Receptor Cleavage in Metabolic Disease

Cell dysfunctions after cleavage of membrane receptors by pancreatic proteases.  

I.  A mechanism for Type II Diabetes and its co-morbidities.

The spontaneously hypertensive rat (SHR) is a model for Arterial Hypertension and Type II Diabetes.  It has chronic pancreatitis, release of pancreatic serine proteases, and activation of extracellular matrix-degrading metalloproteinases (MMPs). The proteases cleave the outer domain of receptors and generate many comorbidities.  

For example:

• Insulin resistance and Type II Diabetes due to cleavage of the insulin receptor;  

• Arterial hypertension due to beta-2 adrenergic receptor cleavage and IGF-1;

• Endothelial apoptosis and capillary rarefaction by cleavage of the endothelial growth factor receptor (VGFR2);

• Immune suppression with attenuated adhesion to the endothelium due to cleavage of leukocyte adhesion receptors (integrin CD18, ICAM-1, P-selectin, PSGL1);

• Defective cell migration and fluid shear stress response by cleavage of the FMLP receptor;

• Macrophage dysfunctions by cleavage of CD36;

• Reduced sleep quality by cleavage of the serotonin receptor;

• Cleavage of the Leptin Receptor causes lack of satiety  and development of obesity;

Chronic protease inhibition restores the diverse cell dysfunctions due to autodigestion.  

II.  Insulin resistance in human volunteers after a high fat diet meal.  

III.  Leptin receptor cleavage by proteases as a mechanism for lack of satiety and development of obesity.