Altered Cardiovascular Responses to Exercise in Type 1 Diabetes

Abstract

Exaggerated cardiovascular responses to exercise increase the risk of myocardial infarction and stroke in individuals with type 1 diabetes (T1D); however, the underlying mechanisms remain largely elusive. This review provides an overview of the altered exercise pressor reflex in T1D, with an emphasis on the mechanical component of the reflex.

Summary:

Effects of type 1 diabetes on the autonomic control of the circulation during exercise.

INTRODUCTION

Although exercise, or physical activity, is a well-established tool to reduce cardiovascular risk in type 1 diabetes (T1D) patients, recent data suggest that hemodynamic regulation during physical activity is altered, leading to adverse cardiovascular responses (1, 2). T1D is thought to be an autoimmune disease causing the deterioration of the pancreatic β cells, which are responsible for producing insulin. This results in a progressive reduction of insulin production until total abolition, leaving T1D patients dependent on exogenous insulin treatment (3). Statistics from the American Diabetes Association (2019) estimate that nearly 1.9 million Americans have been diagnosed with T1D, and epidemiological studies indicate that the incidence is increasing worldwide (4). The prevalence of T1D is approximately 1 in 300 in the US by 18 years of age, and some risk factors such as sex and race/ethnicity are strongly associated with the development of T1D (5). Patients with T1D have an almost 3-fold increased mortality risk compared with the general population, and this has been attributed primarily to cardiovascular diseases (6). Metabolic dysfunction and peripheral neuropathy are other diabetic-related complications that consistently cause excess morbidity and mortality in T1D patients (7).

Overall cardiometabolic benefits of exercise make it a highly recommended treatment strategy in the clinical management of T1D (8). However, previous studies in animals (9–12) and one study in T1D patients (2) indicate that diabetics may be at a heightened risk of experiencing exaggerated cardiovascular responses to exercise, which in turn, increases the risk of acute cardiovascular events. For example, a population-based follow-up study suggested that a systolic blood pressure (BP) exceeding 230 mmHg during exercise is associated with a 2.47-fold greater risk of acute myocardial infarction (13), and an increase of >19.7 mmHg per minute of exercise has a 2.3-fold increased risk of stroke (14). However, both of these studies were conducted in men without T1D and during an exercise test. To the best of our knowledge, there is no evidence showing specifically how great the cardiovascular response to exercise needs to be in T1D to increase the risk of cardiovascular events. Although the underlying mechanisms contributing to this altered cardiovascular response to exercise in T1D are not completely understood, it has been suggested that T1D impairs the autonomic control of circulation.

Appropriate autonomic adjustments are paramount to evoke hemodynamic changes during exercise to meet the metabolic demands of the working skeletal muscle. Reduced parasympathetic nerve activity to the heart contributes to exercise-induced increases in heart rate (HR), ventricular contractility, stroke volume, and thus, cardiac output (15). Subsequent increases in sympathetic outflow to the heart cause further increases in HR and ventricular contractility in an intensity-dependent manner. In addition, sympathetically-mediated vasoconstriction in non-exercising muscles and visceral organs contributes to the redistribution of cardiac output, changes in total peripheral resistance, and ultimately increases in BP (16).

Several neural mechanisms are responsible for these rapid autonomic adjustments to exercise, and precisely control the cardiovascular system through complex interactions. It is well accepted that feedforward signals from higher brain centers (i.e., central command) (17), feedback reflex mechanisms via mechanically and metabolically sensitive afferents fibers from exercising skeletal muscle (i.e., exercise pressor reflex) (18–20), and feedback from the arterial and cardiopulmonary baroreceptors (i.e., arterial and cardiopulmonary baroreflexes) (21, 22) are involved in the neural control of the circulation during exercise. The role of each mechanism and the complexity of their interaction during exercise have been reviewed in detail elsewhere (19, 23).

