study employs a validated mathematical model of the glucose-insulin negative feedback loop to investigate the fundamental mechanisms of this elevation from a systems biology perspective. We specifically analyzed whether hyperglycemia arises from decreased system stability or an upward shift in the steady-state set-point. Our findings demonstrate that the intrinsic stability of the glucose-insulin regulatory system remains largely unchanged from healthy states through early-stage diabetes. Contrary to the hypothesis of stability decay, the essence of elevated fasting glucose is an upward shift of the steady-state level driven primarily by hepatic insulin resistance, which increases basal hepatic glucose output. While system stability is preserved during early progression, the dynamic coupling between glucose and insulin weakens; low-frequency oscillations inherent to the healthy system gradually diminish and eventually disappear as insulin resistance intensifies, signaling a decoupling of dynamics before stability loss. Significant weakening of system stability, characterized by a markedly reduced convergence rate following perturbation, occurs only in late-stage diabetes accompanied by severe pancreatic damage and compromised insulin secretory capacity. These results redefine the pathophysiological understanding of fasting hyperglycemia, suggesting that early therapeutic strategies should target recalibrating the glucose set point and hepatic sensitivity rather than bolstering system stability. This research provides valuable theoretical insights into the pathogenesis of diabetes and highlights potential dynamic biomarkers for monitoring disease progression.
Copyright (c) 2026 Guanyu Wang
This work is licensed under a Creative Commons Attribution 4.0 International License.
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