- Insulin resistance in the skeletal muscle and brain vasculatures represents a unifying pathology linking metabolic, neuro-, and vascular diseases.
- Routine physical activity (PA) is an effective therapeutic approach to optimize vascular insulin signaling in the skeletal muscle and brain.
- PA that involves a large skeletal muscle mass and modulates intensity to recruit more muscle fibers within each muscle, as well as requires a significant central neural recruitment, will maximize vascular adaptations that promote vascular insulin sensitivity in the skeletal muscle and brain.
- Future research should focus on whether vasometabolic and vasoneural treatment outcomes in preclinical and clinical populations with insulin resistance are improved when such mechanistic concepts are integrated into prescriptive-based PA interventions.
In 1939, Abramson et al. (1) examined the vascular actions of insulin shock therapy and reported that insulin-induced hypoglycemia resulted in increased peripheral limb blood flow in patients with schizophrenia. Shortly thereafter, Ferris et al. (2) and later Porta et al. (3) demonstrated that insulin-induced hypoglycemia either had no effect or a small vasodilatory effect on intracranial/cerebral blood flow in patients with schizophrenia. Granted these initial observations do not reflect nonpathological conditions, these findings highlight the earliest direct evidence of insulin-stimulated vasodilation in the peripheral vasculature.
Since then, researchers have validated and extended upon earlier findings by demonstrating that physiological and pharmacological doses of exogenous insulin stimulate peripheral vasodilation during euglycemia (4–8) and by providing evidence that endogenous insulin also stimulates vasodilation (9–12). Notably, the magnitude of insulin-stimulated peripheral vasodilation appears blunted in the setting of various insulin-resistant states in humans (i.e., obesity and type 2 diabetes (T2D)) (9,11,13–15) and in experimental animal models (diet-induced and genetic models of T2D as well as insulin-treated T1D) (16–24). There is growing consensus that insulin-stimulated vasodilation is a physiologically relevant phenomenon and depressed insulin-stimulated vasodilation serves as a hallmark of vascular dysfunction (21,25–28). Being physically active or participating in structured exercise training can improve insulin-stimulated vasodilation in the setting of health and disease, with such improvements occurring most readily in tissue regions that undergo a relative increase in activity during the transition from rest to exercise (21,28). Herein, we address the hypothesis that exercise-induced improvements in vascular insulin sensitivity occur in a region-specific manner within the skeletal muscle and cerebral vasculatures and in relation to local increases in blood flow during exercise (Fig. 1).
Brief Overview of Endothelial Insulin Signaling
Available evidence indicates the peripheral hemodynamic effects of insulin are mediated by a combination of neurohumoral (6,8,29–33) and endothelial vasodilator and vasoconstrictor signals (19,21,25,27,28,34–36). This review will focus primarily on the effects of insulin on the vascular endothelium and endothelial mechanisms through which exercise training exerts therapeutic benefits on vascular insulin sensitivity.
At the molecular level, insulin binds to endothelial insulin receptor substrate-1 (IRS-1), which activates two primary signaling cascades, the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (Akt)/nitric oxide (NO) pathway and the Ras/mitogen-activated protein kinase (MAPK)/endothelin-1 (ET-1) pathway (25,36) (Fig. 2). Activation of the former pathway induces anti-atherogenic and vasodilator signaling, whereas activation of the latter pathway induces pro-atherogenic and vasoconstrictor signaling. Under healthy circumstances (in many vascular beds/arteries), the net effect of insulin administration is a NO-dependent vasodilation suggesting activation of the PI3K/Akt/NO pathway predominates (25,27,36).
Selective vascular insulin resistance refers to a shift in endothelial insulin signaling reflected by decreased IRS-1–induced activation of PI3K/Akt/NO with no change or increased activation of MAPK/ET-1 (25,36). Thus, the imbalance promotes pro-atherogenic and ET-1–dependent vasoconstrictor signaling (16,17). Current evidence suggests that selective vascular insulin resistance may occur early in the development of metabolic derangement (11,18) and is implicated in decreased elasticity and progression of atherosclerosis in conduit arteries, impaired blood flow control, reduced capillary perfusion and nutrient delivery, and limited transendothelial nutrient/insulin transport within specified tissues/organs (21,25–28). The underlying causes of vascular insulin resistance are likely multifactorial. In the setting of insulin deficiency or insulin resistance, lipotoxicity, glucotoxicity, inflammation, and oxidative stress may all serve a role in directly and indirectly impairing insulin signaling (25,36,37). For example, the aforementioned metabolic perturbations are implicated in elevating endothelial cell diacylglycerol that activates protein kinase C isoforms and subsequently reduces tyrosine phosphorylation of IRS-1, decreasing the downstream activation of the Akt and NO pathway. Furthermore, hyperinsulinemia also may enhance MAPK activation directly, which can inhibit subsequent IRS-1 activation and downstream signaling (25,36). Indeed, published animal work shows obesity/T2D or palmitic acid-induced deficits in insulin-stimulated vasodilation in isolated arterioles can be reversed acutely with inhibition of protein kinase C beta (18) or theta (38) as well as ET-1A receptor inhibition (19).
Routine exercise consistently enhances vascular insulin sensitivity (for review, see (21,28)). Initial cross-sectional data reveal insulin-stimulated vasodilation in the lower limb is greater in endurance-trained athletes compared with otherwise healthy sedentary controls (39). In healthy control rodents and rodents with insulin-treated type 1 diabetes, improvements in insulin-stimulated vasodilation after endurance training are associated with increases in endothelial NO synthase protein (20). Of note, in the latter study, insulin treatment was adjusted biweekly to equalize hyperglycemia/blood glucose concentrations for all rats with type 1 diabetes, highlighting that the therapeutic effect of endurance training occurred independent of chronic improvements in hyperglycemia. Furthermore, when comparing wheel-running with metformin or food restriction in obese/T2D rodents, although all treatments exerted similar beneficial effects on body composition and HbA1c, only wheel-running improved insulin-induced dilation in isolated skeletal muscle arterioles (22,40,41). Collectively, these data suggest that the beneficial effect of regular exercise is conferred independent of fat loss and enhanced glycemic control and may be related to local or systemic signals subjected to the vasculature during exercise (Fig. 1). To better understand the mechanisms responsible for the therapeutic benefits of acute and chronic exercise, we now discuss some of the signals experienced by the vasculature in response to exercise as well as some key chronic vascular adaptations to exercise training.
