Sex differences in cardiovascular disease risk in type 1 diabetes: The vascular bed paradox in women

Abstract

Background

Cardiovascular disease (CVD) is the leading cause of death in individuals with type 1 diabetes (T1D). Epidemiological studies indicate that women with T1D are at greater risk of CVD compared to men with T1D. The present study sought to investigate differences in vascular health between men and women with T1D.

Methods

53 women with T1D and 25 men with T1D participated in this study. The flow-mediated dilation (FMD) test assessed endothelial-dependent conduit vessel function and nitroglycerin (NTG) was used to assess endothelial-independent vasodilation. In addition, cutaneous post-occlusive reactive hyperemia (PORH), local thermal heating (LTH), and iontophoresis of acetylcholine (ACH) were conducted to assess microvascular function, and pulse wave velocity (PWV) and pulse wave analysis (AIx75) were used as indices of arterial and aortic stiffness, respectively. Near-infrared spectroscopy was utilized to assess skeletal muscle oxidative capacity (SMOC).

Results

Hemoglobin A_1c (p=0.904) was similar between men and women with T1D. Women with T1D exhibited higher FMD (p=0.010) and AIx75 (p<0.001) compared with men with T1D. There were no differences in PORH, LTH, ACH, PWV, or SMOC between groups (all p>0.05).

Discussion

Findings from the present investigation demonstrate that women with T1D exhibit greater conduit vessel endothelial function yet increased aortic stiffness compared to men with T1D. This paradox of enhanced endothelial function and arterial stiffness highlights the complex relationship between vascular structure and function in T1D and the need to assess multiple indices of vascular health when evaluating cardiovascular disease risk in men and women with T1D.

Keywords

type 1 diabetes sex differences vascular function cardiovascular disease

Introduction

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality globally, accounting for greater than 20 million deaths per year.¹ Among high-risk populations, individuals with type 1 diabetes (T1D) are especially vulnerable to developing cardiovascular complications.² In fact, patients with T1D exhibit up to an eightfold increase in cardiovascular events such as myocardial infarction, stroke, and heart failure compared to age- and sex-matched individuals without diabetes.³ Despite advancements in glycemic management and CVD risk factor control, this elevated risk of CVD persists, highlighting the complex interplay between dysglycemia and vascular dysfunction in T1D.⁴

In the general population, premenopausal women are typically protected against cardiovascular disease (CVD), exhibiting more favorable vascular profiles compared to men.^5,6 However, this cardioprotective advantage appears to be diminished in individuals with type 1 diabetes (T1D). Women with T1D experience a disproportionately elevated relative risk of CVD compared to non-diabetic women, effectively losing the protection normally observed in premenopausal females.^7,8 A large meta-analysis of over 214,000 individuals with T1D demonstrated that the relative risk of cardiovascular events was approximately twofold higher in women compared to men.⁸ Similarly, registry data indicate that women diagnosed with T1D early in life have markedly higher excess cardiovascular risk compared to demographically matched controls, exceeding that observed in men with early-onset disease.⁹

Importantly, this disparity is not fully explained by differences in traditional cardiometabolic risk factors or survival bias. Studies of coronary artery calcification and long-term prospective data from the DCCT/EDIC cohort demonstrate that women with T1D do not experience the expected cardiovascular protection despite more favorable risk profiles.¹⁰ Collectively, these findings suggest that traditional risk stratification may underestimate cardiovascular vulnerability in women with T1D and raise the possibility that sex-specific differences in vascular health contribute to this excess risk. Therefore, the present study aimed to determine whether sex differences in endothelial function, arterial stiffness, microvascular function, and skeletal muscle oxidative capacity exist among adults with T1D.

