Zhenqi Liu, M.D.
Professor of Medicine and Chief
Division of Endocrinology and Metabolism
Department of Medicine
- Graduate: M.D., Hunan Medical University
- Internal Medicine Residency: Washington Hospital Center, Washington, DC
- Endocrinology Fellowship: University of Virginia, Charlottesville, VA
- Endocrinology Research Fellowship: Yale University (New Haven, CT) and University of Virginia (Charlottesville, VA)
My laboratory has long been interested in insulin action and its regulation in health and insulin resistant states. Currently the primary focus is on the regulation of insulin action in the vasculature and its relation to insulin’s metabolic action and the cardiovascular complications of diabetes.
In order for insulin to exert its metabolic actions in muscle, it first must be delivered to muscle interstitium. Insulin regulates its own delivery by acting at three discrete steps: 1) dilation of the resistance vessels to increase total blood flow; 2) relaxation of pre-capillary arterioles to increase microvascular perfusion and endothelial exchange surface area (microvascular recruitment); and 3) trans-endothelial transport of insulin from the plasma to muscle interstitium. These actions are impaired in the insulin-resistant states. My laboratory studies insulin actions at all three steps.
Upon binding to its receptors, insulin at physiological concentrations activates the IRS/PI3-K/Akt/eNOS pathway, leading to increased nitric oxide production and dilation of peripheral resistance arteries and pre-capillary terminal arterioles. Insulin-mediated microvascular recruitment precedes insulin-stimulated glucose uptake in skeletal muscle and contributes up to 40% of insulin-stimulated glucose disposal during insulin clamp.
Microvascular insulin resistance is well established in patients and animal models of obesity and diabetes. In humans, insulin resistance associated with simple obesity blunts insulin-stimulated muscle microvascular perfusion and this is correlated with decreased whole body glucose disposal. The underlying mechanisms are under active investigation in my laboratory. We have found that inflammation, free fatty acids (FFAs), and angiotensin II type 1 receptor activity all cause microvascular insulin resistance. Elevation of plasma concentrations of inflammatory cytokines or FFAs blunts insulin-mediated muscle microvascular recruitment and glucose disposal.
The renin-angiotensin system is up-regulated in the cardiovascular system in the insulin resistant states and many clinical trials have demonstrated a significant cardiovascular benefit of angiotensin receptor blockers. We have recently demonstrated that angiotensin II type 1 (AT1R) and type 2 (AT2R) receptors reciprocally regulate basal perfusion of muscle microvasculature and modulate insulin's microvascular and metabolic action in muscle. AT1R activity decreases basal muscle microvascular blood volume (MBV) and glucose extraction and markedly restrains muscle metabolic responses to insulin via decreased microvascular recruitment and insulin delivery. On the contrary, AT2R activity increases basal muscle MBV and glucose extraction and is required for normal microvascular responses to insulin. Thus, pharmacologic manipulations aimed at increasing the AT2R-to-AT1R activity ratio may afford the potential to improve muscle insulin sensitivity and glucose metabolism.
We are also studying the role of glucagon-like peptide 1 (GLP-1) in the regulation of muscle microvascular perfusion and glucose metabolism and its interaction with insulin. We have recently demonstrated that GLP-1 acutely increases muscle microvascular recruitment and glucose use via a nitric oxide-dependent mechanism independent of its effect on insulin secretion. These effects are associated with increased muscle insulin delivery and action. The underlying mechanisms are under active investigation in my laboratory.
Our research is supported by the NIH and the American Diabetes Association:
- NIH RO1 HL094722 (NIDDK, PI Liu, “Insulin action in human cardiac and skeletal muscle microvasculature,” 04/15/10–2/28/15)
- ADA 7-09-NOVO-11 (PI Liu, “Glucagon-like peptide 1 (GLP-1) regulation of cardiac microvasculature in human diabetes,” 09/01/09–08/31/12)
- ADA 1-11-CT-30 (PI Liu, “Angiotensin II regulation of endothelial surface area and insulin delivery in humans,” 01/01/11–12/31/13)
- NIH R01 DK057878 (NIDDK, PI Barrett [Liu co-investigator], “Insulin’s action on the microvasculature,” 04/01/01–03/31/14)
- NIH R01 DK73759 (NIDDK, PI Barrett [Liu co-investigator], “Microvascular regulation of insulin delivery to human muscle,” 09/17/06–06/30/16)