Shock. 2014 Jan;41(1):55-61.

Pancreatic digestive enzyme blockade in the small intestine prevents insulin resistance in hemorrhagic shock.

Frank A. DeLano and Geert W. Schmid-Schönbein

Microcirculation Laboratory

Department of Bioengineering

Institute of Engineering in Medicine

University of California San Diego

La Jolla, CA, 92093-0412

 

ABSTRACT

Hemorrhagic shock is associated with metabolic defects, including hyperglycemia and insulin resistance but the mechanisms are unknown. We recently demonstrated that reduction of the extracellular domain of the insulin receptor by degrading proteases may lead to a reduced ability to maintain normal plasma glucose values. In shock, transfer of digestive enzymes from the lumen of the intestine into the systemic circulation after breakdown of the intestinal mucosal barrier causes inflammation and organ dysfunction. Suppression of the digestive enzymes in the lumen of the intestine with protease inhibitors is effective in reducing the level of the inflammatory reactions. To determine the degree to which blockade of digestive enzymes affects insulin resistance in shock, rats were exposed to acute hemorrhagic shock (mean arterial pressure of 30 mmHg for 2 hours) at which time all shed blood volume was returned. Digestive proteases in the intestine were blocked with a serine protease inhibitor (tranexamic acid in polyethylene glycol and physiological electrolyte solution) and the density of the insulin receptor was measured with immunohistochemistry in the mesentery microcirculation. The untreated rats without enzyme blockade had significantly attenuated levels of insulin receptor density as compared to control and treated rats. Blockade of the digestive proteases after 60 min of hypotension in the lumen of the small intestine lead to a lesser decrease in insulin receptor density compared to controls without protease blockade which exhibited a significant reduction of insulin receptor binding site. Glucose tolerance test indicates a significant increase in plasma glucose levels two hours after hemorrhagic shock, which are reduced to control values in the presence of protease inhibition in the lumen of the intestine. The transient reduction of the plasma glucose levels after an insulin bolus is significantly attenuated after shock, but is restored when digestive enzymes in the lumen of the intestine are blocked. These results suggest that in hemorrhagic shock elevated microvascular extracellular digestive enzyme activity causes insulin receptor dysfunction, hyperglycemia and reduced ability to regulate blood glucose values.

PMID: 24088998

 

 

Commentary: Autodigestion by Digestive Enzymes and Multi-organ Failure.

Geert W. Schmid-Schönbein, Ph.D.

Pancreatic digestive enzymes are key for digestion and for all the life forms that receive molecular constituents by digesting another organism or plant. Digestive enzymes, e.g. pancreatic proteases, are optimized for this task since they are relatively non-specific and have the ability to degrade any protein. After synthesis as a proform in the pancreas, they are activated when they enter the small intestine and in high concentration they have the ability to digest any tissue, including an intestine itself. The specific issue we raise here is the following: While we have the ability to degrade any protein, what mechanisms protects us from degrading ourselves, for example degrading a membrane receptor? On one hand this issue is important to understand the origin of acute cell failure in shock, such as the insulin resistance, and on the other hand it raises a more general question about the role of digestive enzymes in disease.

So what protects our intestine against autodigestion?

We digest inside the lumen of our small intestine. Protection against autodigestion is provided by the mucosal barrier, which prevents escape of the powerful digestive enzymes into the wall of the intestine. Digestive enzymes are usually compartmentalized in the lumen of our intestine.

Escape of digestive enzymes in shock and autodigestion.

But in many forms of shock the mucosal barrier breaks down. As a consequence the digestive enzymes escape into the wall of the intestine and are carried from there into the circulation. This can be a destructive event with severe pathological consequences. One of these events is that digestive enzymes have the ability to cleave the extracellular domain of receptors, for example we show here the case of the insulin receptor. Consequently insulin cannot bind to its receptor, and the receptor-mediated glucose transport into the cell cytoplasm is compromised, i.e. insulin resistance. The insulin signaling is interrupted at the extracellular level of the receptor and extracellular fragments (“soluble receptors”) are released into the plasma where they are often found in insulin-resistant patients.

Enteral blockade of digestive enzymes.

Furthermore we show, that blockade of digestive proteases inside the lumen of the intestine serves to prevent appearance of active proteases in the systemic circulation, cleavage of the insulin receptor and consequently the typical signatures of acute insulin resistance during shock. This level of protection against extracellular proteolytic cleavage is not limited to the insulin receptor. Blockade of digestive enzymes inside the lumen of the intestine, but not intravenous treatment, protects in several forms of experimental shock models against cell dysfunctions and multiorgan failure and reduces mortality (Science Translational Medicine, 5(169):169ra11, 2013).

Proteolytic receptor cleavage and cell dysfunction

These observations are in line with similar results in a chronic form of insulin resistance (Hypertension, 52: 415-423, 2008). The insulin resistance in both cases is caused by proteolytic cleavage of its extracellular domain. There are other membrane receptors and also plasma proteins that are subject to proteolytic cleavage by extracellular proteases. Loss of the ectodomain of a receptor population is accompanied by reduction of the cell function facilitated by the receptor. We have been able to show this pathogenic mechanism with several receptors, including the VEGFR2 (it leads to endothelial apoptosis and loss of capillaries), leukocyte membrane adhesion receptors (which causes immune suppression), adrenergic receptors (which mediates arteriolar constriction and elevated blood pressure), and others (Curr. Hypertens. Reports, 14:88-96, 2012). The loss of each of these receptors is accompanied by cell dysfunctions that can be attenuated by pharmacological blockade of the extracellular protease activity.

In summary, the pancreatic digestive enzymes serve over a lifetime digestion of food, but there is no assurance that they only digest food. Instead, if they escape into the circulation there may be a price to pay for this advantage, and that price is autodigestion. Insulin resistance may be one of multiple events during autodigestion.

 

 

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