EXERCISE AND VASCULAR SHEAR STRESS — SKELETALMUSCLE
Generally, the skeletal muscle is grouped into three fiber types classified according to both their contractile and metabolic properties (42): slow-twitch oxidative (SO); fast-twitch, glycolytic (FG); and fast-twitch, oxidative, glycolytic (FOG). Skeletal muscle blood flow increases with exercise intensity and is distributed heterogeneously within and among skeletal muscles in relation to fiber-type composition and recruitment during exercise (43–52). During the transition from rest to maximal exercise, skeletal muscle blood flow may increase up to a 10-fold and can reach up to 300–400 mL·100 g−1·min−1 (45,53,54). Of interest, the vasculature supplying skeletal muscle fibers that undergo a relative increase in activity during exercise may experience increased vascular shear stress (i.e., the frictional force of blood acting against the lumen wall) during exercise (45,53).
Vascular shear stress causes the deformation of a population of mechanoreceptors that appear to be coupled to glycocalyx, located on the apical surface of endothelial cells. This in turn activates the mechanosensitive PI3K/Akt/NO signaling pathway (53,55) (Fig. 2). It is currently believed that acute or repeated exposure to exercise-induced increases in vascular shear stress, and by extension acute or repeated exposure to enhanced endothelial PI3K/Akt/NO signaling, is involved in changes in vasomotor control (i.e., improved endothelial-dependent vasodilation) (23,56,57) and vascular remodeling (reflected by an increase in the number, diameter, and density of arterioles and capillaries) in active skeletal muscle (45,49,53,58–71). It is important to note that available evidence, predominantly from animals, suggests that exercise training modulates vascular function and structure of arteries/arterioles in spatially distinct (45,61,71–84), intensity-dependent manner (23,45,58–62,69) and adaptations tend to be concentrated in the muscle tissue that experiences the greatest relative increase in activity during training sessions (58–60,70,85–91). For example, both moderate-intensity continuous endurance and high-intensity interval training increase capillary density in animals (69) and humans (21,63,64); however, work in animals suggests that such increases in capillary density after training occur predominantly in SO versus FOG/FG muscle fibers, respectively (21,49,69,89,90). This phenomenon is perhaps not as clear in humans, as recent work from Cocks et al. (63) shows that although the increase in capillary density in the vastus lateralis of obese men tends to be greater after moderate-intensity continuous (40–60 min·d−1 at 65% V˙O2peak, 5 d·wk−1, for 4 wk) than high-intensity interval sprint (4–6× repeat Wingate tests, interspersed with 4.5 min rest, 5 d·wk−1, for 4 wk) cycling training (19% vs 6%, respectively), training-induced increases in capillary-to-fiber ratio or capillary contacts per fiber were similar between training regimens and not fiber-type specific. Of note, these results may be influenced by the skeletal muscle examined and muscle fibers sampled between groups as well as pre-/posttraining, as the vastus lateralis contains SO, FOG, and FG fibers and the depth and fiber composition of the muscle biopsy may impact the results (92,93).
Acute and Chronic Exercise — Vascular Insulin Signaling
In hallmark studies, Dela et al. (94,95) examined the effect of either one-legged cycling (30 min·d−1 at 70% V˙O2peak, 6 d·wk−1, for 10 wk) (94) or resistance exercise training (leg press, knee extension, and hamstring curls; 3–4 sets of 8–12 repetitions at ~70%–80% 1 repetition-max, performed 3 d·wk−1, for 6 wk) (95) on lower limb blood flow responses during a euglycemic hyperinsulinemic clamp in patients with T2D. They found that insulin-mediated vasodilation and glucose clearance were greater in the trained limb, but not in the untrained limb, from pre- to posttraining. They reported similar findings in young and old men after the same one-legged cycling program (96), and more recently, similar findings were documented after a single bout of one-legged cycling exercise (~50% peak workload for 60 min, with 3 × 5 min intervals at 100% peak workload) (97). Eskelinen et al. (98) examined insulin-stimulated glucose uptake in the upper and lower limbs after either moderate-intensity endurance (40–60 min·d−1 at 60% V˙O2peak, 3 d·wk−1, for 2 wk) or high-intensity interval sprint (4–6× repeat Wingate tests, 3 d·wk−1, for 2 wk) cycling training and reported that training-induced improvements in skeletal muscle glucose uptake were restricted to the lower limbs (i.e., active skeletal muscle). Furthermore, although both training programs improved glucose uptake in the vastus lateralis, intermedius, and medialis, only interval sprint training increased glucose uptake in the rectus femoris (98). The authors speculated that the latter observation related to different muscle activation patterns during exercise and the inability of moderate-intensity endurance exercise to activate the rectus femoris (see Table). The relation between skeletal muscle fiber recruitment during exercise and vascular insulin sensitivity is further exemplified by work in obese rats with T2D that shows that training-induced improvements in insulin-mediated vasodilation of resistance arteries after moderate-intensity continuous and high-intensity interval training are most robust in red and white portions of the gastrocnemius muscle, respectively (23,41). Taken together, these findings highlight the following important concepts: 1) the beneficial effects of exercise training on insulin sensitivity are related to improved insulin-stimulated vasodilation; 2) improvements in insulin-mediated vasodilation occur in relation to skeletal muscle activation and skeletal muscle fiber recruitment within each muscle during exercise (i.e., in relation to the exercise hyperemic response); and 3) such improvements can be conferred with acute and chronic exercise as well as independently of long-term improvements in body composition or metabolic status.