Methods

Experimental design

All participants reported to the Laboratory of Integrative Vascular and Exercise Physiology (LIVEP) in the Georgia Prevention Institute at Augusta University for a preliminary screening visit that consisted of the informed consent process, body composition assessments, blood pressure, and anthropometric measures. A single blood draw was performed to obtain glycated hemoglobin (HbA_1c) and a lipid panel using standard core laboratory techniques (Laboratory Corporation of America Holdings, Birmingham, AL). Height and body mass were determined using a stadiometer and standard platform scale (CN20, DETECTO, Webb City, MO), respectively, and were used to calculate body mass index (BMI). Total body fat was determined using dual energy X-ray absorptiometry (QDR-4500 W; Hologic, Waltham, MA). All vascular assessments were performed in the same laboratory under standardized conditions, with all participants studied in the morning following an overnight fast using identical equipment, the same personnel and testing protocols. Patients were instructed to maintain their basal insulin regimen. A venous blood sample was collected to assess circulating concentrations of insulin and various sex hormones including estradiol, progesterone, and testosterone (Laboratory Corporation of America Holdings, Birmingham, AL). The experimental visit in women occurred during the menses phase of the menstrual cycle.

Participant characteristics

Fifty-three premenopausal women and twenty-five age-matched men with a clinical diagnosis of type 1 diabetes were recruited from the Department of Endocrinology at Augusta University or from the community via word of mouth. The parent study was designed to investigate the role of estrogen on vascular health in patients with T1D; therefore, men were recruited as a comparative reference group, and a target enrollment ratio of approximately 2:1 (women:men) was established a priori. Participants were excluded if they reported a history of hepatic, renal, or overt CVD, uncontrolled hypertension (i.e., systolic/diastolic > 140/90 mm Hg), polycystic ovary syndrome, oligomenorrhea based on self-report, or proteinuria. Eight participants were receiving antihypertensive medication at the time of the study. In addition, women who were pregnant or those trying to become pregnant were excluded from the study. Patients experiencing any vascular-related complications of diabetes or those with an HbA_1c of > 12% were also excluded. All study protocols were approved by the Institutional Review Board at Augusta University, and this study was registered on clinicaltrials.gov (NCT03436992).

Vascular endothelial function

Endothelial-dependent vasodilation was determined using the brachial artery flow-mediated dilation (FMD) test in accordance with previously published guidelines¹¹; consistent with these methodological recommendations, premenopausal women were studied during the first 7 days of the menstrual cycle (menses phase) to minimize hormonal variability, as estrogen is known to augment the FMD response.^11,12 Briefly, participants laid in a rested, supine position for at least 15 minutes to ensure stable blood flow and a hemodynamic steady state. Using a 12 MHz linear transducer, simultaneous B-mode and blood velocity profiles (duplex mode) of the brachial artery were obtained (Logiq 7, GE Medical Systems, Milwaukee, WI). After 30 seconds of baseline data collection, the forearm occlusion cuff (E-20 rapid cuff inflator; D.E. Hokanson) that was placed immediately distal to the medial epicondyle was rapidly inflated to 250 mm Hg. Following 5 minutes of forearm occlusion, the cuff was released, and brachial artery diameter and blood velocity were continuously recorded for 2 minutes. R-wave gating (Accusync 72, Accusync Medical Research Corporation, Milford, CN) was utilized to capture end-diastolic arterial diameters for automated offline analysis of brachial artery vasodilation (Medical Imaging Applications, Coralville, Iowa). FMD (%) is reported as the percent of maximal brachial artery dilation diameter from baseline diameter. Cumulative shear rate (s^− 1, area under the curve, AUC) was determined using the trapezoidal rule, every 4 seconds for the first 20 seconds following cuff release, and every 5 seconds thereafter for the remainder of the 2-minute data collection period. Following completion of the FMD test, baseline measurements were taken for 30 seconds before 0.4 mg of sublingual nitroglycerin (NTG) (Perrigo, Allegan, MI) was administered. Endothelial-independent vasodilation of the brachial artery was continuously recorded for 8–10 minutes to ensure the peak response was obtained, and the percent of maximal brachial artery dilation from baseline was used to represent NTG (%).

Arterial stiffness

Arterial stiffness was determined noninvasively using the SphygmoCor XCEL system (AtCor Medical, Sydney, Australia). Briefly, augmentation index (AIx), a measure of aortic stiffness, was determined using the pulse wave analysis (PWA) test obtained from the left brachial artery in duplicate and was normalized for a heart rate of 75 beats/min (AIx75). The average reading was used for analysis. Aortic and brachial systolic and diastolic blood pressures and aortic augmented pressure (aAP) were recorded during this assessment. In addition, the subendocardial viability ratio (SEVR), also known as the Buckberg index, was assessed during the PWA test as a noninvasive indicator of myocardial oxygen supply relative to demand. In addition, carotid-femoral pulse wave velocity (PWV) was measured using the SphygmoCor XCEL system, which records carotid waveforms via tonometry and femoral waveforms using a leg cuff simultaneously. PWV was calculated as the distance between measurement sites divided by the pulse transit time, with higher velocities indicating greater arterial stiffness, as previously described by our group.¹³

