Patients with type 2 diabetes mellitus (T2DM) frequently develop cardiovascular complications which contribute significantly to morbidity and mortality. Insulin resistance and endothelial dysfunction are two cardinal features of T2DM. Whether microvascular insulin resistance contributes to the increased cardiovascular morbidity and mortality in patients with T2DM remains to be defined. T2DM is associated with humoral and inflammatory changes that can cause insulin resistance and endothelial dysfunction. Among them, elevation of plasma free fatty acids (FFAs) and over-activation of the renin-angiotensin system (RAS) are thought to play pivotal roles in vascular insulin resistance and endothelial dysfunction, and in the increased cardiovascular morbidity and mortality of diabetes. In the proposed studies, we will test the hypotheses that: 1) elevation of plasma FFAs blunts insulin-mediated cardiac and skeletal muscle microvascular perfusion and glucose uptake by activating inflammatory signaling and increasing endothelin 1 (ET- 1) secretion/action;2) AT1R blockade increases cardiac and skeletal muscle microvascular perfusion, augments insulin-mediated glucose uptake, and attenuates FFA-induced dysfunction in the coronary and skeletal muscle microcirculation in healthy humans;and 3) patients with diabetes have decreased coronary microvascular flow reserve and blunted vasodilatory response upon insulin stimulation in the cardiac and skeletal muscle microvasculature, and that these abnormalities are corrected with anti-inflammatory therapy and/or AT1R blockade. We will quantify cardiac and skeletal muscle microvascular perfusion in healthy and diabetic humans and examine the potential mechanisms underlying microvascular insulin resistance. Results from the proposed studies should help to define the mechanisms underlying insulin resistance in cardiac and skeletal muscle microvasculature in diabetic humans and open a new avenue for future mechanistic, diagnostic and/or therapeutic studies.
Patients with type 2 diabetes are prone to suffer heart diseases such as heart attack and heart failure;both cause significant morbidity and mortality. The underlying mechanisms remain unclear. Patients with type 2 diabetes have decreased responses to insulin, a condition called insulin resistance. Insulin resistance has been implicated in the development of cardiovascular diseases in diabetic patients. Insulin increases blood flow, hence oxygen and nutrient delivery, to tissues, including heart and skeletal muscle. We and others have recently shown that insulin resistance is present in the small blood vessels in heart and skeletal muscle. Whether this contributes to the increased cardiovascular morbidity and mortality in persons with diabetes is not known. Diabetes is associated with many biochemical abnormalities which are capable of causing insulin resistance and abnormal vascular function in peripheral tissues. In this proposal, we plan to examine whether these abnormalities impair insulin action in the small vessels in human heart and skeletal muscle and whether patients with type 2 diabetes have an abnormal response to insulin in small blood vessels that nourish the heart and skeletal muscle. We will use state-of-the-art techniques to non- invasively measure small blood vessel perfusion in the human heart and skeletal muscle. Results from the proposed studies should shed light to our understanding of the relationship between type 2 diabetes and cardiovascular diseases in humans and open a new avenue for future mechanistic, diagnostic and/or therapeutic studies.
|Chai, Weidong; Fu, Zhuo; Aylor, Kevin W et al. (2016) Liraglutide prevents microvascular insulin resistance and preserves muscle capillary density in high-fat diet-fed rats. Am J Physiol Endocrinol Metab 311:E640-8|
|Zheng, Chao; Liu, Zhenqi (2015) Vascular function, insulin action, and exercise: an intricate interplay. Trends Endocrinol Metab 26:297-304|
|Zhao, Lina; Fu, Zhuo; Wu, Jing et al. (2015) Globular adiponectin ameliorates metabolic insulin resistance via AMPK-mediated restoration of microvascular insulin responses. J Physiol 593:4067-79|
|Zhao, Lina; Fu, Zhuo; Wu, Jing et al. (2015) Inflammation-induced microvascular insulin resistance is an early event in diet-induced obesity. Clin Sci (Lond) 129:1025-36|
|Zhao, Lina; Fu, Zhuo; Liu, Zhenqi (2014) Adiponectin and insulin cross talk: the microvascular connection. Trends Cardiovasc Med 24:319-24|
|Subaran, Sharmila C; Sauder, Matthew A; Chai, Weidong et al. (2014) GLP-1 at physiological concentrations recruits skeletal and cardiac muscle microvasculature in healthy humans. Clin Sci (Lond) 127:163-70|
|Fu, Zhuo; Zhao, Lina; Aylor, Kevin W et al. (2014) Angiotensin-(1-7) recruits muscle microvasculature and enhances insulin's metabolic action via mas receptor. Hypertension 63:1219-27|
|Chai, Weidong; Zhang, Xingxing; Barrett, Eugene J et al. (2014) Glucagon-like peptide 1 recruits muscle microvasculature and improves insulin's metabolic action in the presence of insulin resistance. Diabetes 63:2788-99|
|Anderson, Amy D; Solorzano, Christine M Burt; McCartney, Christopher R (2014) Childhood obesity and its impact on the development of adolescent PCOS. Semin Reprod Med 32:202-13|
|Liu, Zhenqi (2013) The vascular endothelium in diabetes and its potential as a therapeutic target. Rev Endocr Metab Disord 14:1-3|
Showing the most recent 10 out of 25 publications