Type 2 diabetes and reduced exercise tolerance: a review of the literature through an integrated physiology approach

Abstract

The association between type 2 diabetes mellitus (T2DM) and heart failure (HF) is well established. Early in the course of the diabetic disease, some degree of impaired exercise capacity (a powerful marker of health status with prognostic value) can be frequently highlighted in otherwise asymptomatic T2DM subjects. However, the literature is quite heterogeneous, and the underlying pathophysiologic mechanisms are far from clear. Imaging-cardiopulmonary exercise testing (CPET) is a non-invasive, provocative test providing a multi-variable assessment of pulmonary, cardiovascular, muscular, and cellular oxidative systems during exercise, capable of offering unique integrated pathophysiological information. With this review we aimed at defying the cardiorespiratory alterations revealed through imaging-CPET that appear specific of T2DM subjects without overt cardiovascular or pulmonary disease. In synthesis, there is compelling evidence indicating a reduction of peak workload, peak oxygen assumption, oxygen pulse, as well as ventilatory efficiency. On the contrary, evidence remains inconclusive about reduced peripheral oxygen extraction, impaired heart rate adjustment, and lower anaerobic threshold, compared to non-diabetic subjects. Based on the multiparametric evaluation provided by imaging-CPET, a dissection and a hierarchy of the underlying mechanisms can be obtained. Here we propose four possible integrated pathophysiological mechanisms, namely myocardiogenic, myogenic, vasculogenic and neurogenic. While each hypothesis alone can potentially explain the majority of the CPET alterations observed, seemingly different combinations exist in any given subject. Finally, a discussion on the effects-and on the physiological mechanisms-of physical activity and exercise training on oxygen uptake in T2DM subjects is also offered. The understanding of the early alterations in the cardiopulmonary response that are specific of T2DM would allow the early identification of those at a higher risk of developing HF and possibly help to understand the pathophysiological link between T2DM and HF.

Association between the Mediterranean lifestyle, metabolic syndrome and mortality: a whole-country cohort in Spain

“…When we assessed the separate effect of the three different blocks of the MEDLIFE, the dimension that captured physical activity, social interaction, rest and conviviality was the only one showing statistically significant results, mainly due to physical activity, collective and non-collective sports. Despite the wide supporting evidence of the benefits of physical activity on cardiovascular health and mortality [ 52 – 60 ], we cannot rule out positive effects of other components such as napping, social interaction, or eating in company that are not usually included in other previously published scores [ 22 , 25 , 61 ]. Our findings may highlight the importance of those components in the context of a healthy Mediterranean dietary pattern.…”

Exercise as a Therapeutic Intervention in Gestational Diabetes Mellitus

“…The ability to perform exercise depends on the optimal oxygen delivery and utilization, which is a result of an interplay of multiple physiological functions and reflexes, such as pulmonary ventilation and gas exchange, cardiac output, blood flow and diffusion, skeletal muscle oxidative and force-generating capacity, as well as fatigue perception. In obesity and insulin resistance states, alterations have been described in the majority of these functions (for a review, see Nesti et al [86]).…”

Neurovascular Dysregulation During Exercise in Type 2 Diabetes

“…Nonetheless, there are substantial data reporting that T2D significantly impacts the ability to properly adjust the circulation during exercise, leading to an augmented BP and reduced contracting skeletal muscle BF. For complementary details on exercise impairments in T2D, the reader is referred to other excellent reviews (Reusch et al, 2013;Green et al, 2015;Poitras et al, 2018;Kim et al, 2020;Nesti et al, 2020).…”

“…Specifically, it will be important to determine whether these mechanisms involve greater metabolite accumulation during skeletal muscle contraction, enhanced afferent sensitivity, or increased expression of mechanically or metabolically sensitive receptors and/or channels, or abnormal central integration of afferent feedback. It is possible that a slowed and attenuated hyperemic response to contracting skeletal muscle during exercise enhances muscle metabolite buildup, thereby increasing the activation of the metaboreflex and simultaneously sensitizing the mechanoreflex (Adreani and Kaufman, 1998;Holwerda et al, 2016a;Nesti et al, 2020). Additionally, there are reports of increased reliance on carbohydrate metabolism (Martin et al, 1995;Scheuermann-Freestone et al, 2003), reduced capillary density and recruitment, increased fast twitch muscle fiber type recruitment (Marin et al, 1994;Padilla et al, 2006;Womack et al, 2009), and increased leg lactate output during exercise (Martin et al, 1995) in T2D.…”

“…T2D is a multifactorial disease with many potential contributing factors to the neural vascular dysregulation reported during exercise (e.g., diet, physical inactivity, aging, family history, sex, ethnicity, comorbidities, etc.). This likely contributes to variations in diabetic phenotypes (Stidsen et al, 2018) as well as potentially differential etiologies for exercise impairments (Nesti et al, 2020), making T2D a complex population to study. It is also important to note that differences in T2D characteristics (e.g., duration of diabetes, glycemic control, and varying medications), animal models used, and exercise modality employed (e.g., type, duration, intensity of exercise) may also influence the observed neural cardiovascular responses to exercise in T2D.…”