Emerging evidence suggests that T1D has an altered cardiovascular response to muscle contraction, in part, due to an exaggerated exercise pressor reflex (9, 10, 12, 24). In addition, there is one study describing an attenuated cardiovascular response to the isolated metabolic component of the exercise pressor reflex in T1D patients (1). Additional relevant findings about attenuated hemodynamic adjustments to exercise in T1D were summarized in a recent review (25). The integration of these mechanisms pertaining to cardiovascular control and health in T1D deserves special attention since it is likely developed at a young age and then persists throughout that person’s lifespan, requiring a lifetime of management. In this review, we will explore the hypothesis that the altered autonomic control of circulation during exercise evokes abnormal cardiovascular responses to exercise in T1D, which contributes to adverse cardiovascular health in this population. In addition, we explore the key gaps in the literature, according to our understanding, suggesting new directions for future research. To the best of our knowledge, this is the first review devoted solely to addressing the effects of T1D on the autonomic control of the circulation during exercise.

AUTONOMIC CONTROL OF THE CIRCULATION DURING EXERCISE IN HEALTHY

It has been postulated that central command (17), the exercise pressor reflex (18), and arterial and cardiopulmonary baroreflex (21, 22) are the neural mechanisms working in concert with one another to reflexively adjust the autonomic nervous system during exercise (23). Central command is generally defined as descending neural signals from the higher brain centers that simultaneously increase motor efferent drive and autonomic neural outflow (17). The term exercise pressor reflex is defined as a neural mechanism mediated by afferent fibers emanating from skeletal muscle, contributing to the cardiovascular and respiratory changes to exercise (18, 19, 26). These afferents include thinly-myelinated group III fibers which are predominantly activated by mechanical distortion within the contracting and/or stretching muscles (i.e., muscle mechanoreflex), and unmyelinated group IV fibers that are predominantly stimulated by metabolic-by-product of muscle contraction (i.e., muscle metaboreflex) (20). The arterial and cardiopulmonary baroreflex is a feedback mechanism comprised of the mechanoreceptors present in the carotid sinus bifurcation, aortic arch, and throughout the pulmonary system functioning as sensors that respond to changes in central blood volume and BP (27). During exercise, the carotid baroreflex gain is unaltered (28) but the baroreflex curve is reset to operate functionally around the exercise-induced increase in BP (29). These neural signals converge centrally within cardiovascular control areas (i.e., nucleus tractus solitaries, NTS) in the medulla oblongata resulting in alterations in autonomic outflow to the heart and blood vessels leading to changes in BP appropriate for the intensity and modality of the exercise.

The net result of the interaction between these neural mechanisms is an increase in sympathetic outflow and a decrease in parasympathetic activity during exercise. Central command and group III afferent fibers contribute to the early HR response to exercise principally mediated by the withdrawal of cardiac parasympathetic activity (30), whereas group IV afferent fibers evoke a reflexive increase in sympathetic nerve activity and BP during steady-state exercise (18). In addition, arterial baroreflex resetting during exercise has been demonstrated to occur due to the interaction between central command (31) and exercise pressor reflex (29), and it appears to be crucial to the initiation of the autonomic responses to exercise and subsequent hemodynamic and cardiovascular adjustments.

AUTONOMIC CONTROL OF THE CIRCULATION IN TYPE 1 DIABETES

Autonomic dysfunctions at rest

Previous studies have shown that individuals with T1D have reduced (32) or similar (33) resting muscle sympathetic nerve activity compared to individuals without T1D (i.e., healthy control participants). Despite the absence of sympathetic overactivity and reduced catecholamine levels at rest (34), individuals with T1D present a higher central systolic BP with compromised myocardial perfusion (35). Additionally, morphologic and morphometric dysfunctions in the afferent arm of the baroreflex (i.e., aortic depressor nerve) were found in T1D rats (36). However, the effect of T1D in arterial baroreflex control has still not been well characterized. Several (37–39), but not all (40), studies indicate that T1D attenuates baroreflex sensitivity at rest and suggest that this is likely related to the progression of the disease (39). With autonomic dysfunction at rest, it is reasonable to suggest that T1D has abnormal cardiovascular responses to exercise due to altered neural control of circulation.

