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Habitual aerobic exercise decreases endothelin-1 and restores insulin-induced vasodilation in patients with type 2 diabetes: role shear stress

Grant number: 17/25613-6
Support type:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): June 01, 2018
Effective date (End): May 29, 2019
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Carlos Eduardo Negrão
Grantee:Allan Robson Kluser Sales
Supervisor abroad: Jaume Padilla
Home Institution: Instituto do Coração Professor Euryclides de Jesus Zerbini (INCOR). Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
Local de pesquisa : University of Missouri, Columbia (UM), United States  
Associated to the scholarship:14/11671-6 - Effect of high intensity interval training versus continuous moderate in the peripheral reflex mechanisms of control of the sympathetic activity in patients with heart failure, BP.PD

Abstract

The notion that habitual aerobic exercise increases insulin-induced vasodilation is largely founded on rodent studies, hence the urgent need for human studies, especially in patients with type 2 diabetes (T2D). Based on previous data, we hypothesize that this restoration of vascular actions of insulin is associated with a reduction of protein kinase C (PKC) activation and endothelin-1 (ET-1) expression in the vasculature of skeletal muscle. Indeed, we contend that increased physical activity and associated hemodynamic forces (e.g., shear stress) are a direct form of vascular medicine in humans. Therefore, the purpose of this study is determine the effects of increased walking and shear stress on insulin-stimulated leg blood flow in sedentary patients with T2D. Planned Experiments. Male and female patients with T2D (n=36) who are overweight and obese (BMI 25-39 kg/m2), 40-65 years of age, and will be recruited for study. Patients with T2D will be classified based on physician diagnosis and have a fasting blood glucose >126 mg/dl (but <200 mg/dl) and HbA1c >6.5 (but <10). T2D and non-T2D patients will be matched for BMI, sex, and age. Exclusion criteria: Evidence of 1) cardiovascular disease including myocardial infraction, heart failure, coronary artery disease, stroke; 2) renal or hepatic diseases; 3) active cancer; 4) autoimmune diseases; 5) immunosuppressant therapy; 6) excessive alcohol consumption (>14 drinks/week); 7) current tobacco use; 8) pregnancy and 9) patients with mobility limitations. Hypothesis A: Increased walking decreases vascular PKC activation and ET-1 expression, thus leading to an improvement in insulin-stimulated leg blood flow. To test this hypothesis, subjects will be randomized to a control group (n=12) or walking group (n=12). The walking program will consist of 45 minutes of supervised walking on the treadmill (at 60% of VO2 peak) 5 days per week for 8 weeks. Exercise interventions of similar intensity and duration have produced beneficial vascular effects in humans. Subjects in the control group will be assigned to an upper body stretching program that will meet 3 times/week for 30 min during the 8-week period. Before and after the 8-week period, subjects will come to the Clinical Research Center (CRC) to repeat the tests. On Day 1, subjects will be placed supine in a quiet, climate-controlled room (22-23°C) and flow-mediated dilatation (FMD) in the popliteal artery will be assessed as a marker of leg endothelial function. Next, the (insulin clamp, coupled with measures of leg blood flow, will be performed following standard procedures at the CRC. Subjects will be instrumented for measures of heart rate (ECG), arterial blood pressure (via Finometer), and popliteal artery blood flow (Doppler). After a minimum of 20 min supine rest, baseline cardiovascular measurements will be collected, blood samples obtained and the hyperinsulinemic-euglycemic clamp will start. On Day 2, body composition will be assessed with DEXA. Gastrocnemius muscle biopsie samples will be collected. Arterioles from skeletal muscle biopsies will be isolated for molecular characterization via immunofluorescence. Assessments will include expression/activity of PKC, MAPK, eNOS, and ET-1.Hypothesis B: Increased leg vascular shear stress using a non-exercise stimulus (i.e., leg heating) recapitulates the beneficial vascular effects of increased walking, including a reduction in vascular PKC activation and ET-1 expression, as well as an improvement in insulin-stimulated leg blood flow. To test this hypothesis, subjects (n=12) will undergo unilateral leg heating for 45 min, 5 days per week for 8 weeks at MUPAW. The contralateral leg will serve as the internal control. Before and after the 8-week period, subjects will come to the laboratory for the same two testing days and procedures (Day 1 and Day 2), as stated above.

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
OLVER, T. DYLAN; GRUNEWALD, I, ZACHARY; GHIARONE, THAYSA; RESTAINO, ROBERT M.; SALES, ALLAN R. K.; PARK, LAUREN K.; THORNE, PAMELA K.; GANGA, RAMA RAO; EMTER, CRAIG A.; LEMON, PETER W. R.; SHOEMAKER, J. KEVIN; MANRIQUE-ACEVEDO, CAMILA; MARTINEZ-LEMUS, LUIS A.; PADILLA, JAUME. Persistent insulin signaling coupled with restricted PI3K activation causes insulin-induced vasoconstriction. AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, v. 317, n. 5, p. H1166-H1172, NOV 2019. Web of Science Citations: 0.

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