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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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Related in: MedlinePlus

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).
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fig4: 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).

Mentions: Our understanding of the roles of oxygen free radicals in diabetic complications has recently evolved with the description of the super oxide pathway (Brownlee 2001). In hyperglycemia, experimental endothelial cells have increased flux of glucose through glycolysis, pyruvate decarboxylation, and the citric acid cycle resulting in mitochondrial electron transport chain overload (Nishikawa et al 2000). In turn, overloaded mitochondria produce excessive superoxide anions which ultimately lead to decreases in nitric oxide, DNA damage, AGE formation, and activation of the polyol, PKC, and hexosamine pathways as well as activation of poly (ADP-ribose) polymerase (Figure 4) (Du et al 2000; Nishikawa et al 2000; Brownlee 2001).


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

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

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).
© Copyright Policy
Related In: Results  -  Collection

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

fig4: 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).
Mentions: Our understanding of the roles of oxygen free radicals in diabetic complications has recently evolved with the description of the super oxide pathway (Brownlee 2001). In hyperglycemia, experimental endothelial cells have increased flux of glucose through glycolysis, pyruvate decarboxylation, and the citric acid cycle resulting in mitochondrial electron transport chain overload (Nishikawa et al 2000). In turn, overloaded mitochondria produce excessive superoxide anions which ultimately lead to decreases in nitric oxide, DNA damage, AGE formation, and activation of the polyol, PKC, and hexosamine pathways as well as activation of poly (ADP-ribose) polymerase (Figure 4) (Du et al 2000; Nishikawa et al 2000; Brownlee 2001).

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