Neural mechanisms and the altered cardiovascular responses to exercise

T1D patients have lower exercise capacity and display alterations in cardiac function during exercise (41, 42). In addition, the BP response to muscle contraction is exaggerated in T1D (2, 9, 11, 12, 24). Matteucci et al. (2) found that T1D patients achieved a higher maximal exercise BP with a similar workload in a cycle ergometer test when compared to control subjects. Previous studies also demonstrated that untreated T1D rats have an exaggerated BP and cardioaccelerator response to static (24) and intermittent (10, 11) hindlimb contractions. The determining the underlying mechanisms for an augmented BP response to exercise in T1D is an intriguing area of research, and alterations in the neural control of the cardiovascular system during exercise have been largely implicated.

Our understanding of the neural mechanisms contributing to these altered cardiovascular responses to exercise is incomplete with limited studies conducted in T1D humans. For example, reduced plasma norepinephrine levels have been observed during intense exercise in T1D individuals (34), but whether the sympathetic outflow to the active skeletal muscles (i.e., muscle sympathetic nerve activity) is altered during exercise remains unknown. To the best of our knowledge, there are also no studies investigating the effect of T1D on central command, arterial and cardiopulmonary baroreflex contributing to the altered cardiovascular responses to muscle contraction. On the other hand, the available evidence suggests the exercise pressor reflex plays a significant role in mediating the exaggerated BP response to exercise in T1D (9, 10, 12, 24) (Figure 1).

Figure 1:

A schematic figure of the exercise pressor reflex mediating the altered cardiovascular responses to exercise in type 1 diabetes (T1D). Emerging evidence in animals supports the hypothesis that T1D presents an exaggerated exercise pressor reflex. Briefly, contracting skeletal muscles evoke group III and IV primary afferent neurons which project to the dorsal horn of the spinal cord where several neurotransmitters and neuropeptides are released. Subsequently, the afferent nerve traffic is complete into the cardiovascular control areas within the brain stem (i.e., nucleus tractus solitaries, NTS). The central processing of skeletal muscle somatosensory signals is very complex; however, these signals are known to modulate the autonomic outflow leading to changes in the cardiovascular system. In general, a withdrawal of parasympathetic nerve activity to the heart (green projections), and an increase in sympathetic nerve activity to the heart and blood vessels (yellow projections), evokes changes in heart rate, stroke volume, cardiac output, and total peripheral resistance, ultimately increasing arterial blood pressure. (+++) represents an exaggerated increase in arterial blood pressure due to an over activation of the exercise pressor reflex in T1D. Black dot located in the brainstem represents the NTS. DRG, dorsal root ganglion; PSNA, parasympathetic nerve activity; SNA, sympathetic nerve activity. Created with BioRender.com.

Exercise Pressor Reflex

The exaggerated BP response to exercise in T1D is mediated, at least in part, by an overactive exercise pressor reflex (9, 10, 12, 24). Although this neural mechanism might not be affected by acute changes in glucose level (43), hyperglycemia has been shown to alter the responsiveness of thin skeletal muscle afferent fibers in type 2 diabetes rats via protein kinase C (PKC) signaling pathway, which might contribute to the abnormally enhanced BP response to exercise in diabetes (44). However, further studies are needed to test whether these findings can be extrapolated to T1D. In contrast, a previous study from our laboratory demonstrated that the exaggerated pressor responses to exercise in T1D are related to the duration of the disease (24). In this study, diabetes was induced by streptozotocin (STZ) injections (a toxin that causes degeneration in pancreatic β-cells) and the pressor and cardioaccelerator responses to isometric contractions of the hindlimb muscles were recorded at three different time points of the disease (1, 3, and 6 weeks after injections). They found that the exercise pressor reflex was exaggerated in T1D rats at the early stage (i.e., 1 and 3 weeks after diabetes induction), whereas the reflex was attenuated in the late stage (i.e., 6 weeks after diabetes induction) (Figure 2). This previous study did not attempt to identify the underlying mechanisms causing reflex dysfunction over the course of diabetes. However, one possibility includes an initial sensitization of group III and IV peripheral nerve endings and desensitization with the progression of the disease due to a neuropathy overlay.

