Insulin resistance as a decision of the cellular living system: From the evolutionary abundance reflex to modern addiction and functional inversion of the human brain hierarchy

Nole Guerrero G.L. · Medical Hypotheses (2026) · DOI: 10.1016/j.mehy.2026.111982

Resumen

This article proposes that insulin resistance would represent an adaptive response of the cellular living system rather than a pathological dysfunction. GLUT4 is the only insulin-dependent glucose transporter; in the tissues where it is expressed—skeletal muscle, cardiac muscle, and adipose tissue—its primary function would be to store energy as glycogen or triglycerides, although contraction-stimulated translocation via AMPK/calcium also addresses immediate energy demands. The remaining GLUT transporters operate independently of insulin for energy oxidation. Insulin resistance would compromise the cellular disposition to store energy, not the capacity to obtain it. The convergence of at least six survival signals—glycogen saturation, lipid signaling, stress, cryoprotection, pregnancy, and infection—on serine phosphorylation of IRS-1 with reduced GLUT4 translocation would suggest a conserved program of energy redistribution. Lipid infusion studies in healthy individuals would be consistent with this interpretation, with a reported correlation of r = − 0.98 between circulating triglycerides and glucose uptake. We describe the abundance reflex: a conserved neuroendocrine circuit in which insulin would modulate dopaminergic signaling in the VTA producing satiety at physiological glycemic ranges, whereas at higher glycemic ranges nucleus accumbens activation would produce incentive salience (WANTING) and dose-dependent hyperphagia, with attenuation of leptin signaling and reduced prefrontal inhibitory control. Evidence from the TKTL1 gene, demonstrated in embryonic mouse neocortex and human brain organoids, suggests that fatty acid synthesis would have been a necessary condition for the neocortical expansion defining Homo sapiens . The differential distribution of MCT2 in the neocortex versus GLUT3 in subcortical structures would suggest that this evolved brain requires monocarboxylate substrates—lactate and ketone bodies—to sustain its higher functions. Cerebral lipid supply would depend on a dedicated lipoprotein system in the cerebrospinal fluid, anatomically differentiated from the systemic circulation. The human neocortex may have emerged in a lipid- and ketone-rich metabolic environment and would require that environment to function. Chronic activation of the abundance reflex in the modern environment would produce dual neocortical vulnerability—repetitive functional attenuation plus deprivation of the substrate for which it evolved—with possible progressive functional inversion of the brain hierarchy. Under this framework, insulin resistance itself would not constitute pathology: pathology would emerge when the integrated redistribution capacity of the system—muscular, hepatic, and adipose—is chronically exceeded and the glycemic surplus surpasses the threshold at which non-enzymatic glycation and its molecular consequences cease to be compensable. This hypothesis-generating framework invites empirical validation.