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.

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.

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).)

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).

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).

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).

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.