Figure 2:

Peak changes (∆) in mean arterial pressure (MAP) during static contraction of the hindlimb muscles in control (CLT) and STZ-induced type 1 diabetes rats 1, 3, and 6 weeks after injection. Baseline blood pressures are reported for each group within bars. Values are means ± SE. *significantly greater responses than CLT group (p<0.05). (Reproduced from (24).)

Whether the exercise pressor reflex also plays a role in the exaggerated BP response to dynamic muscle contraction in T1D was uncertain. This is important because dynamic exercise is widely included in the exercise prescription as a treatment in the management of T1D (8). Grotle, et al. (2020) recently tested the effect of T1D on the exercise pressor reflex evoked by simulated dynamic muscle contractions (i.e., intermittent muscle contractions). They found that STZ-induced diabetic rats presented a higher peak pressor, sympathetic nerve activity, and cardioaccelerator responses to intermittent contraction compared with healthy control rats (Figure 3) (10). These results extend the previous findings showing an exaggerated pressor response to static muscle contraction in T1D rats (24) and clearly suggest that T1D exaggerates exercise pressor reflex regardless the type of contraction (i.e., dynamic or static).

Figure 3:

One representative raw data tracing from STZ-induced type 1 diabetes (T1D) rat (left) and healthy control rat (right). Exercise pressor reflex induced by intermittent muscle contractions evokes an exaggerated increase in renal sympathetic nerve activity, blood pressure, and heart rate in T1D when compared with healthy control animals. BP, blood pressure. HR, heart rate. MAP, mean arterial pressure. RSNA, renal sympathetic nerve activity. The top image of RSNA is an unfiltered trace, while the bottom image is the RSNA trace after being rectified, smoothed, and filtered. Reproduced from (10).

MECHANISMS UNDERLYING THE EXAGGERATED EXERCISE PRESSOR REFLEX IN TYPE 1 DIABETES

Metabolic component of the exercise pressor reflex

The metabolic component of the exercise pressor reflex is mediated mainly by group IV afferent fibers during muscle contraction (20). Few studies have investigated the effects of T1D on the metaboreflex, and findings from those studies are not consistent. One study found that T1D patients have a blunted mean BP response during muscle metaboreflex activation compared to control participants (1). In this study, the muscle metaboreflex was experimentally isolated using post-exercise muscle ischemia (PEMI), which is a well-recognized maneuver to maintain exercise-increased sympathetic activity and BP. These findings suggested that the blunted BP response to metaboreflex is due to an impairment of the capacity to elevate the sympathetic tone and consequently increase systemic vascular resistance in T1D patients. Interestingly, Ishizawa, et al. (2020) found that BP and sympathetic responses during metaboreflex activation via capsaicin injection were exaggerated in T1D rats (12).

