The Role of Leucine and Its Metabolite (KIC) in Insulin Signalling and Glucose Transport in L6 Myotubes

Branched-chain Amino Acids (BCAAs) are known to have positive effects in metabolic health through weight management and muscle protein synthesis. However, elevated levels of BCAAs (particularly leucine) and their metabolites have also been implicated in the development of insulin resistance and type 2 diabetes mellitus (T2DM). This study examines the dose-dependent effect of leucine in the presence or absence of other amino acids on glucose transport in L6 rat myotubes. Here we report that leucine significantly suppresses insulin-stimulated glucose uptake in skeletal muscle cells and particularly at 150 M, there is a 75% reduction in insulin-mediated glucose transport (p<0.01). This occurs in parallel with increased activation of proteins involved in the mammalian/mechanistic target of rapamycin complex 1 (mTORC1) pathway (p<0.05), which suggests a link between increased mTORC1 activity and insulin resistance. Interestingly, the suppressive effect of leucine on glucose transport disappears in the presence of other amino acids. We also illustrate that leucines metabolite, -ketoisocaproic acid (KIC) inhibits insulin-stimulated glucose uptake at 200 M by 45% concurrent with increased activation of the mTORC1 pathway (p<0.05). Finally, siRNA knockdown of the branched-chain aminotransferase 2 mitochondrial (BCAT2) enzyme which catalyzes the reversible conversion of leucine to KIC, ameliorated the inhibitory effect of KIC on glucose transport (p<0.05), suggesting that the impairing effects of KIC on glucose transport occur through its conversion back to leucine. Taken together, our results show that in L6 myotubes, leucine and its metabolite significantly suppress insulin-mediated glucose transport. Moreover, modulating the activity of the BCAT2 enzyme could be a new therapeutic approach in patients with high BCAA levels in conditions such obesity and T2DM

Costs of Cardiac Care: Patient Burden and Rehabilitation Delivery

Background: Cardiac rehabilitation (CR) reach is minimal globally, primarily due to financial factors. This study characterized CR funding sources, cost to patients to participate, cost to programs to serve patients, and the drivers of these costs. Methods: In this cross-sectional study, an online survey was administered to CR programs globally. Cardiac associations and local champions facilitated program identification. Costs in each country were reported using purchasing power parity (PPP). Results were compared by World Bank country income classification using generalized linear mixed models. Results: 111/203 (54.68%) countries in the world offer CR, of which data were collected in 93 (83.78% country response rate; N=1082 surveys, 32.0% program response rate). CR was most-often publicly funded (more in high-income countries [HICs]; p<.001), but in 60.20% of countries patients paid some or all of the cost. Funding source impacted capacity (p=.004), number of patients per exercise session (p<.001), personnel (p=.037), and functional capacity testing (p=.039). The median cost to serve 1 patient was $945.91PPP globally. In low and middle-income countries (LMICs), exercise equipment and stress testing were perceived as the most expensive delivery elements, with front-line personnel costs perceived as costlier in HICs (p=.003). Modifiable factors associated with higher costs included CR team composition (p=.001), stress testing (p=.002) and telemetry monitoring in HICs (p=.01), and not offering alternative models in LMICs (p=.02). Conclusions: Too many patients are paying out-of-pocket for CR, and more public funding is needed. Lower-cost delivery approaches are imperative, and include walk tests, task-shifting, and intensity monitoring via perceived exertion

Funding sources and costs to deliver cardiac rehabilitation around the globe: Drivers and barriers

Background: Cardiac rehabilitation (CR) reach is minimal globally, primarily due to financial factors. This study characterized CR funding sources, cost to patients to participate, cost to programs to serve patients, and the drivers of these costs. Methods: In this cross-sectional study, an online survey was administered to CR programs globally. Cardiac associations and local champions facilitated program identification. Costs in each country were reported using purchasing power parity (PPP). Results were compared by World Bank country income classification using generalized linear mixed models. Results: 111/203 (54.68%) countries in the world offer CR, of which data were collected in 93 (83.78% country response rate; N = 1082 surveys, 32.0% program response rate). CR was most-often publicly funded (more in high-income countries [HICs]; p < .001), but in 60.20% of countries patients paid some or all of the cost. Funding source impacted capacity (p = .004), number of patients per exercise session (p < .001), personnel (p = .037), and functional capacity testing (p = .039). The median cost to serve 1 patient was $945.91PPP globally. In low and middle-income countries (LMICs), exercise equipment and stress testing were perceived as the most expensive delivery elements, with front-line personnel costs perceived as costlier in HICs (p = .003). Modifiable factors associated with higher costs included CR team composition (p = .001), stress testing (p = .002) and telemetry monitoring in HICs (p = .01), and not offering alternative models in LMICs (p = .02). Conclusions: Too many patients are paying out-of-pocket for CR, and more public funding is needed. Lower-cost delivery approaches are imperative, and include walk tests, task-shifting, and intensity monitoring via perceived exertion

