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PROTEOLYTIC CLEAVAGE OF INSULIN RECEPTOR BY PANCREATIC DIGESTIVE ENZYMES LEADS TO INSULIN RESISTANCE IN HEMORRHAGIC SHOCK

Hemorrhagic shock is associated with metabolic defects, including hyperglycemia and insulin resistance. The mechanisms are unknown. We recently demonstrated that insulin resistance may involve cleavage of the extracellular domain of the insulin receptor by degrading proteases. In shock, transfer of digestive enzymes 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 was shown in this laboratory to be effective in reducing the level of the inflammatory reactions. To determine what degree 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, 0.3 mM, in polyethylene glycol‐3350, 60 g/L) and the density of the insulin receptor was measured with immunohistochemistry in the mesentery microcirculation. The untreated rat 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. These results suggest that in physiologic shock elevated microvascular digestive enzyme activity leads to proteolytic cleavage of the insulin receptor and subsequent insulin resistance