There are likely several reasons for these discrepancies including the method for measuring sympathetic activity, the homogeneity of samples pertaining specifically to disease duration, and the treatment of high blood glucose with insulin. Roberto et al. (2012) found that T1D patients had a reduced capacity to increase systemic vascular resistance during metaboreflex activation, suggesting that there is a reduced capacity to increase sympathetic tone (1). Importantly, however, this study did not directly measure peripheral sympathetic outflow (i.e., MSNA) or noradrenaline spillover during exercise. When Ishizawa et al. (2020) did directly measure renal sympathetic nerve activity in T1D rats during metaboreflex activation, they found that sympathetic activity was exaggerated compared to healthy controls, suggesting that peripheral sympathetic outflow is not reduced in T1D (12). However, further studies are needed in T1D humans to determine how MSNA is affected by the disease. Additionally, the true onset of the disease is rarely if ever known in T1D patients, whereas the duration of disease is known and controlled in T1D rats. It is likely that the effects of T1D on the metaboreflex could be masked or skewed depending on the disease duration for each T1D patient, as previous findings indicate temporal effects of T1D on the exercise pressor reflex (24). Moreover, T1D patients participating in clinical studies likely follow a stable insulin regimen whereas T1D rats did not. Although the effects of insulin treatment in T1D patients on the blood pressure and sympathetic responses to exercise are not known, studies suggest that insulin itself does affect the autonomic control of circulation during exercise (45). Findings from studies in both T1D patients and T1D rats suggest that T1D presents an autonomic dysfunction during exercise and that it is, in part, mediated by the metaboreflex, and that the effects of T1D may differ depending on the homogeneity of the sample.

Mechanical component of the exercise pressor reflex

The mechanically sensitive component of the exercise pressor reflex is altered in T1D rats (9, 12). Grotle, et al. (2019) demonstrated that STZ-induced diabetes in decerebrate rats causes an exaggerated pressor and cardioaccelerator response to 30s of tendon stretch (9) (Figure 4). In addition, action potential responses to mechanical stimulation in thin skeletal muscle afferents in vitro are greater in group IV fibers from T1D rats compared to healthy controls (12). Although causality was not directly verified in this previous study, it was also found that T1D rats present enhanced sympathetic and BP responses to mechanoreflex activation (12), aligning with the previous findings from our laboratory (9). It is important to note that the magnitude of the pressor response evoked by tendon stretch may not be as large in humans as it is in rats; however, further studies are needed to determine the animal to human translation of the mechanoreflex. Overall, these results suggest that an exaggerated response to exercise in T1D might be explained by an overactivation of the mechanically sensitive component of the exercise pressor reflex. In addition, the hyper-responsiveness to mechanical stimuli in group IV fibers suggests that the exaggerated muscle mechanoreflex in T1D is associated with sensitization of skeletal muscle afferent fibers.

Figure 4:

Original traces from representative healthy control rat (left) and STZ-induced type 1 diabetes (T1D) rat (right) showing exaggerated blood pressure and heart rate response to tendon stretch. BP, blood pressure. HR, heart rate. MAP, mean arterial pressure. Reproduced from (9).

Sensitization of skeletal muscle afferents

Peripheral neuropathy is one of the most prevalent chronic complications of diabetes with diverse clinical manifestations (e.g., pain, hyperalgesia, allodynia) (7). Both myelinated and unmyelinated afferents have been implicated in mediating diabetic neuropathic pain (46). Given the activity of the same type of afferents evoking the exercise pressor reflex is likely related to sensory neuropathy (20, 47), it is reasonable to suggest that the mechanism causing sensitization of groups III and IV afferent fibers evoking pain might also elicit an exaggerated exercise pressor reflex in T1D. Ishizawa, et al. (2020) clearly demonstrated that group IV muscle afferents in T1D rats have a greater response magnitude to mechanical stimuli than control animals, although no difference was found for the mechanical threshold (12). Other studies have reported similar findings in C-fibers from skin showing a marked hyper-responsiveness to mechanical stimuli in a rat model of painful diabetic neuropathy (48, 49). Spontaneous hyperactivity of group III and IV afferents was also found in diabetic animals in the absence of any intentional experimental stimuli (12, 49). Therefore, it was suggested that this hyperactivity at rest could potentially prime these afferents for greater activity during mechanical and chemical stimulation and that it may contribute to the exaggerated exercise pressor reflex observed in T1D.

