Vasopressin's Role in Stress Response and Glucose Homeostasis in a Pig Model of Endotoxin‐Induced Inflammation

Abstract

Both acute stress hyperglycemia and uncontrolled hypoglycemia may serve as indices of disease severity in critically ill patients, yet the mechanisms behind altered glucose control in inflammatory diseases such as acute sepsis is poorly understood. Evidence of the ability of vasopressin to mediate central and peripheral glucose regulation via V1b and V1a receptors has mounted over the years, but the role of vasopressin in glucose homeostasis during sepsis, is unclear. We hypothesized that vasopressin is involved in glycemic control in endotoxin‐induced inflammation seen in sepsis but that this role may be overshadowed by vasopressin's primary role of maintaining blood pressure in the face of septic shock. Thus, we used a piglet model of endotoxin‐induced pulmonary hypertension in the absence of systemic shock to better understand the relationship between vasopressin and glucose homeostasis in a hypoxemia‐induced inflammatory state. The intent was to study effects of vasopressin separate from its role in blood pressure regulation.After hemodynamic equilibration following catheterization of anesthetized Yorkshire cross piglets (8 kg body weight), baseline mean arterial pressure, cardiac output, and blood gasses were assessed, and blood was obtained for measurement of glucose (BG), vasopressin, cortisol, insulin, glucagon, and cytokine profiles. Liver and pancreatic blood flows were assessed via colored microsphere method. E. coli endotoxin (7,500–50,000 units) was administered intravenously to achieve pulmonary hypertension (evidenced by a pulmonary to systemic vascular resistance ratio increase of 120%), which decreased arterial oxygenation to a PaO2 of 78 ± 5 mm Hg without systemic hypotension(ETX, n=16). Piglets were followed for 11 hours after endotoxin administration. Results were compared against control piglets who did not receive endotoxin (CON, n=7). In CON group, all hemodynamics and biomarkers measured remained constant. Endotoxin caused an increase in pro‐inflammatory markers TNFα, IL‐1ra, and IL‐6. Blood glucose levels were elevated at baseline in both CON (189±11 mg/dL) and ETX (199±9 mg/dL), with corresponding elevated vasopressin levels (106 ± 17 pg/ml; and 78 ± 9 pg/ml in CON and ETX, respectively) likely due to piglet susceptibility to anesthesia induction stress. Both BG and vasopressin levels decreased over the duration of the experiment, with no significant changes in cortisol. Liver blood flow tended to decrease and pancreatic blood flow to increase with time in both CON and ETX. Interestingly, insulin increased 6‐fold with endotoxin and then returned toward baseline by 2 hours after endotoxin administration. Glucagon increased after endotoxin and remained elevated over baseline 11 hours later.Stepwise multiple regression analysis was used to determine relationships between BG and vasopressin, cortisol, insulin, glucagon, TNFα, IL‐1ra, and IL‐6, liver and pancreatic blood flows, hemodynamics, and blood oxygenation. BG was most strongly positively associated with circulating vasopressin, liver blood flow and insulin, and negatively correlated with glucagon (r= 0.72, p<0.001). Our results support an important role of vasopressin as a stress hormone regulator of glucose homeostasis both in control conditions and in the response to endotoxin‐induced stress.Support or Funding InformationThis project was funded by the US Army Medical Command. The views expressed in this abstract are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the U.S. Government.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.