scholarly journals Glucose-stimulated insulin secretion fundamentally requires H2O2 signaling by NADPH oxidase 4

2020 ◽  
Author(s):  
Ada Admin ◽  
Lydie Plecitá-Hlavatá ◽  
Martin Jabůrek ◽  
Blanka Holendová ◽  
Jan Tauber ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Nadph Oxidase ◽  
B Cell ◽  
Redox Signaling ◽  
Acid Oxidation ◽  
Nadph Oxidase 4 ◽  
Peripheral Insulin Resistance ◽  
Branched Chain ◽  
Glucose Stimulated Insulin Secretion

NADPH facilitates glucose-stimulated insulin secretion (GSIS) in pancreatic islet (PI) b-cells by an as yet unknown mechanism. We found NADPH oxidase, isoform-4 (NOX4), to be the major producer of cytosolic H<sub>2</sub>O<sub>2</sub>, essential for GSIS, while the increase in ATP/ADP alone was insufficient. The fast GSIS phase was absent in PIs from NOX4-null, b-cell-specific knockout mice (NOX4bKO) (not NOX2KO), and NOX4-silenced or catalase-overexpressing INS-1E cells. Lentiviral NOX4 overexpression or H<sub>2</sub>O<sub>2</sub> rescued GSIS in PIs from NOX4bKO mice. NOX4 silencing suppressed Ca<sup>2+</sup> oscillations and the patch-clamped ATP-sensitive potassium channel (K<sub>ATP</sub>) opened more frequently at high glucose. Mitochondrial H<sub>2</sub>O<sub>2</sub>, decreasing upon GSIS, provided an alternative redox signaling when 2-oxo-isocaproate or fatty acid oxidation formed superoxide by electron-transport flavoprotein:Q-oxidoreductase. Unlike GSIS, this ceased with mitochondrial antioxidant SkQ1. Both NOX4KO and NOX4bKO strains exhibited impaired glucose tolerance and peripheral insulin resistance. Thus the redox signaling previously suggested to cause b-cell-self-checking – hypothetically induces insulin resistance when absent. In conclusion, ATP plus H<sub>2</sub>O<sub>2</sub> elevations constitute an essential switch-on signal of insulin exocytosis for glucose and branched-chain oxoacids as secretagogues (partly for fatty acids). Redox signaling could be impaired by cytosolic antioxidants, hence those targeting mitochondria should be preferred for clinical applications to treat (pre)diabetes at any stage.

scholarly journals Glucose-stimulated insulin secretion fundamentally requires H2O2 signaling by NADPH oxidase 4

2020 ◽  
Author(s):  
Ada Admin ◽  
Lydie Plecitá-Hlavatá ◽  
Martin Jabůrek ◽  
Blanka Holendová ◽  
Jan Tauber ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Nadph Oxidase ◽  
B Cell ◽  
Redox Signaling ◽  
Acid Oxidation ◽  
Nadph Oxidase 4 ◽  
Peripheral Insulin Resistance ◽  
Branched Chain ◽  
Glucose Stimulated Insulin Secretion

NADPH facilitates glucose-stimulated insulin secretion (GSIS) in pancreatic islet (PI) b-cells by an as yet unknown mechanism. We found NADPH oxidase, isoform-4 (NOX4), to be the major producer of cytosolic H<sub>2</sub>O<sub>2</sub>, essential for GSIS, while the increase in ATP/ADP alone was insufficient. The fast GSIS phase was absent in PIs from NOX4-null, b-cell-specific knockout mice (NOX4bKO) (not NOX2KO), and NOX4-silenced or catalase-overexpressing INS-1E cells. Lentiviral NOX4 overexpression or H<sub>2</sub>O<sub>2</sub> rescued GSIS in PIs from NOX4bKO mice. NOX4 silencing suppressed Ca<sup>2+</sup> oscillations and the patch-clamped ATP-sensitive potassium channel (K<sub>ATP</sub>) opened more frequently at high glucose. Mitochondrial H<sub>2</sub>O<sub>2</sub>, decreasing upon GSIS, provided an alternative redox signaling when 2-oxo-isocaproate or fatty acid oxidation formed superoxide by electron-transport flavoprotein:Q-oxidoreductase. Unlike GSIS, this ceased with mitochondrial antioxidant SkQ1. Both NOX4KO and NOX4bKO strains exhibited impaired glucose tolerance and peripheral insulin resistance. Thus the redox signaling previously suggested to cause b-cell-self-checking – hypothetically induces insulin resistance when absent. In conclusion, ATP plus H<sub>2</sub>O<sub>2</sub> elevations constitute an essential switch-on signal of insulin exocytosis for glucose and branched-chain oxoacids as secretagogues (partly for fatty acids). Redox signaling could be impaired by cytosolic antioxidants, hence those targeting mitochondria should be preferred for clinical applications to treat (pre)diabetes at any stage.

