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A Murine Pancreatic Islet Cell-based Screening for Diabetogenic Environmental Chemicals
Published on: June 25, 2018
Suppression of KATP channel activity protects murine pancreatic beta cells against oxidative stress
Belinda Gier1, Peter Krippeit-Drews, Tatiana Sheiko
1Institute of Pharmacy, Department of Pharmacology, University of Tübingen, Tübingen, Germany.
Abstract:
The enhanced oxidative stress associated with type 2 diabetes mellitus contributes to disease pathogenesis. We previously identified plasma membrane-associated ATP-sensitive K+ (KATP) channels of pancreatic beta cells as targets for oxidants. Here, we examined the effects of genetic and pharmacologic ablation of KATP channels on loss of mouse beta cell function and viability following oxidative stress. Using mice lacking the sulfonylurea receptor type 1 (Sur1) subunit of KATP channels, we found that, compared with insulin secretion by WT islets, insulin secretion by Sur1-/- islets was less susceptible to oxidative stress induced by the oxidant H2O2. This was likely, at least in part, a result of the reduced ability of H2O2 to hyperpolarize plasma membrane potential and reduce cytosolic free Ca2+ concentration ([Ca2+]c) in the Sur1-/- beta cells. Remarkably, Sur1-/- beta cells were less prone to apoptosis induced by H2O2 or an NO donor than WT beta cells, despite an enhanced basal rate of apoptosis. This protective effect was attributed to upregulation of the antioxidant enzymes SOD, glutathione peroxidase, and catalase. Upregulation of antioxidant enzymes and reduced sensitivity of Sur1-/- cells to H2O2-induced apoptosis were mimicked by treatment with the sulfonylureas tolbutamide and gliclazide. Enzyme upregulation and protection against oxidant-induced apoptosis were abrogated by agents lowering [Ca2+]c. Sur1-/- mice were less susceptible than WT mice to streptozotocin-induced beta cell destruction and subsequent hyperglycemia and death, which suggests that loss of KATP channel activity may protect against streptozotocin-induced diabetes in vivo.
Insights
Loss of ATP-sensitive potassium (KATP) channels protects pancreatic beta cells from oxidative stress, a key factor in type 2 diabetes. This protection involves enhanced antioxidant defenses and reduced apoptosis, suggesting a therapeutic target.
Area of Science:
- Endocrinology
- Molecular Biology
- Diabetes Research
Background:
- Oxidative stress in type 2 diabetes mellitus (T2DM) damages pancreatic beta cells.
- Plasma membrane-associated ATP-sensitive K+ (KATP) channels in beta cells are targets of oxidants.
- Understanding KATP channel roles in beta cell response to oxidative stress is crucial for T2DM pathogenesis.
Purpose of the Study:
- To investigate the impact of genetic and pharmacologic KATP channel ablation on mouse beta cell function and viability under oxidative stress.
- To elucidate the mechanisms underlying KATP channel-mediated protection against oxidative damage in beta cells.
Main Methods:
- Utilized mice lacking the sulfonylurea receptor type 1 (Sur1) subunit of KATP channels (Sur1-/-) and wild-type (WT) littermates.
- Assessed insulin secretion, plasma membrane potential, cytosolic free Ca2+ concentration ([Ca2+]c), and apoptosis in response to oxidants (H2O2, NO donor).
- Examined the expression of antioxidant enzymes (SOD, glutathione peroxidase, catalase) and the effects of sulfonylureas and calcium-lowering agents.
Main Results:
- Sur1-/- islets exhibited reduced susceptibility to H2O2-induced oxidative stress, with less membrane potential hyperpolarization and [Ca2+]c reduction compared to WT islets.
- Sur1-/- beta cells showed decreased apoptosis from H2O2 or NO donor, attributed to upregulated antioxidant enzymes (SOD, glutathione peroxidase, catalase).
- Pharmacologic inhibition of KATP channels with sulfonylureas mimicked these protective effects, which were dependent on [Ca2+]c levels.
Conclusions:
- Genetic or pharmacologic ablation of KATP channels confers significant protection to pancreatic beta cells against oxidative stress and apoptosis.
- Upregulation of antioxidant enzymes and altered calcium handling mediate the protective effects of KATP channel loss.
- These findings suggest that targeting KATP channels may offer a novel therapeutic strategy to protect beta cells and manage type 2 diabetes.