Microvascular function testing

Cutaneous microvascular blood flow was assessed using Laser-Doppler Imaging (Moor FLPI-2; Moor Instruments), a technique previously described by our group¹⁴ and others.^15,16 Briefly, participants rested supine for 15 minutes before testing. A forearm cuff was placed distal to the medial epicondyle. A round heater probe and iontophoresis chamber were secured on the ventral forearm using double-sided adhesive tape, avoiding areas with tattoos, broken skin, or visible veins. Microvascular function was assessed using three protocols:

Post-Occlusive Reactive Hyperemia (PORH): The cuff was inflated to 250 mmHg for 5 minutes. Peak flux (PORH_MAX), baseline flux (PORH_BL), and time to peak (PORH_TTP) were recorded.

Local Thermal Hyperemia (LTH): A heating probe raised the skin temperature to 44°C over 25 minutes. Peak flux (LTH_MAX), baseline (LTH_BL), and time to peak (LTH_TTP) were recorded.

Iontophoresis of Acetylcholine (ACH): A 2% ACH solution was delivered via iontophoresis (100 μA for 20 seconds, repeated 7 times with 60 second intervals). Peak response (ACH_MAX), baseline (ACH_BL), and time to peak (ACH_TTP) were measured.

Baseline flux for each protocol was calculated as the average of a 30-second period prior to the intervention. PORH was always performed first, followed by LTH and then ACH iontophoresis, ensuring baseline recovery between tests. All responses were reported as maximal red blood cell flux (RBF) in perfusion units (PU).

Skeletal muscle oxidative capacity

Skeletal muscle mitochondrial function was assessed non-invasively in all patients by measuring the rate of muscle oxygen consumption following an increase in muscle metabolism induced by electrical stimulation, as previously described by our team.¹⁷ Briefly, the participant laid in a semi-recumbent position with their right leg in an immobilized position. Near-infrared spectroscopy (NIRS; PortaLite Artinis Medical Systems, Netherlands) was placed on the belly of the right medial gastrocnemius muscle, with electrical stimulation pads (2 x 4 in, PRO Advantage) secured both above and below the NIRS device. To reduce the impact of ambient light on the NIRS signal, the NIRS device was loosely wrapped with Coban. A thigh blood pressure cuff (Delfi Tourniquet Cuffs, Delfi Medical Innovations Inc, Vancouver, BC) was wrapped superior to the kneecap. After ensuring hemodynamic stability and collecting baseline data, thirty seconds of electrical stimulation was administered to increase the metabolic rate of the skeletal muscle. Subsequently, a series of repeated arterial occlusions and reperfusions using the thigh blood pressure cuff was performed to assess the changes in oxygenated and deoxygenated hemoglobin via NIRS. Data was collected at 10 Hz and data analysis was performed using the Hb_DIFF signal. The slopes of each post-electrical stimulation cuff occlusion were fit to a monoexponential curve to obtain a time constant (TC). The TC was then used to calculate the rate constant or oxidative capacity ([1/TC] x 60) as an index of skeletal muscle function. Two complete tests were conducted with at least 3-minutes of rest in between. The average of the two muscle function tests were used for analysis.

Statistical analysis

Statistical analyses were performed using SPSS Version 29. All data are expressed as mean ± standard error of mean (SEM) unless otherwise noted. For demographics, baseline clinical variables and parameters of vascular function testing, chi-square tests or independent t-tests were used to examine differences. Effect sizes for differences between men and women are reported as Cohen’s d values to represent small (Cohen’s d = 0.2), medium (Cohen’s d = 0.5), and large (Cohen’s d = 0.8) effect sizes.¹⁸ Cohen’s d provides a standardized measure of effect magnitude, reflecting the size of group differences independent of sample size. Statistical significance was set at p < 0.05.

