Do adipose tissues at different locations mediate the relationship between T2DM and reduced HRV?

Aims: Evidence suggests that adipose tissue accumulation may be a potential risk factor for neuropathy, independent of hyperglycemia (Ulucan S et al J Hepatol. 2015;62(5):1214; Houghton D et al J Hepatol. 2019;70(6):1203-1213). However, the association between adipose tissues deposition at different locations and cardiac autonomic neuropathy (CAN) in diabetes mellitus (DM) remains unknown. Thus, the aim of this cross-sectional study was to explore the role of fat deposition in mediating the relationship between DM and CAN.

Methods: A total of 380 participants were enrolled, including 249 patients with type 2 DM (T2DM) (age 62.82±13.91 years; 52,2% male; BMI 24.17±3.76 Kg/m²) and 131 non-diabetic controls (age 57.18±13.31 years; 49,6% male; BMI 24.59±2.54 Kg/m²). The thicknesses of four adipose tissues (subcutaneous, SAT; extraperitoneal, EPAT; intraperitoneal, IPAT; epicardial, EAT) were measured by abdominal ultrasound or echocardiography, respectively. Measures of heart rate variability (HRV) by 24-hour Holter were assessed for monitoring both frequency-(LF, HF, and LF/HF) and time-domain indices (SDNN, SDANN, SDNN index, rMSSD and pNN50). A mediation analysis was used to examine whether adipose tissues mediated the relationship between T2DM and each index of HRV.

Results: Compared to non-diabetic controls, T2DM participants exhibited a significant reduction in HRV indices, and a remarkable increase in the thicknesses of adipose tissues. In details, the thickness of EPAT (14.8±2.6 vs. 12.7±3.2 mm), IPAT (72.6±13.4 vs. 65.9±12.1 mm) and EAT (8.6±2.5 vs. 7.4±2.1 mm) were significantly greater in T2DM than in non-diabetic subjects (all P<0.001), while no significant difference was observed in the thicknesses of SAT (19.2±4.5 vs. 18.9±5.9 mm, P=0.575) between two groups. Thickness EAT was significantly correlated with most HRV indicators (all P<0.001) except for LF/HF. Univariate linear regression analysis demonstrated that changes of EAT were significantly related to all HRV indices. Mediation analysis found significant indirect effects of T2DM on six indices of HRV, including HF, SDNN, SDANN, SDNN index, rMSSD, and pNN50, which were mediated by EAT rather than other adipose tissues, with the mediation proportions of 64.21%, 16.38%, 68.33%, 24.34%, 24.10% and 30.51%, respectively. Additionally, EAT partially mediated the relationship between T2DM and reduced HRV burden (24.26%), which was composed by SDNN, SDNN index, rMSSD, and pNN50.

Conclusions: The present study revealed that EAT partially mediated the relationship between T2DM and HRV, suggesting that patients with T2DM may experience impaired regulation of the cardiac autonomic nervous system due to the accumulation of EAT.

Comments. Considering the interesting findings of this study, the mechanisms by which enlarged EAT partially mediates CAN in DM deserve to be elucidated. There are several potential explanations. The insulin resistance with associated inflammation in adipose tissue impairs glucose uptake in adipose cells (Greenhill C Nat Rev Endocrinol. 2018;14:565). The transformation of epicardial brown to white adipose tissue under the disordered glucose metabolism (Packer M J Am Coll Cardiol. 2018;71:2360-2372) can further exacerbate insulin resistance and activate the sympathetic nervous system by norepinephrine, resulting in impairment of beta-adrenergic function and nerve endings (Packer M J Am Coll Cardiol. 2018;71:2360-2372; Mangmool S et al  Biomol Ther (Seoul). 2017;25:44-56). Finally, the unbalanced distribution of parasympathetic and sympathetic ganglia in the epicardium may explain the varied correlations between EAT and different HRV indices. Although relevant limitations exist as the lack of cardiovascular autonomic reflex test as gold standard for assessing CAN and of the analysis of the use of lipid-lowering drugs and antidiabetic drugs, and the observational design of the study, the results reinforce the value of developing effective interventions to prevent CAN in diabetic patients through targeting heart-specific visceral adipose tissue. Thus, prospective and longitudinal studies are warranted to provide further validation of the findings.

Carla Greco

Reference. Ouyang X, Peng L, Huang Z, Wang T, Wang J, Wu H, Zhong J, Wu B, Wu L, Li Y, Lu Y, Li S, Tang X. Effects of adipose tissues on the relationship between type 2 diabetes mellitus and reduced heart rate variability: mediation analysis. Cardiovasc Diabetol. 2024 Sep 28;23(1):353. doi: 10.1186/s12933-024-02438-1. PMID: 39342197; PMCID: PMC11439294.

https://cardiab.biomedcentral.com/articles/10.1186/s12933-024-02438-1