The Interrelationship Between Cardiac Autonomic Activity and Low-Grade Inflammation in Subjects with Obesity and Prediabetes

Abstract

Aim

The study aimed to assess sympathetic (SNS) and parasympathetic (PSNS) activity in individuals with obesity and different states of prediabetes and to assess their associations with markers of inflammation.

Material and methods

A total of 104 participants (mean age 46.7±10.3 years; mean body mass index (BMI) 31.5±6.3 kg/m2) were categorized into three age- and BMI-matched groups based on glucose tolerance: 1) with normal glucose tolerance (n=20); 2) with high 1-h plasma glucose > 8.6 mmol/l (n=25) 3) with impaired glucose tolerance (n=59). All participants underwent an oral glucose tolerance test, and the area under the curves for glucose, insulin, and C-peptide were calculated. Creatinine (CKD-EPI calculation), lipids, glycated haemoglobin, and inflammatory markers (C-reactive protein (CRP), serum amyloid A, soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, interleukin-6 (IL-6), IL-8, and tumor necrosis factor-α) levels were measured. Body composition was assessed by bioimpedance analysis. Tissue advanced glycation end-products (AGEs) were evaluated by AGE-Reader. Autonomic function was measured with the АNX-3.0 autonomic monitoring system.

Results

A progressive decline in resting and stimulated PSNS and SNS activity was observed with worsening glucose tolerance. Some of the inflammatory markers were numerically elevated in prediabetic stages. After adjustment for age, there was a reciprocal relationship between PSNS and SNS tone and CRP (r=-0.23 to-0.40, all p<0.025). An independent inverse relationship was found between PSNS tone and systolic blood pressure and CRP. However, after adjustment for BMI and/or body composition parameters, waist circumference was the only independent predictor of PSNS activity (p<0.0001), explaining 26% of its variation.

Conclusion

This study demonstrates an inverse relationship between PSNS activity and both systolic blood pressure and CRP levels, though this association is largely mediated by visceral obesity.

