Systemic inflammation plays a critical role in atherosclerotic diseases and with cardiovascular and cerebrovascular events, insulin resistance, and the development of type 2 diabetes. Adipocytes of insulin resistant individuals produce and secrete larger amounts of these adipokines and bioactive molecules with the exception of adiponectin, an anti-inflammatory and insulin-sensitizing adipokine. Skeletal muscle adipokine receptors may dictate the impact of these circulating proteins on the degree of insulin resistance and systemic inflammation. Inflammation is a risk factor for stroke and contributes to the progression of cardiovascular disease. Moreover, there is a high prevalence of hyperinsulinemia and individuals are at increased risk for diabetes after stroke. The fundamental hypothesis of this study is that key inflammatory markers (TRNa, adiponectin) in adipose tissue and skeletal muscle are abnormal, skeletal muscle insulin signaling is impaired, and systemic insulin sensitivity is reduced in hemiparetic stroke patients and that these factors are modifiable and improved by exercise training in stroke patients.
The aims of this study are the following: 1) To determine whether key systemic (TRNa and adiponectin circulating levels) and tissue (adipose tissue and skeletal muscle) inflammation (secretion, expression, and cytokine receptor TNFR1, TNFR2, adipoR1, adipoR2 expression) are disturbed in chronic stroke compared to age, sex, BMI, race, and risk-factor matched non-stroke controls and whether a 6-month randomized treadmill training intervention modifies these inflammatory markers in stroke patients;and 2) To determine whether a 6-month randomized treadmill training intervention improves systemic insulin sensitivity compared to stretch control in stroke patients by altering downstream signaling (AMPK, JNK, IRS1- Ser307, Akt and p-38 MAPK phosphorylation) and GS activity in hemiparetic and nonparetic leg skeletal muscles. To accomplish these aims, 90 subjects (n=18 controls and n=72 hemiparetic stroke patients) aged 55-75 years, BMI 20-35 kg/m2 will undergo abdominal and gluteal adipose tissue biopsies, and basal and insulin-stimulated vastus lateralis muscle biopsies during hyperinsulinemic-euglycemic clamps. Stroke subjects will be assigned to 6 month treadmill or education/stretch control intervention using a one-two-one randomization blocked on race, sex, and glucose tolerance status. This clinical translational research trial takes physiological outcomes from the clinic to the bench to determine the molecular mechanisms underlying the systemic insulin resistance in stroke compared to age and risk-factor matched non-stroke controls and whether treadmill training reduces inflammation and improves systemic insulin sensitivity in stroke. Direct measurement of inflammatory modulators in adipose tissue and skeletal muscle will provide novel information as to whether selected cytokines adversely affect insulin signaling at the skeletal muscle. Furthermore, the mechanistic findings will provide the first evidence of the molecular mechanisms by which treadmill training improves inflammatory regulators in adipose tissue and skeletal muscle and improves insulin signaling and action in skeletal muscle to increase insulin sensitivity in older stroke patients. This research will identify a strategy to treat insulin resistance in stroke survivors and establish the biological basis for recommending lifestyle modifications to reduce inflammation and improve the metabolic profile in stroke.
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