Results

Participant characteristics and clinical laboratory values

Participant characteristics and clinical laboratory values for men and women with T1D are presented in Table 1. Men with T1D were taller (p<0.001; Cohen’s d=-1.848) and had less body fat (p<0.001; Cohen’s d=2.123) compared to women with T1D. All other participant demographics were similar between groups (p>0.05). In addition, men with T1D had lower high-density lipoprotein (p=0.008; Cohen’s d=0.665) and higher total testosterone (p<0.001; Cohen’s d=-5.000) and free testosterone (p<0.001; Cohen’s d=-4.189) compared to women with T1D. There was no difference between duration of T1D between men (12±8 years) and women (14±10 years) (p=0.312; Cohen’s d=-0.257). All other clinical laboratory values were similar between groups (all p>0.05).

Table 1.

Overall Participant Characteristics and Clinical Laboratory Values.

Variable	Men with T1D	Women with T1D	p-value
Variable	(n=25)	(n=53)	p-value
Demographic
Age (y)	22±6	26±8	0.064
Height (in)	70.1±2.4	65.0±2.9	<0.001
Weight (lb)	184±40	167±38	0.072
BMI (kg/m²)	26.4±5.7	27.7±5.4	0.318
Body Fat (%)	26.0±8.4	40.4±5.8	<0.001
Clinical Laboratory Values
HbA_1c (%)	8.2±1.4	8.3±1.7	0.904
Glucose (mg/dL)	160±73	147±67	0.472
TC (mg/dL)	163±33	179±40	0.075
HDL (mg/dL)	48±18	61±18	0.008
TRG (mg/dL)	106±125	80±51	0.193
LDL (mg/dL)	91±34	96±38	0.523
Estradiol (ng/dL)	25±11	34±23	0.075
Progesterone (ng/dL)	0.26±0.10	0.35±0.30	0.136
Testosterone, Total (ng/dL)	542±178	34±21	<0.001
Testosterone, Free (ng/dL)	13.5±4.6	2.0±1.2	<0.001

Data are presented as mean ± SD; independent samples t test. Bold values indicate statistically significant. BMI = Body Mass Index, HbA_1c = Hemoglobin A_1c, TC = Total Cholesterol, HDL = High-Density Lipoprotein, TRG = Triglycerides, LDL = Low-Density Lipoprotein.

Vascular endothelial function

Differences in the parameters of the FMD test between men and women with T1D are presented in Table 2. Brachial artery baseline diameter (p<0.001; Cohen’s d=-1.985) and peak diameter (p<0.001; Cohen’s d=-1.893) were greater in men with T1D compared to women with T1D. Additionally, the NTG-mediated vasodilation was similar between men and women with T1D (p=0.161). The differences in FMD and FMD/Shear between men and women with T1D are presented in Figure 1. FMD (p=0.010; Cohen’s d=0.638, Figure 1(A)) and FMD/Shear (p=0.043; Cohen’s d=0.500, Figure 1(B)) were both greater in women with T1D compared to men with T1D.

Table 2.

Parameters of Vascular Function Testing.

Variable	Men with T1D	Women with T1D	p-value
Variable	(n=25)	(n=53)	p-value
Conduit-Vessel Function
FMD_BL (cm)	0.37±0.04	0.30±0.03	<0.001
FMD_Peak (cm)	0.39±0.04	0.32±0.04	<0.001
FMD_Shear (sec^-1, AUC)	44481±18993	48393±18188	0.385
FMD_TTP (sec)	53.1±18.6	47.6±18.7	0.230
ΔNTG (cm)	0.06±0.02	0.07±0.02	0.161
Arterial Stiffness
bSBP (mm Hg)	122±14	118±11	0.172
bDBP (mm Hg)	71±12	74±7	0.239
aSBP (mm Hg)	107±13	106±9	0.679
aDBP (mm Hg)	72±12	74±8	0.259
aAP (mm Hg)	3.6±4.5	5.7±4.1	0.048
AIx75 (%)	4.5±13.4	14.6±10.9	<0.001
SEVR (%)	146±33	132±25	0.036
PWV (m/s)	6.3±1.1	6.0±0.9	0.239
Local Thermal Heating (LTH)
LTH_BL (PU)	44±15	43±10	0.637
LTH_Max (PU)	236±68	233±53	0.856
LTH_TTP (sec)	1162±192	1194±202	0.513
Post Occlusive Reactive Hyperemia (PORH)
PORH_BL (PU)	49±14	49±11	0.993
PORH_Max (PU)	175±41	185±47	0.371
PORH_TTP (sec)	14±5	15±5	0.835
Iontophoresis of Acetylcholine (ACH)
ACH_BL (PU)	42±16	41±11	0.837
ACH_Max (PU)	126±48	151±192	0.527
ACH_TTP (sec)	13±5	16±7	0.136
Skeletal Muscle Oxidative Capacity (SMOC)
RC (min^-1)	2.3±1.1	2.3±0.9	0.993