Keywords

low-grade inflammation - cardiac autonomic function - prediabetes

Publication History

Received: 28 October 2025

Accepted after revision: 03 December 2025

Article published online:
11 February 2026

• References

• 1 Maser RE, Mitchell BD, Vinik AI. et al. The association between cardiovascular autonomic neuropathy and mortality in individuals with diabetes: A meta-analysis. Diabetes Care 2003; 26: 1895-1901
• 2 Vinik AI, Erbas T, Casellini CM. Diabetic cardiac autonomic neuropathy, inflammation and cardiovascular disease. J Diabetes Investig 2013; 4: 4-18
• 3 Ziegler D, Voss A, Rathmann W. et al. Increased prevalence of cardiac autonomic dysfunction at different degrees of glucose intolerance in the general population: The KORA S4 survey. Diabetologia 2015; 58: 1118-1128
• 4 Dimova R, Tankova T, Guergueltcheva V. et al. Risk factors for autonomic and somatic nerve dysfunction in different stages of glucose tolerance. J Diabetes Complications 2017; 31: 537-543
• 5 Dhumad MM, Hamdan FB, Khudhair MS. et al. Correlation of staging and risk factors with cardiovascular autonomic neuropathy in patients with type II diabetes mellitus. Sci Rep 2021; 11: 3576
• 6 Ewing DJ, Campbell IW, Clarke BF. Assessment of cardiovascular effects in diabetic autonomic neuropathy and prognostic implications. Ann Intern Med 1980; 92: 308-311
• 7 International Diabetes Federation releases position statement recommending use of 1-hour plasma glucose test to diagnose intermediate hyperglycaemia and type 2 diabetes.. 12 March 2024 https://idf.org/news/idf-position-statement-1-hour-pg-test/
• 8 Jagannathan R, Sevick MA, Huilin L. et al. Elevated 1-hour plasma glucose levels are associated with dysglycemia, impaired beta-cell function and insulin sensitivity: Pilot study from a real world health care setting. Endocrine 2015;
• 9 Pareek M, Bhatt DL, Nielsen ML. et al. Enhanced predictive capability of a 1-hour oral glucose tolerance test: A prospective population-based cohort study. Diabetes Care 2018; 41: 171-177
• 10 Abdul-Ghani MA, Abdul-Ghani T, Ali N. et al. One-hour plasma glucose concentration and the metabolic syndrome identify subjects at high risk for future type 2 diabetes. Diabetes Care 2008; 31: 1650-1655
• 11 Borovikova LV, Ivanova S, Zhang M. et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 2000; 405: 458-462
• 12 Tracey KJ. Reflex control of immunity. Nat Rev Immunol 2009; 9: 418-428
• 13 Tracey KJ. Immune cells exploit a neural circuit to enter the CNS. Cell 2012; 148: 392-394
• 14 Lieb D, Parson H, Mamikunian G. et al. Cardiac autonomic imbalance in newly diagnosed and established diabetes is associated with markers of adipose tissue inflammation. Exp Diabetes Res 2011; 2012: 1-8 PMID:22110481
• 15 von Kanel R, Nelesen RA, Mills PJ. et al. Relationship between heart rate variability, interleukin-6, and soluble tissue factor in healthy subjects. Brain Behav Immun 2008; 22: 461-468
• 16 Thayer JF, Fischer JE. Heart rate variability, overnight urinary norepinephrine and C-reactive protein: Evidence for the cholinergic anti-inflammatory pathway in healthy human adults. J Intern Med 2009; 265: 439-447
• 17 Meerwaldt R, Links TP, Graaff R. et al. Increased accumulation of skin advanced glycation end-products precedes and correlates with clinical manifestation of diabetic neuropathy. Diabetologia 2005; 48: 1637-1644
• 18 Lee DY, Lee MY, Cho JH. et al. Decreased vagal activity and deviation in sympathetic activity precedes development of diabetes. Diabetes Care 2020; 43: 1336-1343
• 19 Esler M, Rumantir M, Wiesner G. et al. Sympathetic nervous system and insulin resistance: From obesity to diabetes. Am J Hypertens 2001; 14: 304S-309S
• 20 Task Force. of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability, standards of measurement, physiological interpretation, and clinical use. Circulation 1996; 93: 1043-1065
• 21 Arora RR, Aysin E, Aysin B. et al. Therapeutic implications of sympathetic stimulus in orthostatic patients: Measured by spectral domain analysis. AHA Scientific Sessions, Orlando, FL. Circulation 2007; 116
• 22 Hadad R, Akobe SF, Weber P. et al. Parasympathetic tonus in type 2 diabetes and pre‑diabetes and its clinical implications. Sci Rep 2022; 12: 18020
• 23 Wu JS, Yang YC, Lin TS. et al. Epidemiological evidence of altered cardiac autonomic function in subjects with impaired glucose tolerance but not isolated impaired fasting glucose. J Clin Endocrinol Metab 2007; 92: 3885-3889
• 24 Watkins LL, Surwit RS, Grossman P. et al. Is there a glycemic threshold for impaired autonomic control?. Diabetes Care 2000; 23: 826-830
• 25 Williams SM, Eleftheriadou A, Alam U. et al. Cardiac autonomic neuropathy in obesity, the metabolic syndrome and prediabetes: A narrative review. Diabetes Ther 2019; 10: 1995-2021
• 26 Fisher V, Tahrani AA. Cardiac autonomic neuropathy in patients with diabetes mellitus: current perspectives. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 2017; 10: 419-434
• 27 Vinik AI. The conductor of the autonomic orchestra. Front Endocrin 2012; 3: 71
• 28 Herder C, Schamarek I, Nowotny B. et al. Inflammatory markers are associated with cardiac autonomic dysfunction in recent-onset type 2 diabetes. Heart 2017; 103: 63-70
• 29 Hansen CS, Vistisen D, Jørgensen ME. et al. Adiponectin, biomarkers of inflammation and changes in cardiac autonomic function: Whitehall II study. Cardiovasc Diabetol 2017; 16: 153
• 30 Windham BG, Fumagalli S, Ble A. et al. The relationship between heart rate variability and adiposity differs for central and overall adiposity. J Obes 2012; 2012: 149516
• 31 Perciaccante A, Fiorentini A, Paris A. et al. Circadian rhythm of the autonomic nervous system in insulin resistant subjects with normoglycemia, impaired fasting glycemia, impaired glucose tolerance, type 2 diabetes mellitus. BMC Cardiovasc Disord 2006; 6: 19
• 32 Lindmark S, Lönn L, Wiklund U. et al. Dysregulation of the autonomic nervous system can be a link between visceral adiposity and insulin resistance. Obes Res 2005; 13: 717-728
• 33 Laitinen T, Lindstrom J, Eriksson J. et al. Cardiovascular autonomic dysfunction is associated with central obesity in persons with impaired glucose tolerance. Diabet Med 2011; 28: 699-704