Leon  S.  Farhy Degree(s):  PhD Graduate School: Sofia University Primary Appointment: Associate Professor, Medicine, Endocrinology and Metabolism Research Interests: Understanding the mechanisms that regulate glucagon secretion, glucose homeostasis, and growth hormone release. Mathematical modeling of hormone networks. Diabetes, hypoglycemia, artificial pancreas technology. Email Address: leon@virginia.edu

Research Description

My research is in the field of systems endocrinology and focuses on the endocrine mechanisms and relationships between the different cell types in the islets of Langerhans that direct the time-varying secretion patterns of the pancreatic hormones.  We are interested in the mechanisms of glucagon release from the α-cells in response to hypoglycemia, study how these mechanisms are altered in diabetes, and seek to develop strategies for their repair. Through series of interdisciplinary experimental and clinical in vivo work and mathematical modeling in silico studies, we have shown that the abnormalities in the glucagon defenses against hypoglycemia in diabetes are mediated in part by miscommunication between the different cell types in the pancreatic islets and are essentially  of "network origin". The lack of β-cell signaling is the primary deficiency that contributes to two separate network defects: (i) absence of a "switch-off" trigger to the α-cells and (ii) increased intraislet basal glucagon.  We have experimental evidence suggesting that both defects can be potentially repaired by therapeutic strategies based on the use of α-cell inhibiting drugs.
 
To further test the hypothesis that α-cell inhibitors can be used to manipulate the pancreatic network to enhance the glucagon response to hypoglycemia and start translation of our findings into the clinic our lab collaborates with the UVA Center for Diabetes Technology. Taking advantage of the Center's cutting-edge artificial pancreas technologies we work on the development of strategies for dual-hormone automated glucose control in patients with type 1 diabetes that use both insulin and α-cell inhibiting drugs. The addition of an α-cell inhibitor as a second control mechanism is expected to allow us to manipulate the pancreatic endocrine network to achieve better glycemic control with reduced hypoglycemia risk.

Selected Publications

Farhy LS, Chan A, Breton M, Anderson S, Kovatchev B, McCall A. Association of basal hyperglucagonemia with impaired glucagon counterregulation in T1DM. Front Physiol. 3: 40, 2012.

Farhy LS, McCall AL. Optimizing Reduction in Basal Hyperglucagonaemia to Repair Defective Glucagon Counterregulation in Insulin Deficiency. Diabetes, Obesity and Metabolism,13: s1, 133 -143, 2011. 

Farhy LS, Ortiz A, Kovatchev BP, Mora AG, Wolf SE, Wade CE. Average Daily Risk Range (ADRR) as a Measure of Glycemic Risk is Predictive of Mortality in the ICU: A Retrospective Study in a Burn ICU. J Diabetes Sci Technol. 1;5(5):1087-1098, 2011.

Farhy LS, McCall AL. Models of Glucagon Secretion, Their Application to the Analysis of the Defects in Glucagon Counterregulation and Potential Extension to Approximate Glucagon Action. Journal of Diabetes Sci Technol 4(6):1345-1356, 2010.

Farhy LS, McCall AL. System-Level Control to Optimize Glucagon Counterregulation by Switch-Off of α-Cell Suppressing Signals in β-Cell Deficiency. J Diabetes Sci Technol. 3(1):21-33, 2009.

Farhy LS, Du Z, Zeng, Veldhuis PP, Johnson ML, Brayman KL, McCall AL. Amplification of pulsatile glucagon secretion by switch-off of α-cell suppressing signals in Streptozotocin (STZ)-treated rats. Am J Physiol Endocrinol Metab. 295: E575 - E585, 2008.

Nass R*, Farhy LS*, Liu J, Prudom C, Johnson ML, Veldhuis PP, Pezzoli SS, Oliveri MC, Gaylinn BD, Geysen MH, Thorner MO (*two first authors). Evidence for Acyl-Ghrelin Modulation of Growth Hormone Release in the Fed State. J Clin Endocrinol Metab. 93(5):1988 -1994, 2008.

Farhy LS, Bowers CY, Veldhuis JD Model-projected mechanistic bases for sex differences in growth-hormone (GH) regulation in the human. Am J Physiol 292: R1577-R1593, 2007.

Farhy LS, Veldhuis JD. Deterministic construct of amplifying actions of ghrelin on pulsatile growth hormone secretion. Am J Physiol,  288: R1649 - R1663, 2005.

Farhy LS, Veldhuis JD. Putative Growth Hormone (GH) Pulse Renewal: Periventricular Somatostatinergic Control of an Arcuate-Nuclear Somatostatin and GH-Releasing Hormone Oscillator. Am J Physiology 286(6):R1030-42, 2004.