New hypothesis for insulin resistance in hypertension due to receptor cleavage

Abstract

Background: One of the most important unresolved issues in diabetes is the mechanism for the attenuated response to insulin (i.e., insulin resistance). Aims and methods: We hypothesize that the mechanism for insulin resistance is due to uncontrolled protease activity in the plasma, on endothelial cells and in the tissue parenchyma. To examine this hypothesis we made use of microzymographic techniques in the microcirculation, plasma zymography and receptor labeling techniques with antibodies against an extracellular domain of the insulin receptor α. Results: The spontaneously hypertensive rat has an enhanced proteolytic activity and significant cleavage of the insulin receptor with attenuated glucose transport. We also present evidence for insulin receptor cleavage in a high-fat diet and a transgenic model of diabetes. Conclusion: These results suggest that cleavage of the extracellular domain of the insulin receptor, a situation that interferes with the ability for insulin to bind and provide an intracellular signal for glucose transport, may be involved in insulin resistance.

Keywords::

• adhesion
• insulin resistance
• integrin
• leukocyte
• matrix metalloproteases
• protease activity
• receptor cleavage

Financial & competing interests disclosure

Geert Schmid-Schönbein is a scientific consultant for Leading Ventures. This research was supported by NIH grant HL 10881, by an unrestricted research gift of Leading Ventures (Geert Schmid-Schönbein), and by American Heart Association Scientist Development Grant (110350047A) and NIH grants (RO1-HL077566 and RO1-HL085119) to Cuihua Zhang. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state they have obtained appropriate institutional review board approval or have followed the prinicples outlined in the Declaration of Helsinski for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved. All animal protocols were reviewed and approved by the Animals Subjects Committees of the University of California San Diego and the University of Missouri.