Eugene J. Barrett, MD, PhD
Degree(s): MD, PhD
Graduate School: University of Rochester
Primary Appointment: Professor, Medicine, Endocrinology and Metabolism
Diabetes and Insulin Action
Email Address: email@example.com
Research in my laboratory focuses on studies of insulin action and how insulin's action is altered by insulin resistance, obesity, and diabetes mellitus. Specific studies currently underway involve measurement of the action of insulin to regulate its own delivery to skeletal muscle by acting on endothelial cells and smooth muscle cells. Insulin relaxes smooth muscle cells associated with terminal arterioles and dilates microvascular vessels to enhance tissue perfusion, thereby increasing the delivery of both insulin and glucose to the tissues. This vasodilator effect appears to be secondary to insulin's action on the endothelial cell to increase the production of nitric oxide via the activation of the enzyme nitric oxide synthase.
We have also demonstrated a second effect of insulin on the endothelial cell. This involves insulin promoting its own uptake at the luminal surface of the endothelial cell and which then transports the insulin across to the ablumenal surface of the cell where it is released and becomes available to act on target tissues like adipocytes and myocytes. We have experimental evidence that both the ability of insulin to cause smooth muscle relaxation and to promote its own transport are impaired in states of insulin resistance (e.g. obesity, type 2 diabetes). This step involving insulin transport across the endothelium appears to be the rate limiting step for overall insulin action on skeletal muscle (which is the major target tissue for insulin-mediated glucose disposal).
We are also studying how these processes are affected by the action of other growth factors (growth hormone and IGF-I). A major hypothesis which we are exploring is that a significant fraction of the insulin resistance which is encountered in skeletal muscle in states like obesity, diabetes, and hypertension is attributable to impaired action of insulin on the microvasculature in addition to any effect on the muscle cell per se.
Genders AJ, Frison V, Abramson SR, Barrett EJ. Endothelial cells actively concentrate insulin during its transendothelial transport. Microcirculation. 2013 Jan 28. doi: 10.1111/micc.12044.
Barrett EJ, Liu Z. The endothelial cell: An "early responder" in the development of insulin resistance. Rev Endocr Metab Disord. 2013 Jan 10. [Epub ahead of print] PubMed PMID: 23306779.
Eggleston EM, Jahn LA, Barrett EJ. Early microvascular recruitment modulates subsequent insulin-mediated skeletal muscle glucose metabolism during lipid infusion. Diabetes Care. 2013 Jan;36(1):104-10. doi: 10.2337/dc11-2399.
Barrett EJ, Eringa EC. The vascular contribution to insulin resistance: promise, proof, and pitfalls. Diabetes. 2012 Dec;61(12):3063-5. doi: 10.2337/db12-0948.
Barrett EJ, Rattigan S. Muscle perfusion: its measurement and role in metabolic regulation. Diabetes. 2012 Nov;61(11):2661-8. doi: 10.2337/db12-0271.
Wang H, Wang AX, Barrett EJ. Insulin-induced endothelial cell cortical actin filament remodeling: a requirement for trans-endothelial insulin transport. Mol Endocrinol. 2012 Aug;26(8):1327-38. doi: 10.1210/me.2012-1003.
Upchurch CT, Barrett EJ. Clinical review: Screening for coronary artery disease in type 2 diabetes. J Clin Endocrinol Metab. 2012 May;97(5):1434-42. doi: 10.1210/jc.2011-2122.
Chan A, Barrett EJ, Anderson SM, Kovatchev BP, Breton MD. Muscle microvascular recruitment predicts insulin sensitivity in middle-aged patients with type 1 diabetes mellitus. Diabetologia. 2012 Mar;55(3):729-36. doi:10.1007/s00125-011-2402-3.
Majumdar S, Genders AJ, Inyard AC, Frison V, Barrett EJ. Insulin entry into muscle involves a saturable process in the vascular endothelium. Diabetologia. 2012 Feb;55(2):450-6. doi: 10.1007/s00125-011-2343-x.
Barrett EJ, Wang H, Upchurch CT, Liu Z. Insulin regulates its own delivery to skeletal muscle by feed-forward actions on the vasculature. Am J Physiol Endocrinol Metab. 2011 Aug;301(2):E252-63. doi: 10.1152/ajpendo.00186.2011.
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