The Vasculature in Prediabetes

Abstract

The frequency of prediabetes is increasing as the prevalence of obesity rises worldwide. In prediabetes, hyperglycemia, insulin resistance, and inflammation and metabolic derangements associated with concomitant obesity cause endothelial vasodilator and fibrinolytic dysfunction, leading to increased risk of cardiovascular and renal disease. Importantly, the microvasculature affects insulin sensitivity by affecting the delivery of insulin and glucose to skeletal muscle; thus, endothelial dysfunction and extracellular matrix remodeling promote the progression from prediabetes to diabetes mellitus. Weight loss is the mainstay of treatment in prediabetes, but therapies that improved endothelial function and vasodilation may not only prevent cardiovascular disease but also slow progression to diabetes mellitus.

Keywords: cardiovascular disease; extracellular matrix; insulin resistance; metabolic syndrome; obesity.

Figure 1

Endothelial insulin resistance, hyperglycemia and the formation of advanced glycation products, and increased free fatty acids give rise to oxidative stress, inflammation and endothelial vasodilator and fibrinolytic dysfunction in prediabetes.

Figure 2

The microcirculation is a barrier to skeletal muscle insulin access which is delayed in obesity. Interstitial insulin concentrations rise more slowly than arterial insulin concentrations due to capillary insulin egress. This time is prolonged in obesity. Derived from Sjosgrand et al.

Figure 3

Insulin access is determined by i) vascular reactivity; ii) microcirculatory hemodynamics; and iii) capillary insulin permeability (determined by vesicular and/or paracellular fluid phase transport). Vascular reactivity and microcirculatory hemodynamics are determined by endocrine factors, paracrine factors, cytokines, and microcirculatory architecture. Capillary insulin efflux is determined by the balance between hydrostatic and oncotic pressures.

Figure 4

The extracellular matrix (ECM) in the sequelae of prediabetes. Inflammation results in ECM remodeling which creates endothelial dysfunction, capillary regression, spatial barriers, and increased ECM component interaction with cell surface receptors, including the integrin receptor family. These result in a decrease in tissue insulin access and, consequently, insulin action. Modified from Williams et al.