Vascular disease in pre-diabetes: new insights derived from systems biology

Abstract

In many cases vascular disease is present before the clinical onset of type 2 diabetes, that is, during the pre-diabetic period when insulin levels are markedly increased. In pre-diabetes, microvascular dysfunction correlates with plasma insulin levels and not blood glucose. Here we discuss the concept that insulin, at levels found in pre-diabetes, contributes to microvascular disease in skeletal muscle by inhibiting the release of the vasodilator, adenosine triphosphate (ATP), from erythrocytes.

Figures

Proposed mechanism by which erythrocytes participate in the matching of oxygen (O2) supply with demand in skeletal muscle. When O2 demand in the tissue increases, oxygen is released from erythrocytes. The fall in oxygen saturation (SO2) of hemoglobin results in activation of the heterotrimeric G-protein, Gi. This initiates a signal transduction pathway leading to activation of adenylyl cyclase, increases in 3′5′-adenosine monophosphate (cAMP), activation of protein kinase A (PKA) and the cystic fibrosis transmembrane conductance regulator (CFTR) and, ultimately, adenosine triphosphate (ATP) release. The released ATP binds to purinergic receptors (PR) on the endothelium (Endo) which induces the production of vasodilators that relax smooth muscle (SMC) inducing a vasodilation which is conducted upstream. Insulin inhibits ATP release by binding to receptors on the erythrocyte membrane (IR) activating a phosphodiestease (PDE3) that enhances the breakdown of cAMP (see text for additional detail).

Figure 2

Effect of insulin on the response of isolated arterioles perfused with erythrocytes (RBCs) to reduced oxygen tension. Isolated arterioles were exposed to either extra-luminal normoxia or reduced oxygen tension and perfused with buffer containing

Figure 3

Blood sugar (panel A) and plasma insulin (panel B) in ZDF rats. Control = normal leptin receptor expression at 7 or 12 weeks of age; pre-diabetes = 7 weeks of age with defective leptin receptor expression; diabetes = 12 weeks of age with defective leptin receptor expression. Values are means ± SE, n=11. *; different from respective control (P