Piezo Channels

Several studies have suggested that an increased sensitization of muscle afferents causing pain might be mediated by alterations in protein expressions of nociceptive channels and receptors (50). One example is the recently discovered Piezo channels which are a family of mechanically-activated calcium channels expressed in a wide range of tissues and organs (51). Specifically, Piezo 2 channels are localized in peripheral endings of sensory neurons and their dorsal root ganglion (DRG) and play an important role in touch and pain sensation (e.g., mechanical allodynia) (51). A previous study found that injecting a non-selective inhibitor of Piezo 2 channels (Grammostola mechanotoxin 4 - GsMTx-4) into the arterial supply of the hindlimb reduced pressor and sympathetic responses to muscle contraction and tendon stretch in healthy rats (52). These findings indicate that mechanically-sensitive Piezo channels also contribute to the activation of the mechanical component of the exercise pressor reflex (52).

Whether Piezo channels play a role in the exaggerated muscle mechanoreflex in T1D was unknown. To address this gap, a study from our laboratory tested the cardiovascular response to tendon stretch in T1D and healthy control rats before and after injecting GsMTx-4 into the arterial supply of the skeletal muscle (9). Injection of GsMTx-4 into the arterial supply of the hindlimb significantly attenuated the peak BP response to tendon stretch in T1D rats but not in control animals (Figure 5).

Figure 5:

Original traces from a representative STZ-induced type 1 diabetes (T1D) rat showing exaggerated blood pressure and heart rate response to tendon stretch before (left) GsMTx-4 injection. The peak pressor response to tendon stretch was attenuated after the blockade (right). BP, blood pressure. HR, heart rate. MAP, mean arterial pressure. Reproduced from (9).

Recently, Grotle et al. (2021) aimed to determine the role played by Piezo channels in exaggerating the exercise pressor reflex in T1D rats using dynamic muscle contraction, which constitutes a more complex physiological stimulus than stretch (11). Local injection of GsMTx-4 attenuated the exaggerated early onset pressor and the pressor response over time in STZ-induced T1D rats, suggesting that blocking Piezo channels is effective in ameliorating the exaggerated exercise pressor reflex evoked by intermittent muscle contraction (11). The underlying mechanism for the sustained blocking effect of GxMTx-4 on the pressor response to muscle contraction in T1D is not completely understood. For example, additional studies are necessary to investigate whether inhibition of mechanically sensitive Piezo channels also attenuates the sympathetic nerve responses to exercise in T1D. Collectively, Piezo channels were found to play a role in exaggerating the increase in BP in response to stretch (9) and dynamic contraction (11) in T1D rat. These findings strongly suggest that Piezo channels could be a potential therapeutic target to normalize the exercise pressor reflex in T1D. The potential role of Piezo channels in exaggerating BP response to exercise in T1D is schematically represented in Figure 6.

Figure 6:

Schematic illustration of the potential role of Piezo channels in exaggerating blood pressure response to exercise in type 1 diabetes (T1D). The exercise is represented by a dynamic contraction in rats (i.e., exercise wheel) because it is a more complex physiological stimulus than stretch, which involves both skeletal muscles lengthening and shortening. Dynamic exercise evokes an exaggerated sympathetic nerve activity and blood pressure response in T1D. One possible mechanism for these altered cardiovascular responses to exercise in T1D is the abnormal activation of the mechanically sensitive component of the exercise pressor reflex (i.e., mechanoreflex) and the sensitization of group III and IV muscle afferent fibers. Intra-arterial injection of GsMTx-4 (non-selective inhibitor of Piezo 2 mechanosensory channels) reduced the exaggerated pressor response to stretch and dynamic muscle contraction in T1D rats. However, whether inhibition of mechanically sensitive Piezo channels also attenuates the sympathetic nerve responses to exercise in T1D is unknown. Thus, it has been suggested that Piezo channels play a role in the exaggerated increase in blood pressure to exercise in T1D, and also might be a therapeutic target to normalize the exercise pressor reflex in diabetes. Multiple arrows represent an exaggerated increase in sympathetic nerve activity, blood pressure, and mechanoreflex activation in T1D rats when compared to healthy control animals. GsMTx-4, Grammostola mechanotoxin 4. Created with BioRender.com.

