Among the most common non-communicable chronic diseases worldwide, diabetes mellitus (DM) stands out because it affects more than 340 million people in the world.¹ According to Irigoyen et al.,² DM has reached epidemic proportions due to factors such as increased life expectancy, high prevalence of obesity and sedentary lifestyle.²

The main risk factors for the pathogenesis of DM are related to family history and lifestyle, such as impaired fasting blood glucose, reduced glucose tolerance, gestational diabetes, birth weight greater than 4 kg, sedentary lifestyle, dyslipidemia (triglycerides > 250 mg/dl and HDL < 35 mg/dl), severe obesity, polycystic ovary syndrome, age ≥ 45 years, moderate cardiovascular risk, and hypertension (> 140/90 mmHg or antihypertensive use in adults).³ Thus, DM can be associated with different types of complications like autonomic dysfunctions in adult diabetic patients or their relatives with the disease. However, the prevalence of children and adolescents in pre-diabetic states or even with risk factors for type 2 DM is still unknown.⁴

Additionally, one of the complications of DM is its relationship with autonomic imbalance associated and cardiovascular risk, due to its effects on the blood pressure regulatory system.^{5 , 6} Thus, quantification of parasympathetic and sympathetic cardiac autonomic modulation is fundamental as indicator of cardiovascular function,⁷ because the autonomic nervous system plays a relevant role in the maintenance of cardiac homeostasis. Therefore, evaluation of heart rate variability (HRV) allows a sensitive and anticipated indication of the individual’s health impairment.⁶

Studies show that a decrease in HRV promoted by a reduction in vagal activity has been associated with adverse events in normal individuals and patients with chronic diseases, and consequent increased risk of morbidity and mortality.^{8 , 9} Thus, this study aims to evaluate the influence of a family history of diabetes on cardiac autonomic modulation.

The anthropometric and metabolic variables of the Control group and the FHD group are presented in Table 1 . When compared with the Control group, the FHD group showed no statistically significant differences in body composition, age, height, weight, systolic blood pressure (SBP), diastolic blood pressure (DBP), waist circumference (WC), body fat percentage, body mass index, glycemia, sexual maturation index or sleep quality. Nonetheless, although WC was not statistically different between the groups, the size of the effect showed high clinical relevance when comparing the groups.

Table 1

	Controls (n = 46)	FHD (n = 23)	p	Effect size
Age (years)	16.41 ± 1.33	16.16 ± 1.8	0.52	0.16
Height (cm)	163.3 ± 1.173	159.9 ± 1.717	0.10	2.47
Weight (kg)	57.00 ± 1.617	53.97 ± 2.085	0.26	1.69
Waist circumference (cm)	72.4 ± 1.160	70.29 ± 1.462	0.27	1.66
Body fat (%)	26.79 ± 1.374	26.07 ± 1.465	0.74	0.51
Body mass index (kg/m2)	21.33 ± 0.518	21.02 ± 0.612	0.71	0.56
Systolic blood pressure (mmHg)	112.45 ± 2.332	113.54 ± 1.542	0.75	0.51
Diastolic blood pressure (mmHg)	65.16 ± 1.102	67.24 ± 1.595	0.28	1.61
Glycemia	87.15 ± 11.216	83.31 ± 10.725	0.35	0.34
Sexual maturation index	2.92 ± 0.611	2.89 ± 0.311	0.63	0.05
Pittsburgh	1.54 ± 0.658	1.47 ± 0.611	0.65	0.10
IPAQ	1.34 ± 0.487	1.62 ± 0.517	0.21	0.56

IPAQ: International Physical Activity Questionnaire; data presented as mean ± standard error; Student’s t-test. Controls vs FHD (p < 0.05). The size effect was calculated according to the Hedges’g method.

The HRV of the Control and the FHD groups are shown in Figure 1 and Table 2 . No statistically significant differences were observed between the groups in the time domain variables RR average, pNN50 (%) and total variance (ms²), but differences were observed in SDNN, RMSSD, SD1, and SD2. The variables LF (ms²) and HF (ms²), in the frequency domain, also showed statistical differences. The other frequency domain variables in normalized units – LF (nu) and HF (nu) – and the LF/HF balance did not show significant differences. However, it is important to highlight that both LF/HF and the total variance (ms²) showed to have a significant clinical impact when the effect size was evaluated.

Figure 1

SDNN: standard deviation of all NN intervals; RMSSD: root mean square of successive differences of NN intervals (ms); LF: low frequency; HF: high frequency. One-tailed, unpaired Student's t-test. Control vs. family history of diabetes (p < 0,05); es: effect size.

The main finding of this study was a decrease in vagal activity in children of diabetic parents before the manifestation of any change in glycemia, suggesting an impairment in cardiac autonomic modulation.

