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Protein kinase C and the development of diabetic vascular complications
1Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
Abstract:
Hyperglycemic control in diabetes is key to preventing the development and progression of vascular complications such as retinopathy, nephropathy and neuropathy. Increased activation of the diacylglycerol (DAG)-protein kinase C (PKC) signal transduction pathway has been identified in vascular tissues from diabetic animals, and in vascular cells exposed to elevated glucose. Vascular abnormalities associated with glucose-induced PKC activation leading to increased synthesis of DAG include altered vascular blood flow, extracellular matrix deposition, basement membrane thickening, increased permeability and neovascularization. Preferential activation of the PKCbeta isoform by elevated glucose is reported to occur in a variety of vascular tissues. This has lead to the development of LY333531, a PKCbeta isoform specific inhibitor, which has shown potential in animal models to be an orally effective and nontoxic therapy able to produce significant improvements in diabetic retinopathy, nephropathy, neuropathy and cardiac dysfunction. Additionally, the antioxidant vitamin E has been identified as an inhibitor of the DAG-PKC pathway, and shows promise in reducing vascular complications in animal models of diabetes. Given the overwhelming evidence indicating a role for PKC activation in contributing to the development of diabetic vascular complications, pharmacological therapies that can modulate this pathway, particularly with PKC isoform selectivity, show great promise for treatment of vascular complications, even in the presence of hyperglycemia.
Insights
Effective control of blood sugar in diabetes is crucial for preventing vascular complications. Targeting the diacylglycerol-protein kinase C (DAG-PKC) pathway, particularly the PKCbeta isoform, shows promise for novel therapies to treat diabetic vascular damage.
Area of Science:
- Endocrinology
- Vascular Biology
- Pharmacology
Background:
- Hyperglycemia in diabetes accelerates vascular complications like retinopathy, nephropathy, and neuropathy.
- Elevated glucose levels activate the diacylglycerol (DAG)-protein kinase C (PKC) signaling pathway in vascular tissues.
- This activation leads to pathological changes including altered blood flow, extracellular matrix deposition, and neovascularization.
Purpose of the Study:
- To investigate the role of the DAG-PKC pathway in diabetic vascular complications.
- To evaluate the therapeutic potential of inhibiting the PKCbeta isoform and utilizing antioxidants like vitamin E.
Main Methods:
- Studies involved diabetic animal models and vascular cells exposed to high glucose.
- Investigated the effects of elevated glucose on DAG-PKC pathway activation.
- Assessed the efficacy of a PKCbeta-specific inhibitor (LY333531) and vitamin E in preclinical models.
Main Results:
- Elevated glucose preferentially activates the PKCbeta isoform in various vascular tissues.
- LY333531 demonstrated oral efficacy and safety in animal models, significantly improving retinopathy, nephropathy, neuropathy, and cardiac dysfunction.
- Vitamin E also showed potential in reducing vascular complications by inhibiting the DAG-PKC pathway.
Conclusions:
- PKC activation plays a significant role in the pathogenesis of diabetic vascular complications.
- Targeting the DAG-PKC pathway, especially with isoform-selective inhibitors like LY333531, offers a promising therapeutic strategy.
- These interventions may effectively treat vascular complications even when hyperglycemia persists.
Related Concept Videos
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01:24Type II Diabetes II: Pathophysiology
01:27Diabetic Retinopathy
01:28Diabetic Nephropathy