Shear Stress and Insulin Signaling — Crossing Paths
Vascular shear stress and insulin-stimulated vasodilation are both reliant on activation of the PI3K/Akt/NO pathway (36,55) (Fig. 2). Of note, the vascular insulin-sensitizing effect of exercise seems to be restricted to portions of the vasculature that undergo a relative increase in blood flow during exercise (23,41,94,97,99). Furthermore, recent human work reveals that improvements in insulin-stimulated lower limb microvascular perfusion and leg glucose uptake 4 h after one-legged cycling exercise are blunted (to nonexercised levels) with NO inhibition administered during the insulin clamp (97). Given that exercise-related improvements in insulin signaling can occur independent of longstanding changes in metabolic status, are localized to active skeletal muscle, and blunted by NO inhibition, this raises the possibility that vascular shear stress primes endothelial cells to become more insulin sensitive and enhance insulin-stimulated NO signaling. In support of this view, recently published work established that the insulin-sensitizing effects of vascular shear stress are independent of skeletal muscle contraction (100). First, it was demonstrated in cultured human aortic endothelial cells that compared with cells exposed to low shear conditions (3 dynes·cm−2), those exposed to 1 h of increased shear stress (20 dynes·cm−2) subsequently exhibited a shift in insulin signaling characterized by an increased activation of endothelial NO synthase relative to MAPK. Second, it was demonstrated in isolated porcine skeletal muscle resistance arteries that compared with arteries kept under no-flow conditions, those exposed to 1 h of increased shear stress (20 dynes·cm−2) subsequently displayed enhanced insulin-stimulated vasodilation. Previous shear stress only augmented insulin-stimulated vasodilation and not endothelium-independent vasodilation, suggesting that the effect is conferred through an endothelial-dependent mechanism. Lastly, the translational relevance of these in vitro findings was validated by demonstrating that compared with the control leg, single leg heating resulting in increased blood flow, and likely attendant increase in shear stress, caused a subsequent augment in popliteal artery blood flow and calf microvascular perfusion in response to a systemic infusion of insulin. Collectively, these findings support the hypothesis that vascular shear stress may be a primary mechanism through which exercise enhances vascular insulin sensitivity.
Other vascular adaptations likely responsible for the effects of exercise training on insulin-stimulated glucose/insulin delivery and transendothelial insulin transport are increases in microvascular perfusion/capillary recruitment (97,101) and increased capillary volume or density (63,102–104). In this regard, an increased capillary density after moderate continuous aerobic training (45 min·d−1 at 75% V˙O2max, 3 d·wk−1, for 6 months) independently increases insulin sensitivity in older adults (102). Indeed, enhanced vascular density and volume after aerobic training (21) provide greater potential for delivery of nutrients and insulin to the target organ (Fig. 1).
Exercise and Endothelial Insulin Signaling in the Brain
In contrast to the skeletal muscle, global brain blood flow increases only modestly (~0%–20%) during incremental exercise until ~60% V˙O2max and may remain unchanged or decrease at higher intensities (likely the result of decreasing PaCO2 values). However, evidence from miniature swine, dogs, ponies, and humans reveals that exercise increases regional brain blood flow in a structurally specific and intensity-dependent manner (up to ~70% above basal values within the most active structures (45,53,105)). Furthermore, recent human data indicate cerebral blood flow may increase in the recovery period immediately after high-intensity exercise (106). Brain regions recruited at the onset and during sustained exercise include those involved in central command, motor execution, equilibrium, cardiorespiration, auditory, olfactory, and visual regions (45,53). Although much less established, work in humans and animals indicates cerebrovascular adaptations to exercise training may be both structurally and intensity-dependent (53,107,108). With regards to the effects of exercise on vascular insulin signaling in the cerebrovasculature, recent work in obese rats with T2D reveals that increased physical activity (wheel-running) improves insulin-mediated cranial/cerebral vasodilation and maintains cerebellum blood flow during insulin stimulation in vivo. Furthermore, improvements in insulin-stimulated posterior cerebral artery vasodilation after wheel running were associated with an increased contribution of insulin-induced NO and decreased contribution of insulin-induced MAPK/ET-1 signaling (19). Of note, branches of the posterior cerebral artery supply the cerebellum and the cerebellum is believed to be active during exercise, highlighting (similar to the skeletal muscle) exercise training-induced improvements in insulin-stimulated vasodilation may occur in relation to regional brain activation and corresponding blood flow responses during exercise (109–111).
Recent work in obese/T2D swine reveals impaired insulin-induced pial artery vasodilation coincides with depressed insulin-stimulated Akt signaling in the prefrontal cortex (18). The significance of insulin modulation of brain blood flow control and the role of insulin in central nervous system (CNS) function remain to be elucidated fully. However, it has become clearer that insulin signaling is critical to normal CNS function (e.g., insulin action in the brain is involved in improving memory and mood, inhibiting food intake, reducing bodyweight, increasing peripheral insulin sensitivity, reducing gluconeogenesis and lipolysis in the fasting state, and increasing postprandial thermogenesis) and CNS insulin resistance is implicated in the abnormal regulation of behavior and neurocognitive impairment/pathologies (26). The brain relies predominantly on insulin-independent glucose uptake, and insulin stimulation has little effect on brain glucose metabolism in healthy individuals. However, insulin stimulation increases brain glucose uptake in individuals with impaired glucose tolerance (i.e., insulin-stimulated glucose uptake is maximal in the fasting state under healthy but not insulin resistance conditions) (112). In stark contrast to the skeletal muscle, reduced insulin-stimulated brain glucose uptake may reflect improved metabolic/insulin sensitivity. Improvements in insulin sensitivity in the brain may be attributed to enhanced insulin transport across the blood brain barrier. Briefly, one mechanism through which transendothelial insulin transport is achieved is by binding to insulin receptors located on the luminal membrane of brain endothelial cells, becoming internalized through an endocytotic process and being shuttled across the endothelial cell. Insulin is then released and can interact with vascular smooth muscle cells, pericytes, and astrocytes or enter into the brain interstitial fluid and interact directly with neurons (23). Recent work in mice highlights that receptor-mediated transendothelial insulin transport in the microvasculature is NO-dependent (113) and represents a primary mechanism through which insulin uptake is achieved in the brain. Furthermore, diet-induced obesity in mice impairs transendothelial insulin transport in the brain (114). Whether exercise improves transendothelial insulin transport in the brain and whether such improvements are related to exercise-induced vascular shear stress have not been examined.