Values are mean ± SD; independent samples t tests. Bold values indicate statistically significant. bSBP = Brachial systolic blood pressure, bDBP = Brachial diastolic blood pressure, aSBP = Aortic systolic blood pressure, aDBP = Aortic diastolic blood pressure, AIx75 = Augmentation Index, aAP = Augmented aortic pressure, SEVR = Subendocardial Viability Ratio, PWV = Pulse wave velocity, FMD = Flow-mediated dilation, BL = Baseline, TTP = Time to Peak, NTG = Nitroglycerin, LTH = Local Thermal Heating, PORH = Post-Occlusive Reactive Hyperemia, ACH = Iontophoresis of Acetylcholine, RC = Rate Constant.

Figure 1.

Differences in (A) flow-mediated dilation (FMD) and (B) FMD normalized for shear (FMD/Shear) between women with type 1 diabetes (T1D) and men with TID; n= 78 (Women = 53, Men = 25). Independent samples t-test. Data are presented as mean±SEM. *indicates a significant difference from women with T1D.

Arterial stiffness

Indices of the arterial stiffness test are presented in Table 2. There were no differences in brachial systolic, brachial diastolic, aortic systolic, or aortic diastolic blood pressures between men and women with T1D (all p>0.05). Figure 2 illustrates the difference in AIx75 between men and women with T1D. Specifically, women with T1D had higher AIx75 (p<0.001; Cohen’s d=0.858) and aAP (p=0.048; Cohen’s d=0.487) compared to men with T1D. In addition, SEVR was greater in men with T1D compared to women with T1D (p=0.036; Cohen’s d=0.519). No differences in PWV were observed between groups (p=0.239; Cohen’s d=-0.288).

Figure 2.

Differences in augmentation index (AIx75) between women with type 1 diabetes (T1D) and men with TID; n= 77 (Women = 53, Men = 24). Independent samples t-test. Data are presented as mean±SEM. *indicates a significant difference from women with T1D.

Microvascular function testing and skeletal muscle oxidative capacity

Parameters of the microvascular function test are presented in Table 2. There were no differences in baseline flux between groups during the PORH, LTH, or ACH protocols (all p>0.05). Additionally, there were no group differences in maximal flux observed during the PORH (p=0.371; Cohen’s d=-0.219), LTH (p=0.856; Cohen’s d=0.044), or ACH protocols (p=0.264; Cohen’s d=-0.155). Furthermore, there were no differences in the time to peak of the PORH, LTH, or ACH protocols (all p>0.05). There were no differences in skeletal muscle oxidative capacity (p=0.993; Cohen’s d=0.003).

Discussion

Women with T1D have a greater risk of CVD compared to men with T1D¹⁹; however, the mechanisms underlying this increased susceptibility remain uncertain. Sex differences in vascular function have been well-documented in healthy populations yet remain to be elucidated among individuals with T1D. The findings of the present investigation demonstrate that flow-mediated dilation (FMD), an assessment of conduit vessel endothelial function, is significantly higher in women with T1D compared to men with T1D, and these findings persisted after normalization for shear stress. However, augmentation index (AIx75), an assessment of aortic stiffness, was higher in women with T1D. The paradox of enhanced endothelial responsiveness alongside increased arterial stiffness highlights the complex interplay between vascular endothelial function and vessel structure in T1D. Importantly, these sex-based differences in CVD risk do not appear to be driven by metabolic factors as no differences were observed in key parameters such as HbA_1c, glucose, or lipid profiles. Collectively, these data suggest that vascular disparities in T1D extend beyond glycemic control or metabolic status and likely reflect intrinsic, sex-specific vascular mechanisms.