scholarly journals Glucose-stimulated insulin secretion fundamentally requires H2O2 signaling by NADPH oxidase 4

2020 ◽  
Author(s):  
Ada Admin ◽  
Lydie Plecitá-Hlavatá ◽  
Martin Jabůrek ◽  
Blanka Holendová ◽  
Jan Tauber ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Nadph Oxidase ◽  
B Cell ◽  
Redox Signaling ◽  
Acid Oxidation ◽  
Nadph Oxidase 4 ◽  
Peripheral Insulin Resistance ◽  
Branched Chain ◽  
Glucose Stimulated Insulin Secretion

NADPH facilitates glucose-stimulated insulin secretion (GSIS) in pancreatic islet (PI) b-cells by an as yet unknown mechanism. We found NADPH oxidase, isoform-4 (NOX4), to be the major producer of cytosolic H<sub>2</sub>O<sub>2</sub>, essential for GSIS, while the increase in ATP/ADP alone was insufficient. The fast GSIS phase was absent in PIs from NOX4-null, b-cell-specific knockout mice (NOX4bKO) (not NOX2KO), and NOX4-silenced or catalase-overexpressing INS-1E cells. Lentiviral NOX4 overexpression or H<sub>2</sub>O<sub>2</sub> rescued GSIS in PIs from NOX4bKO mice. NOX4 silencing suppressed Ca<sup>2+</sup> oscillations and the patch-clamped ATP-sensitive potassium channel (K<sub>ATP</sub>) opened more frequently at high glucose. Mitochondrial H<sub>2</sub>O<sub>2</sub>, decreasing upon GSIS, provided an alternative redox signaling when 2-oxo-isocaproate or fatty acid oxidation formed superoxide by electron-transport flavoprotein:Q-oxidoreductase. Unlike GSIS, this ceased with mitochondrial antioxidant SkQ1. Both NOX4KO and NOX4bKO strains exhibited impaired glucose tolerance and peripheral insulin resistance. Thus the redox signaling previously suggested to cause b-cell-self-checking – hypothetically induces insulin resistance when absent. In conclusion, ATP plus H<sub>2</sub>O<sub>2</sub> elevations constitute an essential switch-on signal of insulin exocytosis for glucose and branched-chain oxoacids as secretagogues (partly for fatty acids). Redox signaling could be impaired by cytosolic antioxidants, hence those targeting mitochondria should be preferred for clinical applications to treat (pre)diabetes at any stage.

scholarly journals Glucose-stimulated insulin secretion fundamentally requires H2O2 signaling by NADPH oxidase 4

2020 ◽  
Author(s):  
Ada Admin ◽  
Lydie Plecitá-Hlavatá ◽  
Martin Jabůrek ◽  
Blanka Holendová ◽  
Jan Tauber ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Nadph Oxidase ◽  
B Cell ◽  
Redox Signaling ◽  
Acid Oxidation ◽  
Nadph Oxidase 4 ◽  
Peripheral Insulin Resistance ◽  
Branched Chain ◽  
Glucose Stimulated Insulin Secretion