These results can be observed in the HRV of the participants, which does not corroborate the study by Rocha et al.,⁸ which compared the autonomic function of individuals aged 18 to 49 years, with and without a family history of type 2 DM (DM2) in the absence of glucose intolerance. In this study, the authors observed differences in BMI, serum lipids, leptin, and C-reactive protein, in addition to similar autonomic parameters between the groups. In contrast, our results indicated earlier changes in HRV, which, in turn, corroborate the study by Iellamo et al.,¹⁹ which showed that these changes occur primarily in individuals with diabetic parents.

Anthropometric indices, sexual maturation, Pittsburgh’s sleep quality, SBP, DBP, blood glucose and physical activity level were not significantly different between the groups, showing that they were not determining factors to changes in the HRV. However, WC showed a high effect, a result that corroborates studies that relate abdominal fat accumulation with the increase of WC as an important risk factor for the development of DM2.^{20 , 21}

In addition, it was possible to notice a reduction in HRV in individuals with a family history of diabetes, with worse cardiac autonomic modulation, resulting in greater sympathetic activity.^{22 - 24} This suggests that altered autonomic function would precede the onset of glycemic dysfunction, which corroborates the study by Fiorentini et al.,²⁵ with 75 individuals with a mean age of 47.71 years, divided into a group with a family history of DM2 and insulin resistance, a group of descendants with a family history without insulin resistance and a control group. The authors identified that changes related to the reduction in autonomic system function were associated with a family history of diabetes.²⁵

The results in this study showed changes in cardiac autonomic modulation suggestive of lower vagal activity, which was also noted in the study by Kardelen et al.²⁶ in children with an average age of 12 years and insulin dependence.

The time-domain RMSSD (ms²) and SDNN variables confirmed a lower cardiac autonomic modulation in children of diabetic parents found in the analysis of adjacent RR intervals,²⁷ reflecting a decrease in vagal activity.²⁸ Therefore, a significant decrease in RMSSD and SDNN is indicative of a reduction in vagal tone and greater modulation of the cardiac sympathetic autonomic nervous system as shown in adolescents in the family history of diabetes group, corroborating previous studies.^{26 , 29 , 30}

Analysis of the frequency domain revealed that HF (ms²) and LF (ms²) indices are lower in children of diabetics, corroborating the studies by Chen et al.³¹ and Malik et al.,³² including DM2 children aged from eight to 12 years, showing a decrease in the LF (ms²), HF (ms²) components, as well as in total variance. Although our study did not show significant differences in total variance, this parameter showed a high effect size, indicating important clinical representativeness.

The LF/HF ratio, a marker of autonomic imbalance, was lower in children with parents with DM2. This is different from the study by Fiorentini et al.,²⁵ which identified changes in LF/HF ratio indicating lower vagal activity in 70 Caucasian individuals, mean age of 47 years, descended from parents with DM2. The failure to identify autonomic imbalance in the present study may be related to the age range of the groups in our study, since autonomic nervous system disorders in insulin-resistant patients are closely related to longer exposure to the disorder.^{33 , 34} However, it is important to emphasize that the LF/HF balance showed a strong effect, supporting it as an important marker of clinical changes in cardiac autonomic modulation in adolescents with a family history of diabetes.

The SD1 and SD2 values indicated a lower vagal activity in the FHD group, which corroborates the findings of Kaminski et al.³⁵ who evaluated the sympathovagal activity in adult individuals. However, their sample comprised individuals aged 11 to 18 years incomplete, which makes the findings important evidence for a better understanding and early identification of an association of cardiac autonomic dysfunction with a genetic factor in the etiology of this condition.

First-degree relatives of individuals with DM2 are known to have two to six times greater risk of developing the disease compared with individuals with no family history of diabetes.³⁶ In this case, the genetic component is a determining factor, where the possibility of individuals with a family history of diabetes is five to ten times higher for the development of the disease than the general population.³⁷

In terms of clinical and scientific relevance of the findings, some points need to be highlighted. First, in the studies reviewed, there was little scientific evidence, since HRV in adolescents with a family history of diabetes has been poorly studied and deserves further investigation. Our findings may be used in subclinical detection of autonomic dysfunctions, definition of the risk level, and in early diagnosis of hemodynamic and autonomic changes in offspring of individuals with DM. This would reduce overall mortality and the risk of the development of DM2, metabolic complications and other noncommunicable chronic diseases.

In interpreting these results, some limitations need to be considered. The study allowed verifying the existence of a family history of diabetes among participants, however, it was not possible to determine the type of DM in the parents; also, insulin and lipid levels of these individuals were not assessed, which could have provided relevant clinical information and should be explored in future studies.

Global autonomic modulation is decreased in adolescents with a family history of diabetes. It was also observed a vagal activity decrease (RMSSD and SD1 indices), indicating that a sympathetic modulation is predominant in this population.