Patients with Type 2 diabetes (T2DM) have microvascular insulin resistance and dysfunction; both contribute to metabolic insulin resistance and cardiovascular complications. Glucagon-like peptide 1 (GLP-1) potently recruits muscle microvasculature and increases muscle delivery and action of insulin, likely via a protein kinase A and nitric oxide dependent pathway in laboratory animals. In the proposed studies, we will test an overarching hypothesis that sustained activation of the GLP-1 receptor (GLP-1R) enhances muscle microvascular perfusion, promotes angiogenesis, and improves the muscle microvascular response to insulin which leads to increased muscle insulin delivery and action in diabetes. We will examine whether sustained GLP- 1R activation will 1) in healthy humans increase basal muscle microvascular perfusion and rescues muscle microvascular and metabolic insulin responses in the setting of acute lipid-induced insulin resistance; 2) restore muscle microvascular insulin sensitivity, improve muscle capillarization and enhance muscle insulin delivery and action in patients with chronic insulin resistance as seen in pre-diabetes or T2DM; and 3) prevent microvascular insulin resistance, enhance trans-endothelial insulin transport and promotes muscle angiogenesis via an AMPK-mediated pathway in high fat diet (HFD) fed rats. We will use a state-of-the-art technique, contrast-enhanced ultrasound, in combination with forearm arteriovenous balance, muscle biopsy and insulin clamp to quantify the effects of sustained GLP-1R activation on microvascular and metabolic responses to insulin in humans with or without insulin resistance/diabetes and open a new avenue for future mechanistic and/or therapeutic studies. We will further in animal studies explore the underlying mechanisms. By understanding the regulation of muscle microcirculation, it may be possible to correct vascular and ameliorate metabolic insulin resistance and decrease the cardiovascular morbidity and mortality associated with diabetes.

Public Health Relevance

Patients with type 2 diabetes have reduced responses to insulin in blood vessels and skeletal muscle, a condition called insulin resistance, and are prone to suffer cardiovascular complications. They also have reduced incretin effect. In this grant proposal, we will study whether sustained activation of the glucagon-like peptide 1 receptors increase insulin sensitivity in the muscle by increasing muscle endothelial exchange surface area and insulin delivery in health and insulin resistant states. Results from the proposed studies should shed light to our understanding of the relationship between vascular and metabolic insulin resistance, and the cardiovascular complications associated with diabetes in humans and open a whole new avenue for future mechanistic, diagnostic and/or therapeutic studies.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Laughlin, Maren R
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University of Virginia
Internal Medicine/Medicine
Schools of Medicine
United States
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Yan, Fei; Yuan, Zhaoshun; Wang, Nasui et al. (2018) Direct Activation of Angiotensin II Type 2 Receptors Enhances Muscle Microvascular Perfusion, Oxygenation, and Insulin Delivery in Male Rats. Endocrinology 159:685-695
Fu, Zhuo; Wu, Jing; Nesil, Tanseli et al. (2017) Long-term high-fat diet induces hippocampal microvascular insulin resistance and cognitive dysfunction. Am J Physiol Endocrinol Metab 312:E89-E97
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
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