Suppression of KATP channel activity protects murine pancreatic β cells against oxidative stress

Epidemiological studies associate milk consumption with an increased risk of Parkinson’s disease (PD) and type 2 diabetes mellitus (T2D). PD is an α-synucleinopathy associated with mitochondrial dysfunction, oxidative stress, deficient lysosomal clearance of α-synuclein (α-syn) and aggregation of misfolded α-syn. In T2D, α-syn promotes co-aggregation with islet amyloid polypeptide in pancreatic β-cells. Prion-like vagal nerve-mediated propagation of exosomal α-syn from the gut to the brain and pancreatic islets apparently link both pathologies. Exosomes are critical transmitters of α-syn from cell to cell especially under conditions of compromised autophagy. This review provides translational evidence that milk exosomes (MEX) disturb α-syn homeostasis. MEX are taken up by intestinal epithelial cells and accumulate in the brain after oral administration to mice. The potential uptake of MEX miRNA-148a and miRNA-21 by enteroendocrine cells in the gut, dopaminergic neurons in substantia nigra and pancreatic β-cells may enhance miRNA-148a/DNMT1-dependent overexpression of α-syn and impair miRNA-148a/PPARGC1A- and miRNA-21/LAMP2A-dependent autophagy driving both diseases. MiRNA-148a- and galactose-induced mitochondrial oxidative stress activate c-Abl-mediated aggregation of α-syn which is exported by exosome release. Via the vagal nerve and/or systemic exosomes, toxic α-syn may spread to dopaminergic neurons and pancreatic β-cells linking the pathogenesis of PD and T2D.

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AKAP79/150 coordinates leptin-induced PKA signaling to regulate KATP channel trafficking in pancreatic β-cells

Journal of Biological Chemistry ◽

10.1016/j.jbc.2021.100442 ◽

2021 ◽

pp. 100442

Author(s):

Veronica A. Cochrane ◽

Zhongying Yang ◽

Mark L. Dell’Acqua ◽

Show-Ling Shyng

Keyword(s):

Katp Channel ◽

Β Cells ◽

Pancreatic Β Cells ◽

Channel Trafficking

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Cytoprotective Effects of N-Acetylcysteine on Streptozotocin- Induced Oxidative Stress and Apoptosis in RIN-5F Pancreatic β-Cells

Cellular Physiology and Biochemistry ◽

10.1159/000495200 ◽

2018 ◽

Vol 51 (1) ◽

pp. 201-216 ◽

Cited By ~ 8

Author(s):

Arwa M.T. Al-Nahdi ◽

Annie John ◽

Haider Raza

Keyword(s):

Oxidative Stress ◽

Insulin Secretion ◽

Molecular Mechanisms ◽

Protective Action ◽

Mitochondrial Enzymes ◽

Partial Recovery ◽

Β Cells ◽

Pancreatic Β Cells ◽

Mitochondrial Energy Metabolism ◽

Mitochondrial Functions

Background/Aims: Numerous studies have reported overproduction of reactive oxygen species (ROS) and alterations in mitochondrial energy metabolism in the development of diabetes and its complications. The potential protective effects of N-acetylcysteine (NAC) in diabetes have been reported in many therapeutic studies. NAC has been shown to reduce oxidative stress and enhance redox potential in tissues protecting them against oxidative stress associated complications in diabetes. In the current study, we aimed to investigate the molecular mechanisms of the protective action of NAC on STZ-induced toxicity in insulin secreting Rin-5F pancreatic β-cells. Methods: Rin-5F cells were grown to 80% confluence and then treated with 10mM STZ for 24h in the presence or absence of 10mM NAC. After sub-cellular fractionation, oxidative stress, GSH-dependent metabolism and mitochondrial respiratory functions were studied using spectrophotometric, flow cytometric and Western blotting techniques. Results: Our results showed that STZ-induced oxidative stress and apoptosis caused inhibition in insulin secretion while NAC treatment restored the redox homeostasis, enhanced insulin secretion in control cells and prevented apoptosis in STZ-treated cells. Moreover, NAC attenuated the inhibition of mitochondrial functions induced by STZ through partial recovery of the mitochondrial enzymes and restoration of membrane potential. STZ-induced DNA damage and expression of apoptotic proteins were significantly inhibited in NAC-treated cells. Conclusion: Our results suggest that the cytoprotective action of NAC is mediated via suppression of oxidative stress and apoptosis and restoration of GSH homeostasis and mitochondrial bioenergetics. This study may, thus, help in better understanding the cellular defense mechanisms of pancreatic β-cells against STZ-induced cytotoxicity.

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HIV‐1 protease inhibitors suppress insulin secretion in pancreatic β cells : role of oxidative stress and endoplasmic reticulum stress and protection by thymoquinone (TQ)

The FASEB Journal ◽

10.1096/fasebj.22.1_supplement.1131.2 ◽

2008 ◽

Vol 22 (S1) ◽

Author(s):

Surabhi Chandra ◽

Debasis Mondal ◽

Krishna C Agrawal

Keyword(s):

Oxidative Stress ◽

Endoplasmic Reticulum ◽

Insulin Secretion ◽

Endoplasmic Reticulum Stress ◽

Protease Inhibitors ◽

Β Cells ◽

Pancreatic Β Cells ◽

Hiv 1

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Metabolic inhibition impairs ATP-sensitive K+ channel block by sulfonylurea in pancreatic β-cells

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1998.274.1.e38 ◽

1998 ◽

Vol 274 (1) ◽

pp. E38-E44 ◽

Cited By ~ 5

Author(s):

Eri Mukai ◽

Hitoshi Ishida ◽

Seika Kato ◽

Yoshiyuki Tsuura ◽

Shimpei Fujimoto ◽

...