Recently, it was demonstrated that high-intensity interval sprint cycling training (4–6× repeat Wingate tests, 3 d·wk−1, for 2 wk), but not moderate-intensity endurance cycling training (40–60 min·d−1 at 60% V˙O2peak, 3 d·wk−1, for 2 wk), reduced glucose uptake during insulin stimulation in the cerebellum, superior frontal gyrus, medial frontal gyrus, temporal cortex, thalamus, cingulate gyrus, and occipital cortex (115). The authors speculated the superior effect of high-intensity interval sprint training may be the result of greater exercise-related neural recruitment, exercise-related changes in brain metabolism, and possibly improvements in insulin transport across the blood brain barrier. Sprint exercise lasting 30 s (performed on a cycle ergometer similar to the repeat Wingate protocol mentioned previously) is associated with a transient increase in the index of cerebral blood flow during the sprint, followed by a gradual decline to near or below baseline values by the end of the sprint and then a significant hyperemic response during the post-sprint recovery (lasting at least 60 s after the sprint) (106). Thus, it is conceivable that the hemodynamic effects of high-intensity interval exercise contribute to cerebrovascular adaptations to training that improve cerebrovascular insulin sensitivity (i.e., improved insulin-stimulated NO signaling, enhanced vascular density/volume after training, and possibly improvements in transendothelial insulin transport). Indeed, mounting evidence from humans and animal models indicates regular exercise enhances cerebrovascular NO signaling, vascular volume, and capillary density in a region-specific and intensity-dependent manner within the brain (53,107,108). Furthermore, it is speculated that these adaptations are related to regional brain activation and vascular shear stress experienced during the exercise bout (53,107,108). Whether these exercise-induced signals or training-induced adaptations confer a benefit to CNS insulin signaling is an area for further study.
Aerobic and resistance exercise training improve vascular insulin sensitivity with improvements occurring in the vascular supply of the skeletal muscles and possibly brain regions that undergo a relative increase in activity/blood flow during exercise (see Table). We contend that the added benefit of including different exercise modalities and incorporating low-, moderate-, and high-intensity exercise is not simply “more is better.” Consider that different exercise modes and intensities require activation of different skeletal muscles, different fiber recruitment patterns, and different brain regions or populations of neurons within the same brain region. Therefore, using different modes and intensities of exercise will modulate the spatial distribution of functional and structural vascular adaptations to exercise training in both the skeletal muscle and the brain. As such, we postulate that providing the duration of the stimulus is sufficient (i.e., one that exceeds a minimum threshold to induce adaptation); exercise programs designed to activate the most skeletal muscle and the most muscle fibers within each skeletal muscle (i.e., the greatest relative increase in fiber recruitment during exercise) and require global, diverse, and integrated neural output (i.e., learning and using complex and coordinated motor/sensorimotor activation use elements of strategy, consist of repetitive and novel stimuli, and engage multiple senses) will promote the most direct and widespread vascular adaptations. For this reason, we recommend modulating mode and intensity of exercise to maximize skeletal muscle fiber and CNS neural recruitment with the goal of generating the greatest enhancement in vascular insulin signaling in the most amount of vascular tissue (Fig. 1).
Participation in recreational physical activity or structured exercise training is widely accepted to be beneficial for metabolic and neurocognitive function. Likewise, they are essential in maintaining or improving vascular insulin sensitivity; however, the underlying mechanisms remain unresolved. We speculate that exercise-induced improvements in vascular insulin signaling are conferred, at least in part, through exercise-induced vascular shear stress. Accordingly, going forward, it is important that future research experimentally tests if indeed exercise-induced shear stress enhances vascular insulin sensitivity, as well as determines the molecular mechanisms by which this occurs. Additional unanswered questions are as follows:
- to what extent the skeletal muscle and brain microvasculature is subjected to increased shear stress during exercise?
- are the molecular mechanisms by which exercise enhances micro- and macrovascular insulin sensitivity the same?
- do exercise-induced improvements in vascular insulin signaling contribute to improvements in metabolic and neurocognitive function?
- do the effects of exercise-induced vascular shear stress extend beyond the vasculature (i.e., does vascular NO production impart benefits in surrounding tissues?)?
These and other questions are critical in elucidating the underlying mechanisms responsible for the insulin-sensitizing effects of exercise on the vasculature and essential for the development of prescriptive-based personalized exercise medicine.
J.P. is supported by the National Institutes of Health Grants K01-HL-125503 and R01-HL-137769. T.D.O. is supported by the Saskatchewan Health Research Foundation Establishment Grant.
1. Abramson DI, Schkloven N, Margolis MN, Mirsky IA. Influence of massive doses of insulin on peripheral blood flow
in man. Am. J. Physiol
. 1939; 128:124–32.
2. Ferris EB, Rosebaum M, Aring CD, Ryder HW, Roseman E, Hawkins JR. Intracranial blood flow
in insulin coma. Arch. Neur. Psych
. 1941; 46(3):509–12.
3. Porta DP, Maiolo AT, Negri VU, Rossella E. Cerebral blood flow
and metabolism in therapeutic insulin coma. Metabolism
. 1964; 13(2):131–40.
4. Richter EA, Kiens B, Mizuno M, Strange S. Insulin action in human thighs after one-legged immobilization. J. Appl. Physiol
. 1989; 67(1):19–23.
5. Richter EA, Mikines KJ, Galbo H, Kiens B. Effect of exercise
on insulin action in human skeletal muscle
. J. Appl. Physiol
. 1989; 66(2):876–85.
6. Steinberg HO. Effects of insulin on the vascular system. In: Johnstone MT, Veves A, editors. Diabetes and Cardiovascular Disease
. Springer: Humana Press; 2001. p. 265–84.
7. Creager MA, Liang CS, Coffman JD. Beta adrenergic-mediated vasodilator response to insulin in the human forearm. J. Pharmacol. Exp. Ther
. 1985; 235(3):709–14.
8. Liang CS, Doherty JU, Faillace R, et al. Insulin infusion in conscious dogs. J. Clin. Invest
. 1982; 69:1321–36.
9. Baron AD, Laakso M, Brechtel G, Hoit B, Watt C, Edelman SV. Reduced postprandial skeletal muscle blood flow
contributes to glucose intolerance in human obesity. J. Clin. Endocrinol. Metab
. 1990; 70(6):1525–33.
10. Olver TD, Mattar L, Grisé KN, et al. Glucose-stimulated insulin secretion causes an insulin-dependent nitric oxide-mediated vasodilation in the blood supply of the rat sciatic nerve. Am. J. Physiol. Regul. Integr. Comp. Physiol
. 2013; 305(2):R157–63.
11. Olver TD, Hazell TJ, Hamilton CD, Shoemaker JK, Lemon PW. Impaired superficial femoral artery vasodilation and leg blood flow
in young obese women following an oral glucose tolerance test. Appl. Physiol. Nutr. Metab
. 2012; 37(1):176–83.
