The shear complexity of insulin‐stimulated vasodilatation

Insulin‐stimulated blood flow is critical to delivery and disposal of glucose in skeletal muscle. The vasodilatory action of insulin is mediated largely through activation of endothelial nitric oxide synthase (eNOS) by Akt phosphorylation. However, insulin also activates Ras/mitogen‐activated protein kinase (MAPK) resulting in the release of the potent vasoconstrictor peptide endothelin‐1 (Eringa et al. 2007). Thus, the vasoactive effects of insulin depend on a delicate balance between these divergent vasomotor signalling pathways.

It is well understood that acute and chronic aerobic exercise sensitizes the vasodilatory action of insulin. However, the mechanisms by which this vascular insulin sensitization occurs remain unclear due to the challenges associated with isolating the various physiological systems (cardiovascular, thermoregulatory, locomotor, etc.) altered by exercise. One of the most profound responses to aerobic exercise is the more than 10‐fold increase in blood flow to contracting skeletal muscle (Andersen & Saltin, 1985). This hyperaemic response increases frictional drag (i.e. shear stress) of red blood cells along the innermost layers of the vessel wall in both large conducting vessels and the microvasculature, and has been considered one of the primary signals by which chronic exercise training exerts beneficial changes on the vascular phenotype. However, the effects of vascular shear stress on insulin‐stimulated blood flow, independent of skeletal muscle contraction, were unknown until recently.

In the current issue of The Journal of Physiology, Walsh and colleagues (2019) advance our understanding of the isolated effects of vascular shear stress on insulin‐stimulated blood flow and associated vasoactive signalling mechanisms. In a series of complementary experiments using cultured endothelial cells, isolated skeletal muscle arterioles from swine, and humans exposed to unilateral lower leg heating, they demonstrated that acutely elevating shear stress improves insulin‐stimulated vasodilatation, the results of which appear to be mediated, in part, by shifting the vasoactive balance in favour of eNOS activation (i.e. greater eNOS/MAPK ratio). These findings highlight the important role shear stress has in modifying vascular insulin sensitivity and, ultimately, in promoting vascular and metabolic health.

The work by Walsh and colleagues represents an important investigative step in our comprehension of the interaction between insulin and vasodilator function. However, several intriguing questions remain unanswered. For example, it remains unknown if augmented shear stress (via thermal hyperaemia) also increases insulin‐stimulated skeletal muscle glucose disposal during a hyperinsulinaemic–euglycaemic clamp. Indeed, establishing if glucose uptake is limited by blood supply, by the skeletal muscle itself, or a combination thereof, requires follow‐up invasive studies. Moreover, heat stress alone increases eNOS activity and improves agonist‐stimulated nitric oxide release (Harris et al. 2003). In addition, despite a maintenance of body core temperature during unilateral lower leg hot water immersion, the temperature of skeletal muscle increases upwards of 39°C and can remain elevated for at least 30 min following acute exposure (Romero et al. 2017). Thus, tissue hyperthermia could augment eNOS activity independent of its effects on shear stress. Interestingly, the temperature profile of skeletal muscle exposed to lower leg hot water immersion closely resembles that of aerobic exercise, suggesting that both tissue hyperthermia and shear stress could contribute to the increased insulin‐stimulated vasodilatory response that occurs following exercise.

In conclusion, the findings of Walsh et al. contribute to our understanding of the effects of vascular shear stress on insulin‐stimulated vasodilatation. Future studies should determine if augmenting shear stress by thermal hyperaemia can increase the eNOS/MAPK balance and improve glucose uptake in individuals with insulin resistance or type 2 diabetes who also have a diminished bioavailability of endothelial nitric oxide. A hot bath taken before a meal, common in Japanese culture, could therefore improve glucose uptake through greater insulin‐stimulated vasodilatation in patients with type 2 diabetes.

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Competing interests

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