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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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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).
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fig3: 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).

Mentions: The PKC family consists of a group of 12 seronine/threonine kinases involved in intracellular signaling related to a variety of vascular, cardiac, immunologic, and other systemic functions (Mellor and Parker 1998; Sheetz and King 2002). Diacylglycerol (DAG) is an upstream activator in the majority of PKC isoforms (Koya and King 1998; Inoguchi et al 1992). De novo DAG formation increases with elevated intracellular glucose with a resultant increase of primarily PKC-β1/2 and PKC-δ isoform activity (Figure 3) (Koya and King 1998). PKC may also be activated by growth factors, and hyperglycemia-induced superoxide and AGE formation (Koya and King 1998; Sheetz and King 2002).


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

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

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).
© Copyright Policy
Related In: Results  -  Collection

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

fig3: 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).
Mentions: The PKC family consists of a group of 12 seronine/threonine kinases involved in intracellular signaling related to a variety of vascular, cardiac, immunologic, and other systemic functions (Mellor and Parker 1998; Sheetz and King 2002). Diacylglycerol (DAG) is an upstream activator in the majority of PKC isoforms (Koya and King 1998; Inoguchi et al 1992). De novo DAG formation increases with elevated intracellular glucose with a resultant increase of primarily PKC-β1/2 and PKC-δ isoform activity (Figure 3) (Koya and King 1998). PKC may also be activated by growth factors, and hyperglycemia-induced superoxide and AGE formation (Koya and King 1998; Sheetz and King 2002).

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