12. Mikus CR, Fairfax ST, Libla JL, et al. Seven days of aerobic exercise
training improves conduit artery blood flow
following glucose ingestion in patients with type 2 diabetes. J. Appl. Physiol
. 2011; 111(3):657–64.
13. Laakso M, Edelman SV, Brechtel G, Baron AD. Impaired insulin-mediated skeletal muscle blood flow
in patients with NIDDM. Diabetes
. 1992; 41(9):1076–83.
14. Laakso M, Edelman SV, Brechtel G, Baron AD. Decreased effect of insulin to stimulate skeletal muscle blood flow
in obese man. A novel mechanism for insulin resistance. J. Clin. Invest
. 1990; 85(6):1844–52.
15. Reynolds LJ, Credeur DP, Manrique C, Padilla J, Fadel PJ, Thyfault JP. Obesity, type 2 diabetes, and impaired insulin-stimulated blood flow
: role of skeletal muscle
NO synthase and endothelin-1. J. Appl. Physiol
. 2016; 122(1):38–47.
16. Eringa EC, Stehouwer CD, Merlijn T, Westerhof N, Sipkema P. Physiological concentrations of insulin induce endothelin-mediated vasoconstriction during inhibition of NOS or PI3-kinase in skeletal muscle
arterioles. Cardiovasc. Res
. 2002; 56(3):464–71.
17. Eringa EC, Stehouwer CD, Roos MH, Westerhof N, Sipkema P. Selective resistance to vasoactive effects of insulin in muscle resistance arteries of obese Zucker (fa/fa) rats. Am. J. Physiol. Endocrinol. Metab
. 2007; 293(5):E1134–9.
18. Olver TD, Grunewald ZI, Jurrissen TJ, et al. Microvascular insulin resistance in skeletal muscle
occurs early in the development of juvenile obesity in pigs. Am. J. Physiol. Regul. Integr. Comp. Physiol
. 2017; 314(2):R252–64.
19. Olver TD, McDonald MW, Klakotskaia D, et al. A chronic physical activity
treatment in obese rats normalizes the contributions of ET-1 and NO to insulin-mediated posterior cerebral artery vasodilation. J. Appl. Physiol
. 2017; 122(4):1040–50.
20. Olver TD, McDonald MW, Grisé KN, et al. Exercise
training enhances insulin-stimulated nerve arterial vasodilation in rats with insulin-treated experimental diabetes. Am. J. Physiol. Regul. Integr. Comp. Physiol
. 2014; 306(12):R941–50.
21. Olver TD, Laughlin HM. Endurance, interval sprint, and resistance exercise
training: impact on microvascular dysfunction in type 2 diabetes. Am. J. Physiol. Heart Circ. Physiol
. 2016; 310:H337–50.
22. Crissey JM, Padilla J, Jenkins NT, et al. Metformin does not enhance insulin-stimulated vasodilation in skeletal muscle
resistance arteries of the OLETF rat. Microcirculation
. 2013; 20(8):764–75.
23. Martin JS, Padilla J, Jenkins NT, et al. Functional adaptations in the skeletal muscle
microvasculature to endurance and interval sprint training in the type 2 diabetic OLETF rat. J. Appl. Physiol
. 2012; 113(8):1223–32.
24. Katakam PV, Snipes JA, Steed MM, Busija DW. Insulin-induced generation of reactive oxygen species and uncoupling of nitric oxide synthase underlie the cerebrovascular insulin resistance in obese rats. J. Cereb. Blood Flow Metab
. 2012; 32(5):792–804.
25. King GL, Park K, Li Q. Selective insulin resistance and the development of cardiovascular diseases in diabetes: the 2015 Edwin Bierman Award lecture. Diabetes
. 2016; 65(6):1462–71.
26. Kullmann S, Heni M, Hallschmid M, Fritsche A, Preissl H, Häring H-U. Brain
insulin resistance at the crossroads of metabolic and cognitive disorders in humans. Physiol. Rev
. 2016; 96:1169–209.
27. Barrett EJ, Wang H, Upchurch CT, Liu Z. Insulin regulates its own delivery to skeletal muscle
by feed-forward actions on the vasculature. Am. J. Physiol. Endocrinol. Metab
. 2011; 301(2):E252–63.
28. Padilla J, Olver TD, Thyfault JP, Fadel PJ. Role of habitual physical activity
in modulating vascular actions of insulin. Exp. Physiol
. 2015; 100(7):759–71.
29. Vollenweider P, Randin D, Tappy L, Jequier E, Nicod P, Scherrer U. Impaired insulin-induced sympathetic neural activation and vasodilation in skeletal muscle
in obese humans. J. Clin. Invest
. 1994; 93:2365–71.
30. Scherrer U, Vollenweider P, Randin D, Jequier E, Nicod P, Tappy L. Suppression of insulin-induced sympathetic activation and vasodilation by dexamethasone in humans. Circulation
. 1993; 88:388–94.
31. Allwood MJ, Ginsburg J, Paton A. The effect of insulin hypoglycaemia on blood flow
in intact and sympathectomized extremities in man. J. Physiol
. 1957; 139:97–107.
32. Dela F, Stallknecht B, Biering-Sørensen F. An intact central nervous system is not necessary for insulin-mediated increases in leg blood flow
in humans. Eur. J. Physiol
. 2000; 441(2–3):241–50.
33. Sartori C, Trueb L, Nicod P, Scherrer U. Effects of sympathectomy and nitric oxide synthase inhibition on vascular actions of insulin in humans. Hypertension
. 1999; 34(4):586–9.
34. Cardillo C, Nambi SS, Kilcoyne CM, et al. Insulin stimulates both endothelin and nitric oxide activity in the human forearm. Circulation
. 1999; 100(8):820–5.
35. Mahmoud AM, Szczurek MR, Blackburn BK, et al. Hyperinsulinemia augments endothelin-1 protein expression and impairs vasodilation of human skeletal muscle
arterioles. Physiol. Rep
. 2016; 4(16):1–15.
36. Muniyappa R, Montagnani M, Koh KK, Quon MJ. Cardiovascular actions of insulin. Endocr. Rev
. 2007; 28(5):463–91.