NADPH facilitates glucose-stimulated insulin secretion (GSIS) in pancreatic islet (PI) b-cells by an as yet unknown mechanism. We found NADPH oxidase, isoform-4 (NOX4), to be the major producer of cytosolic H<sub>2</sub>O<sub>2</sub>, essential for GSIS, while the increase in ATP/ADP alone was insufficient. The fast GSIS phase was absent in PIs from NOX4-null, b-cell-specific knockout mice (NOX4bKO) (not NOX2KO), and NOX4-silenced or catalase-overexpressing INS-1E cells. Lentiviral NOX4 overexpression or H<sub>2</sub>O<sub>2</sub> rescued GSIS in PIs from NOX4bKO mice. NOX4 silencing suppressed Ca<sup>2+</sup> oscillations and the patch-clamped ATP-sensitive potassium channel (K<sub>ATP</sub>) opened more frequently at high glucose. Mitochondrial H<sub>2</sub>O<sub>2</sub>, decreasing upon GSIS, provided an alternative redox signaling when 2-oxo-isocaproate or fatty acid oxidation formed superoxide by electron-transport flavoprotein:Q-oxidoreductase. Unlike GSIS, this ceased with mitochondrial antioxidant SkQ1. Both NOX4KO and NOX4bKO strains exhibited impaired glucose tolerance and peripheral insulin resistance. Thus the redox signaling previously suggested to cause b-cell-self-checking – hypothetically induces insulin resistance when absent. In conclusion, ATP plus H<sub>2</sub>O<sub>2</sub> elevations constitute an essential switch-on signal of insulin exocytosis for glucose and branched-chain oxoacids as secretagogues (partly for fatty acids). Redox signaling could be impaired by cytosolic antioxidants, hence those targeting mitochondria should be preferred for clinical applications to treat (pre)diabetes at any stage.

scholarly journals Glucose-stimulated insulin secretion fundamentally requires H2O2 signaling by NADPH oxidase 4

2020 ◽  
Author(s):  
Ada Admin ◽  
Lydie Plecitá-Hlavatá ◽  
Martin Jabůrek ◽  
Blanka Holendová ◽  
Jan Tauber ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Nadph Oxidase ◽  
B Cell ◽  
Redox Signaling ◽  
Acid Oxidation ◽  
Nadph Oxidase 4 ◽  
Peripheral Insulin Resistance ◽  
Branched Chain ◽  
Glucose Stimulated Insulin Secretion

NADPH facilitates glucose-stimulated insulin secretion (GSIS) in pancreatic islet (PI) b-cells by an as yet unknown mechanism. We found NADPH oxidase, isoform-4 (NOX4), to be the major producer of cytosolic H<sub>2</sub>O<sub>2</sub>, essential for GSIS, while the increase in ATP/ADP alone was insufficient. The fast GSIS phase was absent in PIs from NOX4-null, b-cell-specific knockout mice (NOX4bKO) (not NOX2KO), and NOX4-silenced or catalase-overexpressing INS-1E cells. Lentiviral NOX4 overexpression or H<sub>2</sub>O<sub>2</sub> rescued GSIS in PIs from NOX4bKO mice. NOX4 silencing suppressed Ca<sup>2+</sup> oscillations and the patch-clamped ATP-sensitive potassium channel (K<sub>ATP</sub>) opened more frequently at high glucose. Mitochondrial H<sub>2</sub>O<sub>2</sub>, decreasing upon GSIS, provided an alternative redox signaling when 2-oxo-isocaproate or fatty acid oxidation formed superoxide by electron-transport flavoprotein:Q-oxidoreductase. Unlike GSIS, this ceased with mitochondrial antioxidant SkQ1. Both NOX4KO and NOX4bKO strains exhibited impaired glucose tolerance and peripheral insulin resistance. Thus the redox signaling previously suggested to cause b-cell-self-checking – hypothetically induces insulin resistance when absent. In conclusion, ATP plus H<sub>2</sub>O<sub>2</sub> elevations constitute an essential switch-on signal of insulin exocytosis for glucose and branched-chain oxoacids as secretagogues (partly for fatty acids). Redox signaling could be impaired by cytosolic antioxidants, hence those targeting mitochondria should be preferred for clinical applications to treat (pre)diabetes at any stage.

scholarly journals Redox Signaling is Essential for Insulin Secretion

2021 ◽  
Author(s):  
Petr Ježek ◽  
Blanka Holendová ◽  
Martin Jabůrek ◽  
Jan Tauber ◽  
Andrea Dlasková ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Insulin Secretion ◽  
Redox Signaling ◽  
H2o2 Production ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Nadph Oxidase 4 ◽  
Elevated Glucose ◽  
Branched Chain ◽  
Glucose Stimulated Insulin Secretion