Sex differences in vascular endothelial function

Flow-mediated dilation is a functional assay of nitric-oxide (NO) bioavailability and a non-invasive assessment of vascular endothelial function.¹¹ Evaluation of endothelial function using the FMD test has been shown to predict cardiovascular events and holds prognostic value across various patient populations.^20,21 Indeed, endothelial dysfunction has been consistently reported in patients with T1D²²; however, research examining sex differences in FMD within this population remains limited. In the general population, prior studies have shown sex-based differences in vascular physiology, with men typically having larger baseline arterial diameters that result in a lower shear rate compared to women.²³ Consistent with these previous findings, men with T1D in the present investigation had larger baseline arterial diameters compared to women. However, women with T1D demonstrated significantly greater FMD compared to men, even after normalization for shear stress, suggesting greater vascular endothelial function when controlling for differences in baseline diameter and cuff-induced shear.

The greater endothelial function in women; however, may be influenced by hormonal status. Indeed, the increase in estrogen during the late follicular phase of the menstrual cycle in healthy, premenopausal women has been shown to facilitate an increase in FMD.¹² However, the increase in estrogen in the presence of T1D contributes to a decrease in FMD suggesting that estrogen may paradoxically impair endothelial function in this patient population.¹² Notably, in the present investigation, the higher FMD was observed in women with T1D despite testing during the menses phase of the menstrual cycle, when concentrations of estrogen are low. Importantly, NTG-mediated dilation, which reflects endothelium-independent smooth muscle responsiveness, was similar between men and women with T1D. Collectively, these data indicate that the observed sex difference in FMD is primarily endothelial in origin rather than due to differences in either concentrations of estrogen or vascular smooth muscle function. These findings raise important questions regarding the role of hormonal influences in modulating vascular health in women with T1D; however, further mechanistic and longitudinal studies are required before clinical implications can be determined. Conversely, the consistently impaired endothelial function in men with T1D reinforces the importance of targeted CVD prevention efforts that are sex-dependent in this patient population.

Sex differences in arterial stiffness

Arterial stiffness reflects the cardiovascular system’s ability to respond to pressure changes via vasodilation or vasoconstriction.²⁴ Increased arterial stiffness promotes vascular remodeling and is strongly associated with elevated blood pressure and adverse cardiovascular events, which increases the risk of overt CVD.^25,26 In the present study, aortic stiffness assessed by PWA, was greater in women with T1D compared to men. Notably, no significant differences were observed in brachial or aortic blood pressures between men and women with T1D, which is consistent with previous reports in the literature.²⁷ Nonetheless, sensitivity analysis that excluded participants receiving antihypertensive medications did not alter the primary findings. The higher aortic augmented pressure observed in women in the present study indicates greater wave reflection and central systolic load, which are factors that increase myocardial workload and promote long-term vascular remodeling. This finding aligns with the observation that SEVR was lower in women compared to men with T1D, suggesting that women experience less favorable coronary perfusion and myocardial oxygen supply-demand balance.

Given that arterial stiffness often precedes changes in central aortic stiffness and is associated with impaired cardiac performance,²⁵ findings of the present study underscore a possible mechanism for the greater cardiovascular disease risk observed in women with T1D. However, arterial stiffness alone is unlikely to fully explain the sex-specific differences in CVD risk. Other contributing factors, such as hormonal fluctuations, age-related vascular changes, systemic inflammation, autonomic dysfunction, and differences in microvascular health, likely interact with macrovascular abnormalities to shape long-term outcomes. The interplay between sex-specific physiology and T1D pathology is complex and warrants further investigation in larger, longitudinal studies to better understand the multifactorial drivers of increased cardiovascular risk in women with T1D.