37. Kim F, Gallis B, Corson MA. TNF-alpha inhibits flow and insulin signaling leading to NO production in aortic endothelial cells. Am. J. Physiol. Cell Physiol
. 2001; 280:C1057–65.
38. Bakker W, Sipkema P, Stehouwer CD, et al. Protein kinase C theta activation induces insulin-mediated constriction of muscle resistance arteries. Diabetes
. 2008; 57(3):706–13.
39. Hardin D, Azzarelli B, Edwrads J, et al. Mechanisms of enhanced insulin sensitivity in endurance-trained athletes: effects on blood flow
and differential expression of GLUT 4 in skeletal muscles. J. Endocrinol. Metab
. 1995; 80:2437–46.
40. Mikus CR, Rector RS, Arce-Esquivel AA, et al. Daily physical activity
enhances reactivity to insulin in skeletal muscle
arterioles of hyperphagic Otsuka Long-Evans Tokushima Fatty rats. J. Appl. Physiol
. 2010; 109(4):1203–10.
41. Mikus CR, Roseguini BT, Uptergrove GM, et al. Voluntary wheel running selectively augments insulin-stimulated vasodilation in arterioles from white skeletal muscle
of insulin-resistant rats. Microcirculation
. 2012; 19(8):729–38.
42. Saltin B, Gollnick PD. Skeletal muscle
adaptability: significance for metabolism and performance. In: Handbook of Physiology: Skeletal Muscle Section
. Bethesda (MD): American Physiological Society; 1983. p. 10. p. 555–631.
43. Delp MD, Laughlin MH. Regulation of skeletal muscle
perfusion during exercise
. Acta Physiol. Scand
. 1998; 162:411–9.
44. Laughlin MH, Armstrong RB. Muscular blood flow
distribution patterns as a function of running speed in rats. Am. J. Physiol. Heart Circ. Physiol
. 1982; 12:296–306.
45. Laughlin MH, Davis MJ, Secher NH, et al. Peripheral circulation. Compr. Physiol
. 2012; 2(1):321–447.
46. Jasperse JJ, Laughlin MH. Exercise
and skeletal muscle
microcirculation. In: Microvascular Research: Biology and Pathology
. San Diego (CA): Elsevier; 2005. p. 527–35.
47. Laughlin MH, Woodman CR, Schrage WG, Gute D, Price EM. Interval sprint training enhances endothelial function and eNOS content in some arteries that perfuse white gastrocnemius muscle. J. Appl. Physiol
. 2004; 96(1):233–44.
48. McAllister RM, Jasperse JL, Laughlin MH. Nonuniform effects of endurance exercise
training on vasodilation in rat skeletal muscle
. J. Appl. Physiol
. 2005; 98(2):753–61.
49. Laughlin MH, Cook JD, Tremble R, Ingram D, Colleran PN, Turk JR. Exercise
training produces nonuniform increases in arteriolar density of rat soleus and gastrocnemius muscle. Microcirculation
. 2006; 13(3):175–86.
50. Binder KW, Murfee WL, Song JI, Laughlin MH, Price RJ. Computational network model prediction of hemodynamic alterations due to arteriolar remodeling in interval sprint trained skeletal muscle
. 2007; 14(3):181–92.
51. Armstrong RB, Laughlin MH. Blood flows within and among rat muscles as a function of time during high speed treadmill exercise
. J. Physiol
. 1983; 344:189–208.
52. Armstrong RB, Laughlin MH. Rat muscle blood flows during high-speed locomotion. J. Appl. Physiol
. 1985; 59(4):1322–8.
53. Olver TD, Ferguson BS, Laughlin MH. Molecular mechanisms for exercise
training-induced changes in vascular structure and function: skeletal muscle
, cardiac muscle, and the brain
. In: Bouchard C, editor. Prog Mol Biol Transl Sci
. 2015; 135:227–57.
54. Andersen P, Saltin B. Maximal perfusion of skeletal muscle
in man. J. Physiol
. 1985; 366:233–49.
55. Dimmeler S, Assmus B, Hermann C, Haendeler J, Zeiher AM. Fluid shear stress
stimulates phosphorylation of Akt in human endothelial cells: involvement in suppression of apoptosis. Circ. Res
. 1998; 83:334–41.
56. Jenkins NT, Padilla J, Martin JS, et al. Differential vasomotor effects of insulin on gastrocnemius and soleus feed arteries in the OLETF rat model: role of endothelin-1. Exp. Physiol
. 2014; 99(1):262–71.
57. Bender SB, Newcomer SC, Harold Laughlin M. Differential vulnerability of skeletal muscle
feed arteries to dysfunction in insulin resistance: impact of fiber type and daily activity. Am. J. Physiol. Heart Circ. Physiol
. 2011; 300(4):H1434–41.
58. Laughlin MH, Korthuis RJ, Sexton WL, Armstrong RB. Regional muscle blood flow
capacity and exercise
hyperemia in high-intensity trained rats. J. Appl. Physiol
. 1988; 64(6):2420–7.
59. Armstrong RB, Laughlin MH. Exercise blood flow
patterns within and among rat muscles after training. Am. J. Physiol. Heart Circ. Physiol
. 1984; 246(1 Pt 2):H59–68.
60. Sexton WL, Laughlin MH. Influence of endurance exercise
training on distribution of vascular adaptations in rat skeletal muscle
. Am. J. Physiol. Heart Circ. Physiol
. 1994; 266(2 Pt 2):H483–HH490.
61. Laughlin MH, Korthius RJ, Dunker DJ, Bache RJ. Control of Blood Flow to Cardiac and Skeletal Muscle During Exercise
. New York (NY): American Physiological Society and Oxford University Press; 1996. p. Chapter 16.
62. Musch TI, Haidet GC, Ordway GA, Longhurst JC, Mitchell JH. Training effects on regional blood flow
response to maximal exercise
in foxhounds. J. Appl. Physiol
. 1987; 62(4):1724–32.
63. Cocks M, Shaw CS, Shepherd SO, et al. Sprint interval and moderate-intensity continuous training have equal benefits on aerobic capacity, insulin sensitivity, muscle capillarisation and endothelial eNOS/NAD(P)Hoxidase protein ratio in obese men. J. Physiol
. 2016; 594(8):2307–21.