In this review, we place redox signaling in pancreatic β-cells to the context with signaling pathways leading to insulin secretion, acting for example upon the action of incretins (GLP-1, GIP) and the metabotropic receptor GPR40. Besides a brief description of ion channel participation in depolarization/repolarization of the plasma membrane, we emphasize a prominent role of the elevated glucose level in pancreatic β-cells during glucose-stimulated insulin secretion (GSIS). We focus on our recent findings, which revealed that for GSIS, not only elevated ATP synthesis is required, but also fundamental redox signaling originating from the NADPH oxidase 4- (NOX4-) mediated H2O2 production. We hypothesized that the closing of the ATP-sensitive K+ channel (KATP) is only possible when both ATP plus H2O2 are elevated in INS-1E cells. KATP alone or with synergic channels provides an element of logical sum, integrating both metabolic plus redox homeostasis. This is also valid for other secretagogues, such as branched chain ketoacids (BCKAs); and partly for fatty acids (FAs). Branched chain aminoacids, leucine, valine and isoleucine, after being converted to BCKAs are metabolized by a series of reactions resembling β-oxidation of FAs. This increases superoxide formation in mitochondria, including its portion elevated due to the function of electron transfer flavoprotein ubiquinone oxidoreductase (ETF:QOR). After superoxide conversion to H2O2 the oxidation of BCKAs provides the mitochondrial redox signaling extending up to the plasma membrane to induce its depolarization together with the elevated ATP. In contrast, experimental FA-stimulated insulin secretion in the presence of non-stimulating glucose concentrations is predominantly mediated by GPR40, for which intramitochondrial redox signaling activates phospholipase iPLA2γ, cleaving free FAs from mitochondrial membranes, which diffuse to the plasma membrane and largely amplify the GPR40 response. These events are concomitant to the insulin release due to the metabolic component. Hypothetically, redox signaling may proceed by simple H2O2 diffusion or via an SH-relay enabled by peroxiredoxins to target proteins. However, these aspects have yet to be elucidated.

scholarly journals Glucose-Stimulated Insulin Secretion Fundamentally Requires H2O2 Signaling by NADPH Oxidase 4

Diabetes ◽  
2020 ◽  
Vol 69 (7) ◽  
pp. 1341-1354 ◽  
Author(s):  
Lydie Plecitá-Hlavatá ◽  
Martin Jabůrek ◽  
Blanka Holendová ◽  
Jan Tauber ◽  
Vojtěch Pavluch ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Nadph Oxidase ◽  
Nadph Oxidase 4 ◽  
Glucose Stimulated Insulin Secretion

scholarly journals The Pancreatic β-Cell: The Perfect Redox System

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 197
Author(s):  
Petr Ježek ◽  
Blanka Holendová ◽  
Martin Jabůrek ◽  
Jan Tauber ◽  
Andrea Dlasková ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Redox Homeostasis ◽  
Redox System ◽  
Redox Signaling ◽  
K Channel ◽  
H2o2 Production ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Nadph Oxidase 4 ◽  
Glucose Stimulated Insulin Secretion

Pancreatic β-cell insulin secretion, which responds to various secretagogues and hormonal regulations, is reviewed here, emphasizing the fundamental redox signaling by NADPH oxidase 4- (NOX4-) mediated H2O2 production for glucose-stimulated insulin secretion (GSIS). There is a logical summation that integrates both metabolic plus redox homeostasis because the ATP-sensitive K+ channel (KATP) can only be closed when both ATP and H2O2 are elevated. Otherwise ATP would block KATP, while H2O2 would activate any of the redox-sensitive nonspecific calcium channels (NSCCs), such as TRPM2. Notably, a 100%-closed KATP ensemble is insufficient to reach the −50 mV threshold plasma membrane depolarization required for the activation of voltage-dependent Ca2+ channels. Open synergic NSCCs or Cl− channels have to act simultaneously to reach this threshold. The resulting intermittent cytosolic Ca2+-increases lead to the pulsatile exocytosis of insulin granule vesicles (IGVs). The incretin (e.g., GLP-1) amplification of GSIS stems from receptor signaling leading to activating the phosphorylation of TRPM channels and effects on other channels to intensify integral Ca2+-influx (fortified by endoplasmic reticulum Ca2+). ATP plus H2O2 are also required for branched-chain ketoacids (BCKAs); and partly for fatty acids (FAs) to secrete insulin, while BCKA or FA β-oxidation provide redox signaling from mitochondria, which proceeds by H2O2 diffusion or hypothetical SH relay via peroxiredoxin “redox kiss” to target proteins.

