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Trauma Research Laboratory

Dr. Brian Harbrecht In Focus: The Role of Glucagon and Insulin in Surgical Sepsis
Brian G. Harbrecht, MD
Professor of Surgery
University of Louisville
Department of Surgery

Brian G. Harbrecht, MD, and his team are focusing on glucagon and hepatic gene expression in surgical sepsis—research for which they were awarded an NIH R01 grant.

The immune response to sepsis involves a series of complex, highly integrated homeostatic responses that, if prolonged and excessive, can lead to organ dysfunction and death. Nitric oxide (NO) synthesis is upregulated by sepsis in many tissues and is an essential component of the host immune response. Nitric oxide synthesis can be beneficial and improve immune and organ function but if synthesis is excessive and prolonged, NO can promote organ injury, tissue inflammation, and death. NO is produced in hepatocytes by the inducible nitric oxide synthase (iNOS) that is stimulated by cytokines and proinflammatory stimuli.

Going to the Excess
Excessive NO from iNOS produces cellular dysfunction and hepatic injury. Glucagon and cyclic adenosine monophosphate (cAMP) regulate hepatic iNOS expression in vitro and in vivo and, by doing so, decrease NO-mediated hepatic injury. Our preliminary data demonstrate that insulin also down-regulates cytokine-induced iNOS expression.

Understanding the Regulators
Interest in the mechanisms regulating the effect of glucagon and insulin on cellular metabolism has been rekindled with the emphasis on tightly controlling blood glucose levels in critically ill patients. Glucagon and insulin alter specific intracellular signaling pathways in hepatocytes but the mechanisms involved in their regulation of hepatocyte function in sepsis, and specifically, the regulation of hepatocyte iNOS expression, have not been identified.

In our laboratory, we are investigating how glucagon and insulin work to regulate hepatocyte iNOS expression, which would provide a framework for understanding the basic pathophysiologic cellular events in shock and sepsis that may lead to novel cellular-based therapies for critically ill patients.

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