64. Cocks M, Shaw CS, Shepherd SO, et al. Sprint interval and endurance training are equally effective in increasing muscle microvascular density and eNOS content in sedentary males. J. Physiol
. 2013; 591:641–56.
65. Kim HJ, Lee JS, Kim CK. Effect of exercise
training on muscle glucose transporter 4 protein and intramuscular lipid content in elderly men with impaired glucose tolerance. Eur. J. Appl. Physiol
. 2004; 93(3):353–8.
66. Prior SJ, Blumenthal JB, Katzel LI, Goldberg AP, Ryan AS. Increased skeletal muscle
capillarization after aerobic exercise
training and weight loss improves insulin sensitivity in adults with IGT. Diabetes Care
. 2014; 37(5):1469–75.
67. Egginton S, Hudlická O. Selective long-term electrical stimulation of fast glycolytic fibres increases capillary supply but not oxidative enzyme activity in rat skeletal muscles. Exp. Physiol
. 2000; 85(5):567–74.
68. Egginton S. Invited review: activity-induced angiogenesis. Eur. J. Physiol
. 2009; 457:963–77.
69. Laughlin MH, Roseguini B. Mechanisms for exercise
training-induced increases in skeletal muscle blood flow
capacity: differences with interval sprint training versus aerobic endurance training. J. Physiol. Pharmacol
. 2008; 59(Supp 7):71–88.
70. Laughlin MH, Newcomer SC, Bender SB. Importance of hemodynamic forces as signals for exercise
-induced changes in endothelial cell phenotype. J. Appl. Physiol
. 2008; 104(3):588–600.
71. Lash JM, Bohlen HG. Time- and order-dependent changes in functional and NO-mediated dilation during exercise
training. J. Appl. Physiol
. 1997; 82(2):460–8.
72. Mcallister M, Kimani JK, Webster JL, Parker JL, Laughlin MH. Effects of exercise
training on responses of peripheral and visceral arteries in swine. J. Appl. Physiol
. 1996; 80(1):216–25.
73. Parker JL, Mattox ML, Laughlin MH. Contractile responsiveness of coronary arteries from exercise
-trained rats. J. Appl. Physiol
. 1997; 83(2):434–43.
74. Sessa WC, Pritchard K, Seyedi N, Wang J, Hintze TH. Chronic exercise
in dogs increases coronary vascular nitric oxide production and endothelial cell nitric oxide synthase gene expression. Circ. Res
. 1994; 74(2):349–53.
75. Wang J, Wolin MS, Hintze TH. Chronic exercise
enhances endothelium-mediated dilation of epicardial coronary artery in conscious dogs. Circ. Res
. 1993; 73(5):829–38.
76. Sun D, Huang A, Koller A, Kaley G. Adaptation of flow-induced dilation of arterioles to daily exercise
. Microvasc. Res
. 1998; 56(1):54–61.
77. Olver TD, Reid SM, Smith AR, et al. Effects of acute and chronic interval sprint exercise
performed on a manually propelled treadmill on upper limb vascular mechanics in healthy young men. Physiol. Rep
. 2016; 4(13):pii: e12861.
78. Delp MD, Laughlin MH. Time course of enhanced endothelium-mediated dilation in aorta of trained rats. Med. Sci. Sport Exerc
. 1997; 1454–61.
79. Delp MD, Mcallister RM, Harold MH. Exercise
training alters aortic vascular reactivity in hypothyroid rats. Am. J. Physiol. Heart Circ. Physiol
. 1995; 268(19):H1428–35.
80. Delp MD, McAllister RM, Laughlin MH. Exercise
training alters endothelium-dependent vasoreactivity of rat abdominal aorta. J. Appl. Physiol
. 1993; 75(3):1354–63.
81. Koller A, Huang A, Sun D, Kaley G. Exercise
training augments flow-dependent dilation in rat skeletal muscle
arterioles. Role of endothelial nitric oxide and prostaglandins. Circ. Res
. 1995; 76:544–50.
82. Laughlin MH, Pollock JS, Amann JF, Hollis ML, Woodman CR, Price EM. Training induces nonuniform increases in eNOS content along the coronary arterial tree. J. Appl. Physiol
. 2001; 90(2):501–10.
83. McAllister RM, Laughlin MH. Short-term exercise
training alters responses of porcine femoral and brachial arteries. J. Appl. Physiol
. 1997; 82(5):1438–44.
84. Muller JM, Myers PR, Laughlin MH. Vasodilator responses of coronary resistance arteries of exercise
- trained pigs. Circulation
. 1994; 89(5):2308–14.
85. Sexton WL, Korthuis RJ, Laughlin MH. High-intensity exercise
training increases vascular transport capacity of rat hindquarters. Am. J. Physiol
. 1988; 254(2 Pt 2):H274–8.
86. Bevegård BS, Shepherd JT. Reaction in man of resistance and capacity vessels in forearm and hand to leg exercise
. J. Appl. Physiol
. 1966; 21(1):123–32.
87. Clausen JP, Trap-Jensen J. Effects of training on the distribution of cardiac output in patients with coronary artery disease. Circulation
. 1970; 42(4):611–24.
88. Rowell LB. Human Cardiovascular Control
. New York (NY): Oxford University Press; 1993.
89. Gute D, Fraga C, Laughlin MH, Amann JF. Regional changes in capillary supply in skeletal muscle
of high-intensity endurance-trained rats. J. Appl. Physiol
. 1996; 81(2):619–26.
90. Gute D, Laughlin MH, Amann JF. Regional changes in capillary supply in skeletal muscle
of interval-sprint and low-intensity, endurance-trained rats. Microcirculation
. 1994; 1:183–93.
91. Mackie BG, Terjung RL. Blood flow
to different skeletal muscle
fiber types during contraction. Am. J. Physiol. Heart Circ. Physiol
. 1983; 245(2):H265–75.
92. Edgerton VR, Smith JL, Simpson DR. Muscle fibre type populations of human leg muscles. Histochem. J
. 1975; 7(3):259–66.
93. Dwyer D, Browning J, Weinstein S. The reliability of muscle biopsies taken from vastus lateralis. J. Sci. Med. Sport
. 1999; 2(4):333–40.
94. Dela F, Larsen JJ, Mikines KJ, Ploug T, Petersen LN. Insulin-stimulated muscle glucose clearance in patients with NIDDM. Effects of one-legged physical training. Diabetes
. 1995; 44:1010–20.
