Chapter 7 - Fibrosis and diabetes: Chronic hyperglycemia triggers organ-specific fibrotic mechanisms

Abstract

Fibrosis is defined as an excess of extracellular matrix (ECM) components, or a failure in degradation of existing ECM components. The ECM provides structural support for cells, comprising principally collagen, and other proteins such as elastin, glycoproteins, and integrins. Hyperglycemia, as a result of diabetes, can cause stimulation of signaling pathways, which lead to either of these outcomes, resulting in fibrosis. Many organs are affected in diabetes; principally the skin, causing chronic wounds and peripheral neuropathy, but also commonly the kidneys and large vessels. The pathogenesis of microvascular changes, which lead to these end-organ complications, includes under- or overexpression of growth factors, namely, transforming growth factor-β (TGF-β). Other fibrotic mechanisms include the renin angiotensin aldosterone system (RAAS), and formation and interaction of free radicals via oxidative stress, and advanced glycation end products (AGEs). Monitoring progression of fibrosis along with treatment is organ specific, utilizing biomarkers, which target the growth factors and signaling molecules involved as well as key ECM components in that organ; and while specific therapeutic targets have been identified in affected organs, ultimately maintaining good glycemic control prevents progression of fibrosis and further complications.