Keyword(s):

Metabolic Inhibition ◽

K Channel ◽

High Dose ◽

Dependent Manner ◽

Channel Activity ◽

Β Cells ◽

Pancreatic Β Cells ◽

Patch Clamp Technique ◽

Channel Inhibition ◽

Dose Dependent

The effect of metabolic inhibition on the blocking of β-cell ATP-sensitive K+ channels (KATP channels) by glibenclamide was investigated using a patch-clamp technique. Inhibition of KATP channels by glibenclamide was attenuated in the cell-attached mode under metabolic inhibition induced by 2,4-dinitrophenol. Under a low concentration (0.1 μM) of ATP applied in the inside-out mode, KATP channel activity was not fully abolished, even when a high dose of glibenclamide was applied, in contrast to the dose-dependent and complete KATP channel inhibition under 10 μM ATP. On the other hand, cibenzoline, a class Ia antiarrhythmic agent, inhibits KATP channel activity in a dose-dependent manner and completely blocks it, even under metabolic inhibition. In sulfonylurea receptor (SUR1)- and inward rectifier K+ channel (Kir6.2)-expressed proteins, cibenzoline binds directly to Kir6.2, unlike glibenclamide. Thus, KATPchannel inhibition by glibenclamide is impaired under the condition of decreased intracellular ATP in pancreatic β-cells, probably because of a defect in signal transmission between SUR1 and Kir6.2 downstream of the site of sulfonylurea binding to SUR1.

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Pharmacological modulation of KATP channels

Biochemical Society Transactions ◽

10.1042/bst0300333 ◽

2002 ◽

Vol 30 (2) ◽

pp. 333-339 ◽

Cited By ~ 43

Author(s):

F. M. Gribble ◽

F. Reimann

Keyword(s):

Type 2 Diabetes ◽

Cardiac Muscle ◽

Katp Channel ◽

Katp Channels ◽

Β Cells ◽

Pancreatic Β Cells ◽

Tissue Specific ◽

Pharmacological Modulation ◽

Clinical Conditions

Pharmacological modulation of ATP-sensitive K+ (KATP) channels is used in the treatment of a number of clinical conditions, including type 2 diabetes and angina. The sulphonylureas and related drugs, which are used to treat type 2 diabetes, stimulate insulin secretion by closing KATP channels in pancreatic β-cells. Agents used to treat angina, by contrast, act by opening KATP channels in vascular smooth and cardiac muscle. Both the therapeutic KATP channel inhibitors and the KATP channel openers target the sulphonylurea receptor (SUR) subunit of the KATP channel, which exists in several isoforms expressed in different tissues (SUR1 in pancreatic β-cells, SUR2A in cardiac muscle and SUR2B in vascular smooth muscle). The tissue-specific action of drugs that target the KATP channel is attributed to the properties of these different SUR subtypes. In this review, we discuss the molecular basis of tissue-specific drug action, and its implications for clinical practice.

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Diabetes induced by gain-of-function mutations in the Kir6.1 subunit of the KATP channel

The Journal of General Physiology ◽

10.1085/jgp.201611653 ◽

2016 ◽

Vol 149 (1) ◽

pp. 75-84 ◽

Cited By ~ 4

Author(s):

Maria S. Remedi ◽

Jonathan B. Friedman ◽

Colin G. Nichols

Keyword(s):

Insulin Secretion ◽

Katp Channel ◽

Vascular System ◽

Wild Type Mouse ◽

Neonatal Diabetes ◽

Katp Channels ◽

Β Cells ◽

Pancreatic Β Cells ◽

Gain Of Function ◽

Insulin Promoter

Gain-of-function (GOF) mutations in the pore-forming (Kir6.2) and regulatory (SUR1) subunits of KATP channels have been identified as the most common cause of human neonatal diabetes mellitus. The critical effect of these mutations is confirmed in mice expressing Kir6.2-GOF mutations in pancreatic β cells. A second KATP channel pore-forming subunit, Kir6.1, was originally cloned from the pancreas. Although the prominence of this subunit in the vascular system is well documented, a potential role in pancreatic β cells has not been considered. Here, we show that mice expressing Kir6.1-GOF mutations (Kir6.1[G343D] or Kir6.1[G343D,Q53R]) in pancreatic β cells (under rat-insulin-promoter [Rip] control) develop glucose intolerance and diabetes caused by reduced insulin secretion. We also generated transgenic mice in which a bacterial artificial chromosome (BAC) containing Kir6.1[G343D] is incorporated such that the transgene is only expressed in tissues where Kir6.1 is normally present. Strikingly, BAC-Kir6.1[G343D] mice also show impaired glucose tolerance, as well as reduced glucose- and sulfonylurea-dependent insulin secretion. However, the response to K+ depolarization is intact in Kir6.1-GOF mice compared with control islets. The presence of native Kir6.1 transcripts was demonstrated in both human and wild-type mouse islets using quantitative real-time PCR. Together, these results implicate the incorporation of native Kir6.1 subunits into pancreatic KATP channels and a contributory role for these subunits in the control of insulin secretion.

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