Sex differences in microvascular function and muscle function

The microvascular network plays a critical role in nutrient delivery and tissue perfusion, and its dysfunction is a known predictor of CVD and adverse cardiac events.²⁸ While PORH is influenced in part by prostanoid pathways with NO playing a relatively minor role,²⁹ the plateau phase of LTH is primarily mediated by NO-dependent mechanisms.¹⁶ In contrast, the vasodilatory response to ACH iontophoresis involves multiple endothelial pathways, including those dependent on NO, cyclooxygenase, prostanoids, and endothelium-derived hyperpolarizing factors.³⁰ In the present investigation, no differences in PORH, LTH, or ACH were observed between men and women with T1D. The absence of sex differences in microvascular responses, despite an increase in endothelial function and the increase in arterial stiffness, raises an important question regarding the mechanism of increased CVD risk in women with T1D. Could this paradox reflect sex-specific alterations in vascular-structural remodeling, autonomic regulation, or hormonal modulation that offset the protective effects of enhanced endothelial function? Future investigations should explore potential contributors, including oxidative stress, systemic inflammation, autonomic dysregulation, and androgenic hormonal influence.

Impaired skeletal muscle oxidative capacity³¹ is an established risk factor for CVD³² that has been observed in individuals with T1D. The results of the present study identified that skeletal muscle oxidative capacity was similar between men and women with T1D. The present findings are in contrast to previous research¹⁷ that reported lower skeletal muscle oxidative capacity in women with T1D compared to men with T1D. However, in the present investigation, the larger cohort size may have greater statistical power and supports that muscle function may be similar between men and women with T1D. In addition, the small effect size (Cohen’s d=0.003) observed for muscle function suggests that sex may not play a meaningful role in determining skeletal muscle oxidative capacity in individuals with T1D, although further research is certainly warranted to confirm this observation.

Clinical relevance

Women with T1D are known to have a greater risk of cardiovascular disease compared to men with T1D, yet the present findings reveal that premenopausal women with T1D exhibit higher FMD and greater arterial stiffness compared to men with T1D. Given that the FMD and AIx75 tests are independent predictors of CVD risk, this paradox suggests that arterial structure and function may be affected differently throughout the course of the disease in men and women. It is plausible that in women, arterial stiffening develops earlier in the disease process and preceding systemic endothelial dysfunction. In men with T1D; however, vascular endothelial dysfunction may occur first and facilitate the subsequent structural changes and stiffening of the arteries. The increased arterial stiffness that was observed in women with T1D, albeit relatively young and in good glycemic control, may indicate an early marker of subclinical vascular remodeling that contributes to their elevated CVD risk over time. Indeed, vascular health was assessed during a low estrogen phase of the menstrual cycle, suggesting that hormonal fluctuations may further modulate CVD risk in T1D and could partially explain the paradox of preserved endothelial function despite increased arterial stiffness. In contrast, the lower FMD, which reflects impaired endothelial-dependent vasodilation, observed in men with T1D should not be ignored and underscores the need for early, sex-specific CVD risk prevention strategies. Future studies evaluating sex differences in CVD risk in T1D that integrate long term follow-up, assessments throughout the hormonal phases, and direct measures of vascular remodeling are needed to elucidate the mechanistic pathways contributing to the epidemiological data.

An important experimental consideration of the present investigation is the relatively small sample size. While this may limit the detection of more subtle or interaction-level effects, the observed differences were accompanied by large effect sizes, suggesting that the physiological patterns identified are robust and meaningful. Although multiple vascular domains were assessed, each represented an independent physiological construct, and the magnitude of the observed effect sizes supports that these findings are unlikely to be attributable solely to chance. Additionally, each vascular outcome assessed represents an individual dependent variable, reflecting a distinct physiological construct rather than components of a shared multivariate model, which reduces concern for correlated Type I error. Nevertheless, larger, multi-site studies are needed to validate these findings and enhance their generalizability.

Conclusion

Sex differences in T1D pathophysiology and clinical outcomes have been well-documented, yet the mechanisms for the increased risk of CVD in women with T1D remain incompletely understood. Findings of the present investigation are the first to report that there may be sex-dependent differences with respect to specific vascular bed health in T1D. Specifically, women with T1D not only exhibit greater conduit artery endothelial function; they also exhibit increased arterial stiffness compared to men with T1D. Indeed, the present observations provide preliminary mechanistic insight into the heightened CVD risk observed in women with T1D, suggesting that sex-specific vascular alterations may contribute to this disparity. Nonetheless, the present results support the need for sex-specific strategies in cardiovascular risk assessment and prevention in T1D.

Footnotes

ORCID iDs

Abigayle B. Simon

Ryan A. Harris

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by 1R01HL137087 (RAH).

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Clinical trials number

NCT03436992

Disclosures

The authors have no disclosures.

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