Cardiac autonomic neuropathy (CAN) is a common complication of diabetes mellitus, and can be assessed using heart rate variability (HRV) and the correlations between systolic blood pressure (SBP) and ECG R-R intervals (RRIs), namely baroreflex sensitivity (BRS). In this study, we propose a novel parameter for the nonlinear association between SBP and RRIs based on multiscale cross-approximate entropy (MS-CXApEn). Sixteen male adult Wistar Kyoto rats were equally divided into two groups: streptozotocin-induced diabetes and age-matched controls. RRIs and SBP were acquired in control rats and the diabetic rats at the onset of hyperglycemia and insulin-treated euglycemia to determine HRV by the ratio of low-frequency to high-frequency power (LF/HF) and Poincaré plot as SSR (SD1/SD2), BRS, and MS-CXApEn. SSR and BRS were not significantly different among the three groups. The LF/HF was significantly higher in the hyperglycemic diabetics than those in the controls and euglycemic diabetic rats. MS-CXApEn was higher in the diabetic hyperglycemic rats than the control rats from scales 2 to 10, and approached the values of controls in diabetic euglycemic rats at scales 9 and 10. Conclusions: We propose MS-CXApEn as a novel parameter to quantify the dynamic nonlinear interactions between SBP and RRIs that reveals more apparent changes in early diabetic rats. Furthermore, changes in this parameter were related to correction of hyperglycemia and could be useful for detecting and assessing CAN in early diabetes.

Background: Cardiac autonomic neuropathy (CAN) is a common yet frequently underdiagnosed complication of diabetes. While our previous study demonstrated the utility of multiscale cross-approximate entropy (MS-CXApEn) in detecting early CAN, the present study further investigates the use of frequency-domain coherence analysis between systolic blood pressure (SBP) and R-R intervals (RRI) and evaluates the effects of insulin treatment on autonomic function in diabetic rats. Methods: At the onset of diabetes induced by streptozotocin (STZ), rats were assessed for cardiovascular autonomic function both before and after insulin treatment. Spectral and coherence analyses were performed to evaluate baroreflex function and autonomic regulation. Parameters assessed included low-frequency power (LFP) and high-frequency power (HFP) of heart rate variability, coherence between SBP and RRI at low and high-frequency bands (LF_Coh and HF_Coh), spontaneous and phenylephrine-induced baroreflex sensitivity (BRS_spn and BRS_phe), HRV components derived from fast Fourier transform, and MS-CXApEn at multiple scales. Results: Compared to normal controls (LF_Coh: 0.14 ± 0.07, HF_Coh: 0.19 ± 0.06), early diabetic rats exhibited a significant reduction in both LF_Coh (0.08 ± 0.04, p < 0.05) and HF_Coh (0.16 ± 0.10, p > 0.05), indicating impaired autonomic modulation. Insulin treatment led to a recovery of LF_Coh (0.11 ± 0.04) and HF_Coh (0.24 ± 0.12), though differences remained statistically insignificant (p > 0.05 vs. normal). Additionally, low-frequency LFP increased at the onset of diabetes and decreased after insulin therapy in most rats significantly, while MS-CXApEn at all scale levels increased in the early diabetic rats, and MS-CXApEn_large declined following hyperglycemia correction. The BRS_spn and BRS_phe showed no consistent trend. Conclusions: Coherence analysis provides valuable insights into autonomic dysfunction in early diabetes. The significant reduction in LF_Coh in early diabetes supports its role as a potential marker for CAN. Although insulin treatment partially improved coherence, the lack of full recovery suggests persistent autonomic impairment despite glycemic correction. These findings underscore the importance of early detection and long-term management strategies for diabetic CAN.