Belkheiri, Nadji (2026) Toward a Bioelectric Systems Theory of Chronic Disease: A Mechanistic and Philosophical Analysis of Insulin Resistance A Theoretical Investigation at the Intersection of Biophysics, Biochemistry, and Philosophy of Medicine. [Preprint]
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Abstract
Contemporary biomedicine confronts a persistent epistemic tension: biochemical reductionism has delivered extraordinary explanatory and therapeutic power for acute, linear pathologies, yet remains structurally inadequate for the escalating global burden of complex chronic diseases. We argue that this inadequacy partly reflects a systematic underappreciation of the bioelectrical regulatory architecture that orchestrates molecular processes. Integrating philosophical critiques of reductionism, findings from developmental bioelectricity, and principles of complex systems biology, we advance a neo-bioelectric framework that reconceptualizes the organism as a hierarchically organized, information-processing system in which resting membrane potential (Vmem) gradients constitute an underexplored regulatory layer. This framework is operationalized through a mechanistic analysis of insulin resistance, proposing four chemically specified, testable pathways that may bridge sustained Vmem depolarization to impaired insulin signaling: electrostatic modulation of the insulin receptor, voltage-gated calcium channel-mediated IRS-1 serine phosphorylation, membrane potential-dependent GLUT4 vesicle trafficking, and plasma–mitochondrial membrane potential coupling. We engage alternative models including inflammation-first, mitochondrial dysfunction, and autonomic dysregulation and specify a series of falsifiable predictions with explicit disconfirming outcomes. We further identify the central empirical gap, namely the absence of direct in vivo Vmem mapping in insulin-resistant human tissue, as the core research agenda the framework defines. By recognizing membrane potential gradients as a physical language of physiological control, this framework offers a disciplined expansion of the prevailing paradigm and opens new experimental and conceptual territory for understanding and addressing complex chronic disease.
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