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

Cumbie BC, Hermayer KL - Vasc Health Risk Manag (2007)

Bottom Line: Microvascular complications characterized by retinopathy, nephropathy, and neuropathy are highly prevalent among diabetics.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology, Diabetes & Medical Genetics, Department of Medicine, Medical University of South Carolina, Charleston 29425, USA.

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.

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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).
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fig2: 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).

Mentions: AGEPs are a heterogeneous group of modified proteins, lipids, and nucleic acids implicated in the aging process and diabetes. In intracellular hyperglycemia, these products are formed primarily through nonenzymatic reactions (Maillard reactions) between amino groups and glucose or highly reactive glucose derivatives known as dicarbonyls (Figure 2) (Brownlee 2001). Hyperglycemia may also drive AGEP formation through polyol pathway-derived intermediates and oxidative stress (Hamada et al 1996). AGEPs alter intracellular and extracellular proteins and their functions (Brownlee 2001; Goldin et al 2006; Huebschmann et al 2006). Receptors for AGEPs (RAGE) may also bind AGEPs causing the NF-κB-mediated activation of various cytokines, pro-coagualtory and pro-inflammatory factors, and increased vascular permeability (Brownlee 2001; Goldin et al 2006; Huebschmann et al 2006).


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

Cumbie BC, Hermayer KL - Vasc Health Risk Manag (2007)

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).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2350125&req=5

fig2: 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).
Mentions: AGEPs are a heterogeneous group of modified proteins, lipids, and nucleic acids implicated in the aging process and diabetes. In intracellular hyperglycemia, these products are formed primarily through nonenzymatic reactions (Maillard reactions) between amino groups and glucose or highly reactive glucose derivatives known as dicarbonyls (Figure 2) (Brownlee 2001). Hyperglycemia may also drive AGEP formation through polyol pathway-derived intermediates and oxidative stress (Hamada et al 1996). AGEPs alter intracellular and extracellular proteins and their functions (Brownlee 2001; Goldin et al 2006; Huebschmann et al 2006). Receptors for AGEPs (RAGE) may also bind AGEPs causing the NF-κB-mediated activation of various cytokines, pro-coagualtory and pro-inflammatory factors, and increased vascular permeability (Brownlee 2001; Goldin et al 2006; Huebschmann et al 2006).

Bottom Line: Microvascular complications characterized by retinopathy, nephropathy, and neuropathy are highly prevalent among diabetics.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology, Diabetes & Medical Genetics, Department of Medicine, Medical University of South Carolina, Charleston 29425, USA.

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.

Show MeSH
Related in: MedlinePlus