Sympathovagal Imbalance and Insulin Resistance: The Autonomic Nervous System as a Convergent Therapeutic Target for Breaking a Bidirectional Pathogenic Cycle.

The autonomic nervous system (ANS) and insulin resistance (IR) are linked through a bidirectional pathogenic cycle established during the normoglycaemic, hyperinsulinaemic phase of metabolic disease, years before conventional glucose thresholds are crossed. This review identifies the ANS and IR as convergent therapeutic targets for breaking this vicious cycle, synthesising evidence from autonomic physiology, clinical diabetology, and neuroscience into an integrated mechanistic framework. Two mechanistically distinct arms sustain the cycle: a fast, potentially reversible functional arm driven by hyperinsulinaemia - mediated sympathoexcitation via hypothalamic insulin-signalling pathways, and a slow, progressively irreversible structural arm driven by hyperglycaemia-induced autonomic neuropathy. Experimental evidence demonstrates that inducible peripheral sympathetic blockade prevents overnutrition-induced insulin resistance, establishing sympathetic overactivity as a primary causal driver rather than a consequence. Cross-sectional data have identified cardiac autonomic dysfunction in normoglycaemic individuals with elevated 1-hour post-load glucose who meet no pre-diabetes definition, revealing a population undetectable by current screening criteria. Prospective data from a landmark randomised prevention trial confirmed that autonomic improvement independently predicts diabetes prevention beyond weight loss, with hazard ratios of 0.84-0.85 for incident diabetes. Cardiac autonomic neuropathy, detectable via heart rate variability analysis, is present in 9-39% of pre-diabetic populations and confers a pooled relative mortality risk of 2.14 across 15 studies. Therapeutic interventions targeting both autonomic rebalancing and insulin sensitisation - including structured exercise, bariatric surgery, vagal nerve stimulation, renal denervation, and metabolic pharmacotherapy - converge on identifiable nodes of this feedback loop, enabling stage-matched targeting. We propose a risk stratification framework integrating autonomic assessment with glycaemic staging, including a proposed "Stage 0" category for normoglycaemic individuals with elevated 1-hour post-load glucose, to guide early, targeted intervention when the cycle remains breakable.