Altered transendothelial transport of hormones as a contributor to diabetes

Abstract

The vascular endothelium is a dynamic structure responsible for the separation and regulated movement of biological material between circulation and interstitial fluid. Hormones and nutrients can move across the endothelium either via a transcellular or paracellular route. Transcellular endothelial transport is well understood and broadly acknowledged to play an important role in the normal and abnormal physiology of endothelial function. However, less is known about the role of the paracellular route. Although the concept of endothelial dysfunction in diabetes is now widely accepted, we suggest that alterations in paracellular transport should be studied in greater detail and incorporated into this model. In this review we provide an overview of endothelial paracellular permeability and discuss its potential importance in contributing to the development of diabetes and associated complications. Accordingly, we also contend that if better understood, altered endothelial paracellular permeability could be considered as a potential therapeutic target for diabetes.

Keywords: Adherens junctions; Adiponectin; Endocrine; Endothelial transport; Hormones; Insulin; Paracellular; Tight junctions; Transcellular.

Fig. 1

Routes of transendothelial transport. A schematic representation of paracellular and transcellular routes for transport of blood-borne hormones and solutes to interstitial space of underlying tissue.

Fig. 2

Diversity of paracellular transport characteristics in different vascular beds. The size and structure of tight junctions varies significantly between different tissues and in this figure we summarize this by defining three arbitrary categories of leaky, moderately tight and tight endothelia. The typical resistance values associated with these definitions and examples of tissues where each category of endothelium is characteristic is shown. N/A, not applicable.

Fig. 3

Paracellular movement of adiponectin. A conceptual model showing the potential significance of paracellular transendothelial movement of adiponectin. When vascular endothelium is leaky (left side) there is significant flux of all forms of adiponectin from bloodstream to interstitial space. However, as endothelium becomes tighter there is likely to be a gradient of decrease in high molecular weight or other multimeric forms of adiponectin whereas the smaller globular fragment of adiponectin may still be able to access underlying target tissue such as skeletal muscle. TJ, tight junctions; fAd, full length adiponectin; gAd, globular adiponectin.