Future directions

T1D presents an exaggerated BP response to exercise (2, 24) and it is mediated, in part, by an overactive exercise pressor reflex (9–12). Although there are convincing evidence implicating alterations in the muscle metaboreflex (1), mechanoreflex (9), skeletal muscle afferent sensitivity (12), and mechano-gated Piezo channels (9, 11), further studies are needed to better understand the precise mechanisms leading to these alterations.

The limited studies, especially in humans, on the effects of T1D on the neural control of the circulation impede a complete understanding of the altered cardiovascular responses to exercise. To date, no studies have explored the effects of T1D on central command and/or baroreflex mechanisms contributing to the cardiovascular changes during muscle contraction. These studies, however, are imperative to the comprehensive understanding of how T1D affects the autonomic control of circulation during exercise.

The precise mechanism mediating the exaggerated pressor reflex in T1D is not fully understood; however, Piezo channels likely play an important role (9). Of notable interest, studies have shown that GsMTx-4 is able to attenuate the mechanoreflex in healthy (52), peripheral artery disease (simulated) (53), and T1D rats (9, 11). From a translational perspective, however, future research is required to determine the potential role of Piezo channels as a therapeutic target to ameliorate exaggerated cardiovascular response to muscle contraction in diabetes.

Identifying risk factors for T1D patients is also an area that needs to be explored. More than 85% of all diabetes cases are in young <20 years of age worldwide with peaks between the ages of 10–14 years during puberty (5). Recent observation demonstrated an exaggerated pressor reflex in T1D rats at the early stage of the disease, but not later (24). However, whether this temporal effect of T1D on exercise pressor reflex can be extrapolated to humans is unknown. Thus, it is suggested that researchers dive deeper into the effects of T1D on cardiovascular responses to exercise in humans using mechanistic studies and controlling for varying stages of the disease. Rates of the prevalence of T1D are higher in non-Hispanic white youth individuals and greater in females as compared to males in the US (5). Moreover, further investigation is needed to examine if the effects of T1D on the exercise pressor reflex differ by sex.

CONCLUSIONS

T1D patients have heightened risk for adverse cardiac events and stroke during exercise or daily physical activities. Our work and others support the hypothesis that the altered autonomic control of circulation during exercise evokes abnormal cardiovascular responses to exercise in T1D, which contributes to adverse cardiovascular health in this population. This review presents the current understanding of the mechanisms contributing to the altered cardiovascular responses to exercise in T1D. Exaggerated BP response to exercise in T1D are mediated by an augmented exercise pressor reflex, and possible mechanisms for this altered reflex include an augmented muscle mechanoreflex, sensitization of muscle afferent fibers and mechano-gated Piezo channels. Moreover, we identified several gaps in the literature where future studies are urgently needed to advance the knowledge of how T1D affects the neural control of the circulation contributing to the altered cardiovascular responses to exercise.

KEY POINTS.

• Type 1 diabetes (T1D) negatively affects the cardiovascular response to exercise, in part, due to alterations in the neural control of the circulation.

• The exercise pressor reflex is involved in mediating the altered cardiovascular response to exercise in T1D and its expression appears to change with disease duration, where an exaggerated reflex is seen in the early stage of the disease but not later.

• Emerging data suggest that the mechanically sensitive arm of the reflex (i.e., mechanoreflex) contributes to the exaggerated blood pressure response to exercise in T1D and inhibition of mechano-gated channels reduces or normalizes the reflex.

• Given that exercise is a highly recommended treatment strategy in the clinical management of diabetes, understanding the mechanisms contributing to this altered cardiovascular response is urgently needed.