|Fluorescent micrographs show significant differences in the insulin receptor density in microvessels of a rat before (control), after hemorrhagic shock (SHOCK) and after treatment by blocking the digestive enzymes in the lumen of the intestine with the protease inhibitor tranexamic acid (right panel). The red color is generated by use of an antibody that binds to the outer domain of the insulin receptor revealing its density. Credit: Microcirculation Lab at UC San Diego|
San Diego, CA, October 8, 2013 -- Bioengineers at the University of California, San Diego have discovered that insulin resistance in shock patients is caused by the leakage of powerful digestive enzymes from the small intestine that eat away and destroy the insulin receptor in cells. Reporting online in the journal Shock, the team has also found a way to stop these enzymes’ destructive path by blocking them in the intestine, where they are normally used to digest food.
The research team includes Frank DeLano, lead investigator, and co-investigator Geert Schmid-Schönbein, professor and chair of bioengineering at UC San Diego Jacobs School of Engineering.
Doctors have long known that trauma patients going into shock are at risk of developing acute insulin resistance, leading to hyperglycemia. The pancreas releases insulin to deliver glucose to cells to convert into energy for the body. When cells are unable to process insulin properly, a condition known as insulin resistance, blood sugars rise and the pancreas releases more insulin, compounding the problem. Until now, doctors have not known what mechanism causes insulin resistance to develop in shock patients or how to treat it.
"Despite our best efforts, clinicians have been limited in our ability to treat the sickest patients who are in intensive care units because we don't fully understand the basic pathology of what's going on with them,” said Dr. Edwin Deitch, a professor in the Department of Surgery at Rutgers New Jersey Medical School. “The basic insights about how these digestive enzymes can destroy healthy tissue in shock patients opens up our understanding and new avenues of treatment which can hopefully be applied to the benefit of our patients."
Hank Loy, president of Leading BioSciences, which partially funded the research, said “We are encouraged by the results we have seen to date as we may finally have an answer for this unmet need. This new treatment has the potential to significantly improve outcomes for patients while reducing the overall healthcare cost to hospitals which exceeds $40 billion per year in the USA alone.”
Their findings build on decades of research led by Schmid-Schönbein into the underlying causes of shock in trauma patients, particularly as they relate to the powerful, concentrated digestive enzymes in the intestine. These digestive enzymes need to be restricted to the inside of the small intestine by its mucosal barrier. Once this barrier is disrupted, which can occur for a variety of reasons including dramatic loss of blood, physical puncture or opening (as in shrapnel injury or appendicitis), or degradation by bacterial toxins, digestive enzymes leak into the wall of the intestine and begin digesting it, a phenomenon the UC San Diego researchers call “autodigestion.” Once beyond the mucosal barrier of the small intestine, the researchers believe the digestive enzymes damage other organs by indiscriminately starting to degrade them, which can lead to multiorgan failure and death.
“While basic research on the body’s physiological response to trauma has led to advances that have helped increase survival rates, much remains unknown” said Scott Somers, Ph.D., of the National Institutes of Health's National Institute of General Medical Sciences, which partially funded the research. “This new work adds to our understanding of the cascade of events that occur after shock and, even more importantly, suggests that stopping autodigestion may be a new therapeutic approach for halting the devastating downward spiral that can occur after traumatic injury.”
The team reported last January in Science Translational Medicine that blocking these enzymes in the intestine using an already FDA-approved enzyme inhibitor successfully stopped multiorgan failure in experiments with rats. In particular, by administering digestive enzyme blockers directly into the small intestines of rats an hour after the onset of different types of shock, the researchers reversed the often fatal conditions, reduced injury to the heart and lungs, and greatly increased long-term survival of the animals from about 16 percent to 86 percent.
In a new experiment focused specifically on insulin resistance, rats were exposed to acute hemorrhagic shock and then treated with an enzyme inhibitor one hour later. Rats that were treated with the enzyme inhibitor had less damage in the insulin receptors of their cells compared to untreated rats. The blood sugar levels of treated rats also returned to normal ranges following a significant increase before the treatment was administered.
John Rodenrys, executive director of research and development for Leading BioSciences, believes that the research team’s finding has significant implications beyond insulin resistance as the team has discovered that other receptors are also damaged in autodigestion. These receptors include ones implicated in eating disorders, sleep deprivation, and blood pressure control among others.
The research was supported by the National Institute of Health (NIH GM85072) and an unrestricted gift by Leading BioSciences, Inc. The authors own equity in Inflammagen, a company by Leading BioSciences, Inc., which develops therapy for shock patients.