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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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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).
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fig1: 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).

Mentions: The polyol pathway reduces toxic aldehydes generated by ROS to inactive alcohols (Figure 1) (Brownlee 2001; Sheetz and King 2002). Aldose reductase (AR), via the consumption of NADPH, is responsible for the initial and rate-limiting step in the process. Glucose can be reduced to sorbitol, and eventually fructose, through this pathway, but AR has a low affinity for glucose at normal concentrations. Elevated intracellular glucose can increase AR activity, resulting in significantly decreased NADPH. NADPH is also required for glutathione reductase activity, which reduces glutathione (GSH)–a major mechanism for reducing intracellular oxidative stress (Lee and Chung 1999). Decreased NADPH and resulting decreased GSH reductase activity ultimately increases oxidative stress and activates pathways that increase cellular damage.


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

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

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).
© Copyright Policy
Related In: Results  -  Collection

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

fig1: 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).
Mentions: The polyol pathway reduces toxic aldehydes generated by ROS to inactive alcohols (Figure 1) (Brownlee 2001; Sheetz and King 2002). Aldose reductase (AR), via the consumption of NADPH, is responsible for the initial and rate-limiting step in the process. Glucose can be reduced to sorbitol, and eventually fructose, through this pathway, but AR has a low affinity for glucose at normal concentrations. Elevated intracellular glucose can increase AR activity, resulting in significantly decreased NADPH. NADPH is also required for glutathione reductase activity, which reduces glutathione (GSH)–a major mechanism for reducing intracellular oxidative stress (Lee and Chung 1999). Decreased NADPH and resulting decreased GSH reductase activity ultimately increases oxidative stress and activates pathways that increase cellular damage.

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