Sympathovagal Imbalance and Insulin Resistance: The Autonomic Nervous System as a Convergent Therapeutic Target for Breaking a Bidirectional Pathogenic Cycle
- 1Complex Cardiovascular Centre, Hospital AGEL Trinec-Podlesi, Trinec, Czech Republic
- 2Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
- 3Faculty of Medicine and Dentistry, Palacký University Olomouc, Olomouc, Czech Republic
Abstract
Jan Alexander Mohr,1,2 Otakar Jiravsky,1 Lucjan Rucki,1 Bogna Jiravska Godula,1 Jan Samiec,1,3 Anna Pekarova,2 Eva Jakubovicova,1,3 Jan Chovancik,1 Marie Novakova,2 Matej Pekar1,21Complex Cardiovascular Centre, Hospital AGEL Trinec-Podlesi, Trinec, Czech Republic; 2Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic; 3Faculty of Medicine and Dentistry, Palacký University Olomouc, Olomouc, Czech RepublicCorrespondence: Otakar Jiravsky, Complex Cardiovascular Centre, Hospital AGEL Trinec-Podlesi, Konska 453, Trinec, 73961, Czech Republic, Tel +420 558 309 111, Email [email protected]: 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.Keywords: autonomic nervous system, insulin resistance, cardiac autonomic neuropathy, heart rate variability, therapeutic target, sympathovagal balance, pre-diabetes, neuromodulation
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BibTeX
@article{mohr2026sympathovagal,
title = {{Sympathovagal Imbalance and Insulin Resistance: The Autonomic Nervous System as a Convergent Therapeutic Target for Breaking a Bidirectional Pathogenic Cycle}},
author = {Jan Alexander Mohr and Otakar Jiravsky and Lucjan Rucki and Bogna Jiravska Godula and Jan Samiec and Anna Pekarova and Eva Jakubovicova and Jan Chovancik and Marie Novakova and Matej Pekar},
journal = {Diabetes, Metabolic Syndrome and Obesity},
year = {2026},
month = oct,
doi = {10.2147/dmso.s604281},
url = {https://www.dovepress.com/sympathovagal-imbalance-and-insulin-resistance-the-autonomic-nervous-s-peer-reviewed-fulltext-article-DMSO},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Sympathovagal Imbalance and Insulin Resistance: The Autonomic Nervous System as a Convergent Therapeutic Target for Breaking a Bidirectional Pathogenic Cycle
AU - Jan Alexander Mohr
AU - Otakar Jiravsky
AU - Lucjan Rucki
AU - Bogna Jiravska Godula
AU - Jan Samiec
AU - Anna Pekarova
AU - Eva Jakubovicova
AU - Jan Chovancik
AU - Marie Novakova
AU - Matej Pekar
PY - 2026
DA - 2026/10/01
JO - Diabetes, Metabolic Syndrome and Obesity
DO - 10.2147/dmso.s604281
UR - https://www.dovepress.com/sympathovagal-imbalance-and-insulin-resistance-the-autonomic-nervous-s-peer-reviewed-fulltext-article-DMSO
AB - Jan Alexander Mohr,1,2 Otakar Jiravsky,1 Lucjan Rucki,1 Bogna Jiravska Godula,1 Jan Samiec,1,3 Anna Pekarova,2 Eva Jakubovicova,1,3 Jan Chovancik,1 Marie Novakova,2 Matej Pekar1,21Complex Cardiovascular Centre, Hospital AGEL Trinec-Podlesi, Trinec, Czech Republic; 2Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic; 3Faculty of Medicine and Dentistry, Palacký University Olomouc, Olomouc, Czech RepublicCorrespondence: Otakar Jiravsky, Complex Cardiovascular Centre, Hospital AGEL Trinec-Podlesi, Konska 453, Trinec, 73961, Czech Republic, Tel +420 558 309 111, Email [email protected]: 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.Keywords: autonomic nervous system, insulin resistance, cardiac autonomic neuropathy, heart rate variability, therapeutic target, sympathovagal balance, pre-diabetes, neuromodulation
SN - 1178-7007
ER -