We discovered a previously undescribed mechanism for Type II Diabetes, i.e. a deficient glucose transport into across the cell membrane and into the cell interior in response to insulin.

We showed in an experimental model of Type II Diabetes (SHR) an enhanced proteolytic activity in the microcirculation with elevated and unchecked levels of serine proteases and matrix-degrading metalloproteinases (MMPs) proteins. This protease activity cleaves the extracellular domain of the insulin receptor-α and causes a deficiency in glucose transmembrane transport with elevated levels of blood glucose and glycated hemoglobin.

Blockade of MMPs with a broad acting inhibitor (doxycycline) reduces protease activity in plasma and microvessels, it blocks the proteolytic cleavage of the insulin receptor and consequently the reduced glucose transport. The blood glucose levels and glycated hemoglobin levels become normalized.

The insulin receptor is not the only receptor cleaved by the in-vivo unchecked protease activity. There is also immune suppression since leukocyte have a reduce adhesion to the endothelium. Our results show there is also cleavage of the binding domain of the leukocyte integrin receptor CD18. Blockade of the protease activity restores normal levels of CD18 receptor density and the deficiency in leukocyte adhesion.

These results show the first time that Type II Diabetes may be due to proteolytic cleavage of receptors, i.e. it is an auto-digestion process.