Type II diabetes accentuates diaphragm blood flow increases during submaximal exercise in the rat
Introduction
Approximately 30 million Americans have diabetes mellitus, of which ∼90−95% have Type 2 diabetes mellitus (T2DM), and an additional ∼84 million Americans are considered prediabetic (Benjamin et al., 2019). Patients suffering from T2DM are characterized by compromised exercise tolerance (Gurdal et al., 2015; Poitras et al., 2018) and a lack of adherence to physical activity guidelines (Morrato et al., 2007; Thomas et al., 2004). This is unfortunate given that physical activity/exercise has protective effects on glycemia and insulin sensitivity (Colberg et al., 2010; Kearney and Thyfault, 2016; Sigal et al., 2004). Thus, understanding the mechanistic underpinnings of exercise intolerance is crucial to improve clinical outcomes and quality of life for this patient population.
Patients with T2DM exhibit pulmonary system alterations that likely contribute to reduced exercise capacity and would be expected to increase the work of the respiratory muscles and thus blood flow (BF) requirement to these muscles during exercise. For example, compared to healthy controls, T2DM patients exhibit a reduced vital capacity and total lung volume (Anandhalakshmi et al., 2013; Fontaine-Delaruelle et al., 2016), loss of elastic properties of the lung and respiratory muscle strength (Anandhalakshmi et al., 2013; Correa et al., 2011; Fuso et al., 2012; Zineldin et al., 2015), thickening of the alveolar epithelial and endothelial capillary basal lamina (Foster et al., 2010; Weynand et al., 1999), and impaired lung diffusion capacity at rest and during submaximal exercise (Anandhalakshmi et al., 2013; Chance et al., 2008; Saler et al., 2009). During exercise, T2DM patients, compared to healthy adults, have an exaggerated ventilatory response relative to CO2 production (i.e. higher V̇E/V̇CO2) to maintain alveolar ventilation (Roberts et al., 2018; Tantucci et al., 1996; Vukomanovic et al., 2019), which is independent of common comorbidities such as coronary artery disease and heart failure (Gurdal et al., 2015). Together, these structural and functional pulmonary system derangements may culminate in greater respiratory muscle work and therefore demand a higher respiratory muscle BF during exercise in T2DM than healthy counterparts; however, this has not been investigated.
We have used the Goto-Kakizaki (GK) rat model of T2DM to determine the effect of T2DM on capillary hemodynamics (Padilla et al., 2006), microvascular oxygen pressures (Padilla et al., 2007), and on hindlimb muscle weight and muscle BF at rest and during submaximal running (Copp et al., 2010). Most relevant to the current investigation, we found ∼20 % lower hindlimb muscle weight normalized to body weight ratios in GK rats (Copp et al., 2010), which is consistent with multiple reports of lower lean body mass in human T2DM patients compared to healthy adults (Kiely et al., 2014; Kim et al., 2014; Park et al., 2006). Further, we found that during submaximal treadmill exercise, BF was not different between GK and Wistar control rats for the majority of the hindlimb muscles, but was significantly higher in GK rats for several primarily glycolytic muscles and muscle regions (Copp et al., 2010). The lower hindlimb muscle weight normalized to body weight ratio and higher BF to primarily glycolytic muscle may mechanistically contribute to a higher respiratory muscle BF in T2DM subjects compared to healthy adults, although this has yet to be investigated. Specifically, an increased recruitment of glycolytic muscle fibers may produce a higher CO2 and contribute to the greater ventilatory response during exercise reported in T2DM patients (Roberts et al., 2018; Tantucci et al., 1996; Vukomanovic et al., 2019). Thus, there is a pressing need to investigate the effect of T2DM on respiratory muscle BF during exercise.
The purpose of this investigation was to determine the effects of T2DM on respiratory muscle BF and vascular conductance (VC) at rest and during exercise. Specifically, we tested the hypothesis that diaphragm, intercostal, and transverse abdominis muscle BFs and VCs would be higher during submaximal treadmill running (20 m/min, 10 % incline) in the GK rat model of T2DM compared to CON rats. The same absolute submaximal treadmill running speed was selected as the exercise paradigm because individuals with T2DM and healthy individuals often perform daily tasks, such as walking and climbing stairs, that are equivalent in absolute terms.
Section snippets
Experimental animals and ethical approval
The present investigation focuses on the effect of T2DM on respiratory muscle BF at rest and during submaximal exercise in the same animals used in a previously published dataset (Copp et al., 2010). The T2DM model selected for this investigation was the male GK rat (Taconic Farm, Germantown, NY; 6–8 mo old; n = 10). Healthy male Wistar controls (CON) rats (Taconic Farm, Germantown, NY; 6–8 mo old; n = 8) served as age-matched controls. Healthy Wistar rats are appropriate controls because they
Blood glucose, body weight and heart morphometrics
Blood glucose levels were significantly higher while body weights were significantly lower in the GK rats compared to CON rats (Table 1). LVEDP, LV dP/dt, lung weight normalized to body weight were not different between GK and CON rats. Lastly, LV and RV weights normalized to body weight were significantly greater, whereas diaphragm weights and diaphragm weights normalized to body weight were significantly lower in GK compared to CON rats.
Hemodynamic responses
MAP was not different between GK rats and CON rats at
Discussion
This investigation is the first to determine the effect of T2DM on respiratory muscle BF at rest and during submaximal exercise and revealed the following novel findings: 1) diaphragm muscle BF and VC are greater in the GK rat model of T2DM compared to healthy CON rats during submaximal exercise and 2) diaphragm muscle BF during submaximal exercise is negatively correlated with absolute diaphragm weights and diaphragm weights normalized to body weight. Our data have important implications for
Conclusions
This investigation demonstrates that diaphragm BF and VC are greater during submaximal exercise in the GK rat model of T2DM compared to healthy CON. In addition, our data suggest that the smaller diaphragm weights in GK rats elicited a greater diaphragm BF requirement for a given diaphragm muscle weight, independent of any altered pulmonary/ventilatory requirements. In the absence of an augmented BF capacity of the diaphragm in T2DM this would reduce the BF reserve and potentially place the
Funding
This work was supported in part by the National Institutes of Health Grants (HL-50306 to D.C.P. and T.I.M.), (AG-19228 D.C.P. and T.I.M.) and (HL-142877 to S.W.C.), and a grant-in-aid from the American Heart Association, Heartland Affiliate (0455582Z to D.C.P. and T.I.M.), the American Heart Association (18POST3990251 to J.R.S.).
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