95. Holten MK, Zacho M, Gaster M, Juel C, Wojtaszewski JF, Dela F. Strength training increases insulin-mediated glucose uptake, GLUT4 content, and insulin signaling in skeletal muscle
in patients with type 2 diabetes. Diabetes
. 2004; 53:294–305.
96. Dela F, Mikines KJ, Larsen JJ, Galbo H. Training-induced enhancement of insulin action in human skeletal muscle
: the influence of aging. J. Gerontol. A Biol. Sci. Med. Sci
. 1996; 51(4):B247–52.
97. Sjøberg KA, Frøsig C, Kjøbsted R, et al. Exercise
increases human skeletal muscle
insulin sensitivity via coordinated increases in microvascular perfusion and molecular signaling. Diabetes
. 2017; 66(6):1501–10.
98. Eskelinen J-J, Heinonen I, Löyttyniemi E, et al. Muscle-specific glucose and free fatty acid uptake after sprint interval and moderate intensity training in healthy middle-aged men. J. Appl. Physiol
. 2015; 118:1172–80.
99. McDonald MW, Olver TD, Dotzert MS, et al. Aerobic exercise
training improves insulin-induced vasorelaxation in a vessel-specific manner in insulin-treated experimental diabetes. Diabetes Vasc. Dis. Res
. 2019; 16(1): 77–86.
100. Walsh L, Ghiarone T, Olver TD, et al. Increased endothelial shear stress
improves insulin-stimulated vasodilation in skeletal muscle
. J. Physiol
. 2019; 597(1):57–69.
101. Wagenmakers AJ, Strauss JA, Shepherd SO, Keske MA, Cocks M. Increased muscle blood supply and transendothelial nutrient and insulin transport induced by food intake and exercise
: Effect of obesity and ageing. J. Physiol
. 2016; 594(8):2207–22.
102. Prior SJ, Goldberg AP, Ortmeyer HK, et al. Increased skeletal muscle
capillarization independently enhances insulin sensitivity in older adults after exercise
training and detraining. Diabetes
. 2015; 64(10):3386–95.
103. Lillioja S, Young AA, Culter CL, et al. Skeletal muscle
capillary density and fiber type are possible determinants of in vivo
insulin resistance in man. J. Clin. Invest
. 1987; 80:415–24.
104. Akerstrom T, Laub L, Vedel K, et al. Increased skeletal muscle
capillarization enhances insulin sensitivity. Am. J. Physiol. Endocrinol. Metab
. 2014; 307(12):E1105–16.
105. Hiura M, Nariai T, Ishii K, et al. Changes in cerebral blood flow
during steady-state cycling exercise
: a study using oxygen-15-labeled water with PET. J. Cereb. Blood Flow Metab
. 2014; 34(3):389–96.
106. Curtelin D, Morales-Alamo D, Torres-Peralta R, et al. Cerebral blood flow
, frontal lobe oxygenation and intra-arterial blood pressure during sprint exercise
in normoxia and severe acute hypoxia in humans. J. Cereb. Blood Flow Metab
. 2018; 38(1):136–50.
107. Schmidt W, Endres M, Dimeo F, Jungehulsing GJ. Train the vessel, gain the brain
: physical activity
and vessel function and the impact on stroke prevention and outcome in cerebrovascular disease. Cerebrovasc. Dis
. 2013; 35(4):303–12.
108. Lucas SJ, Cotter JD, Brassard P, Bailey DM. High-intensity interval exercise
and cerebrovascular health: curiosity, cause, and consequence. J. Cereb. Blood Flow Metab
. 2015; 35(6):902–11.
109. Delp MD, Armstrong RB, Godfrey DA, Laughlin MH, Ross CD, Wilkerson MK. Exercise
increases blood flow
to locomotor, vestibular, cardiorespiratory and visual regions of the brain
in miniature swine. J. Physiol
. 2001; 533(3):849–59.
110. Isaacs KR, Anderson BJ, Alcantara AA, Black JE, Greenough WT. Exercise
and the brain
: angiogenesis in the adult rat cerebellum after vigorous physical activity
and motor skill learning. J. Cereb. Blood Flow Metab
. 1992; 12(1):110–9.
111. Vissing J, Andersen M, Diemer NH. Exercise
-induced changes in local cerebral glucose utilization in the rat. J. Cereb. Blood Flow Metab
. 1996; 16(4):729–36.
112. Hirvonen J, Virtanen KA, Nummenmaa L, et al. Effects of insulin on brain
glucose metabolism in impaired glucose tolerance. Diabetes
. 2011; 60(2):443–7.
113. Wang H, Wang AX, Aylor K, Barrett EJ. Nitric oxide directly promotes vascular endothelial insulin transport. Diabetes
. 2013; 62(12):4030–42.
114. Meijer RI, Gray S, Aylor K, Barrett EJ. Pathways for insulin access to the brain
: the role of the microvascular endothelial cell. Am. J. Physiol. Heart Circ. Physiol
. 2016; 311:H1132–8.
115. Honkala SM, Johansson J, Motiani KK, et al. Short-term interval training alters brain
glucose metabolism in subjects with insulin resistance. J. Cereb. Blood Flow Metab
. 2018; 38(10):1828–38.
116. Ebeling P, Bourey R, Koranyi L, et al. Mechanism of enhanced insulin sensitivity in athletes. Increased blood flow
, muscle glucose transport protein (GLUT-4) concentration, and glycogen synthase activity. J. Clin. Invest
. 1993; 92:1623–31.
117. Bisquolo VA, Cardoso JC Jr., Ortega KC, et al. Previous exercise
attenuates muscle sympathetic activity and increases blood flow
during acute euglycemic hyperinsulinemia. J. Appl. Physiol
. 2005; 98:866–71.
118. Vinet A, Obert P, Dutheil F, et al. Impact of a lifestyle program on vascular insulin resistance in metabolic syndrome subjects: the RESOLVE study. J. Clin. Endocrinol. Metab
. 2015; 100(2):442–50.
119. Russell RD, Hu D, Greenaway T, et al. Skeletal muscle
microvascular-linked improvements in glycemic control from resistance training in individuals with type 2 diabetes. Diabetes Care
. 2017; 40(9):1256–63.