Cardiac Rehabilitation Costs

Background: Despite the clinical benefits of cardiac rehabilitation (CR) and its cost-effectiveness, it is not widely received. Arguably, capacity could be greatly increased if lower-cost models were implemented. The aims of this review were to describe: the costs associated with CR delivery, approaches to reduce these costs, and associated implications. Methods: Upon finalizing the PICO statement, information scientists were enlisted to develop the search strategy of MEDLINE, Embase, CDSR, Google Scholar and Scopus. Citations identified were considered for inclusion by the first author. Extracted cost data were summarized in tabular format and qualitatively synthesized. Results: There is wide variability in the cost of CR delivery around the world, and patients pay out-of-pocket for some or all of services in 55% of countries. Supervised CR costs in high-income countries ranged from PPP$294 (Purchasing Power Parity; 2016 United States Dollars) in the United Kingdom to PPP$12,409 in Italy, and in middle-income countries ranged from PPP$146 in Venezuela to PPP$1095 in Brazil. Costs relate to facilities, personnel, and session dose. Delivering CR using information and communication technology(mean cost PPP$753/patient/program), lowering the dose and using lower-cost personnel and equipment are important strategies to consider in containing costs, however few explicitly low-cost models are available in the literature. Conclusion: More research is needed regarding the costs to deliver CR in community settings, the cost-effectiveness of CR in most countries, and the economic impact of return-to-work with CR participation. A low-cost model of CR should be standardized and tested for efficacy across multiple healthcare systems

A Longitudinal Examination of the Social-Ecological Correlates of Exercise in Men and Women Following Cardiac Rehabilitation

Cardiac patients who engage in &#8805;150 min of moderate- to vigorous-intensity physical activity (MVPA)/week have lower mortality, yet MVPA declines even following cardiac rehabilitation (CR), and is lower in women. A randomized trial of nine socioecological theory-based exercise facilitation contacts over 50 weeks versus usual care (1:1 parallel arms) was undertaken (NCT01658683). The tertiary objective, as presented in this paper, was to test whether the intervention impacted socioecological elements, and in turn their association with MVPA. The 449 participants wore an accelerometer and completed questionnaires post-CR, and 26, 52 and 78 weeks later. At 52 weeks, exercise task self-efficacy was significantly greater in the intervention arm (p = 0.01), but no other differences were observed except more encouragement from other cardiac patients at 26 weeks (favoring controls). Among women adherent to the intervention, the group in whom the intervention was proven effective, physical activity (PA) intentions at 26 weeks were significantly greater in the intervention arm (p = 0.04), with no other differences. There were some differences in socioecological elements associated with MVPA by arm. There were also some differences by sex, with MVPA more often associated with exercise benefits/barriers in men, versus with working and the physical environment in women

A Randomized Controlled Trial of an Exercise Maintenance Intervention in Men and Women After Cardiac Rehabilitation (ECO-PCR Trial)

Background Exercise maintenance interventions are needed for cardiac rehabilitation (CR) graduates to maintain moderate and vigorous-intensity physical activity (MVPA). We tested an exercise facilitator intervention (EFI) to promote exercise maintenance compared with usual care (UC) separately in men and women. Methods This was a 3-site, randomized (1:1), parallel-group, superiority trial (ECO-PCR). CR graduates were stratified by site and sex and randomly allocated (concealed). EFI participants received a face-to-face introductory session, 5 small-group counseling teleconferences, and 3 personal calls from a trained facilitator over 50 weeks. In-person assessments were undertaken at baseline and 26 and 52 weeks after randomization. The primary outcome was weekly minutes of MVPA, measured by accelerometer. Secondary outcomes were exercise capacity, risk factors, quality of life, and enrollment in community-based exercise programs. Effects were tested with the use of linear mixed models. Results A total of 449 CR graduates (135 women, 314 men) were randomised (n = 226 EFI, n = 223 UC). In the intention-to-treat analysis for men and for women, there were no significant effects for treatment or time on MVPA. In a planned secondary analysis that considered only those adherent to EFI (completed ≥ 66% of sessions; per-protocol), bouted MVPA (ie, in sustained bouts of ≥ 10 min) was higher in women in the EFI group (mean = 132.6 ± 135.2 min/wk at 52 weeks) compared with UC (111.8 ± 113.1; P = 0.013). Regarding secondary outcomes, in women, a treatment group main effect was observed for blood pressure (P = 0.011) and exercise capacity (P = 0.019; both per-protocol) favouring EFI; no other differences were observed. Conclusions In this trial of CR completers, an EFI showed promise for women, but was ineffective in men.This trial was supported by Heart and Stroke Foundation of Canada grant-in-aid #G-14-0006126. S.L.G. is supported in her work by the Toronto General & Toronto Western Hospital Foundation and the Peter Munk Cardiac Centre, University Health Network. The sponsor had no involvement in: the design of the study; the collection, analysis and interpretation of the data; or in the decision to approve publication of the finished manuscript