Current concepts in targeted therapies for the pathophysiology of diabetic microvascular complications

Abstract

Microvascular complications characterized by retinopathy, nephropathy, and neuropathy are highly prevalent among diabetics. Glycemic control has long been the mainstay for preventing progression of these complications; however, such control is not easily achieved. Currently, alternative adjunctive approaches to treating and preventing microvascular damage are being undertaken by targeting the molecular pathogenesis of diabetic complications. This review summarizes the specific pathogenic mechanisms of microvascular complications for which clinical therapies have been developed, including the polyol pathway, advanced glycation end products, protein kinase c, vascular epithelium growth factor, and the superoxide pathway. The review further focuses on therapies for these targets that are currently available or are undergoing late-stage clinical trials.

Figure 1

Aldose reductase and the polyol pathway. Aldose reductase reduces aldehydes generated by ROS to inactive alcohols, and glucose is converted to sorbitol, using NADPH as a co-factor. For cells in which aldose reductase activity is sufficient to deplete reduced GSH, oxidative stress is augmented. Sorbitol dehydrogenase (SDH) oxidizes sorbitol to fructose using NAD+ as a co-factor (Brownlee 2001) (Adapted by permission from Macmillan Publishers Ltd: Nature, Vol. 414, 2001).

Figure 2

Mechanisms by which intracellular production of advanced glycation end-product (AGE) precursors damages vascular cells. Covalent modification of intracellular proteins by dicarbonyl AGE precursors alters several cellular functions. Modification of extracellular matrix proteins causes abnormal interactions with other matrix proteins and with integrins. Modification of plasma proteins by AGE precursors creates ligands that bind to AGE receptors, inducing changes in gene expression in endothelial cells, mesangial cells and macrophages (Brownlee 2001) (Adapted by permission from Macmillan Publishers Ltd: Nature, Vol. 414, 2001).

Figure 3

Consequences of hyperglycemia-induced activation of protein kinase C (PKC). Hyperglycemia increases diacylglycerol (DAG) content, which activates PKC, primarily the b- and d-isoforms. Activation of PKC has a number of pathogenic consequences by affecting expression of endothelial nitric oxide synthetase (eNOS), endothelin-1 (ET-1), VEGF, TGF-β, and plasminogen activator inhibitor-1 (PAI-1), and by activating NF-κB and NAD(P)H oxidases (Brownlee 2001) (Adapted by permission from Macmillan Publishers Ltd: Nature, Vol. 414, 2001).

Figure 4

Potential mechanism by which hyperglycemia-induced mitochondrial superoxide overproduction activates four pathways of hyperglycemic damage. Excess superoxide partially inhibits the glycolytic enzyme GAPDH, thereby diverting upstream metabolites from glycolysis into pathways of glucose overutilization. This results in increased flux of dihydroxyacetone phosphate (DHAP) to DAG, an activator of PKC, and of triose phosphates to methylglyoxal, the main intracellular AGE precursor. Increased flux of fructose-6-phosphate to UDP-N-acetylglucosamine increases modification of proteins by O-linked N-acetylglucosamine (GlcNAc) and increased glucose flux through the polyol pathway consumes NADPH and depletes GSH (Brownlee 2001) (Adapted by permission from Macmillan Publishers Ltd: Nature, Vol. 414, 2001).