Seasonal changes in pancreatic B-cell function in euthermic yellow-bellied marmots

1985 ◽  
Vol 249 (2) ◽  
pp. R159-R165 ◽  
Author(s):  
G. L. Florant ◽  
A. K. Lawrence ◽  
K. Williams ◽  
W. A. Bauman
Keyword(s):  
Insulin Resistance ◽  
Body Weight ◽  
B Cell ◽  
Cell Function ◽  
Peripheral Resistance ◽  
The Body ◽  
Pancreatic B Cell ◽  
Peripheral Insulin Resistance ◽  
Body Weights ◽  
System Input

Fasting plasma insulin (PI) and glucose (PG) concentrations were measured throughout the body weight cycle of marmots. Animals gained weight during summer, and in late fall body weight peaked, after which they ceased feeding. Each month euthermic animals were injected intra-arterially with either dextrose (500 mg/kg) or porcine insulin (0.1 U/kg), and blood samples were collected over the subsequent 2 h. During weight gain fasting PI concentration and pancreatic B-cell response to injected dextrose increased markedly. Maximal insulin release to a dextrose challenge was measured during peak body weight or when body weight initially began to decline. The PG concentration after exogenous insulin administration was slight (less than 10%) in the fall but increased approximately 25% in the spring after marmots lost weight. Basal PG levels were not significantly different throughout the year. Basal fasting PI concentrations were significantly higher during the fall (P less than 0.01). It is suggested that in the fall, when marmots are obese, hyperinsulinemia and peripheral insulin resistance appear. Furthermore, in two animals with an increase in body weight of approximately 30% or less over the summer, peripheral resistance was demonstrable, albeit not as marked as in animals that appropriately doubled their body weights when given food ad libitum. Thus we hypothesize that factors other than adiposity, i.e., food intake, central nervous system input to the pancreatic B-cell, and/or changes in B-cell sensitivity to PG, may contribute to the observed peripheral insulin resistance and may be involved in body weight regulation.

scholarly journals Dual Mechanism for Type-2 Diabetes Resolution after Roux-en-Y Gastric Bypass

2009 ◽  
Vol 75 (6) ◽  
pp. 498-503 ◽  
Author(s):  
Edward Lin ◽  
S. Scott Davis ◽  
Jahnavi Srinivasan ◽  
John F. Sweeney ◽  
Thomas R. Ziegler ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Weight Loss ◽  
Gastric Bypass ◽  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Cell Function ◽  
Β Cell ◽  
Peripheral Insulin Resistance

Resolution of Type-2 diabetes mellitus (DM) after weight loss surgery is well documented, but the mechanism is elusive. We evaluated the glucose-insulin metabolism of patients undergoing a Roux-en-Y gastric bypass (RYGB) using the intravenous glucose tolerance test (IVGTT) and compared it with patients who underwent laparoscopic adjustable gastric band (AB) placement. Thirty-one female patients (age range, 20 to 50 years; body mass index, 47.2 kg/m2) underwent RYGB. Nine female patients underwent AB placement and served as control subjects. All patients underwent IVGTT at baseline and 1 month and 6 months after surgery. Thirteen patients undergoing RYGB and one patient undergoing AB exhibited impaired glucose tolerance or DM defined by the American Diabetes Association. By 6 months post surgery, diabetes was resolved in all but one patient undergoing RYGB but not in the patient undergoing AB. Patients with diabetes undergoing RYGB demonstrated increased insulin secretion and β-cell responsiveness 1 month after surgery and continued this trend up to 6 months, whereas none of the patients undergoing AB had changes in β-cell function. Both patients undergoing RYGB and those undergoing AB demonstrated significant weight loss (34.6 and 35.0 kg/m2, respectively) and improved insulin sensitivity at 6 months. RYGB ameliorates DM resolution in two phases: 1) early augmentation of beta cell function at 1 month; and 2) attenuation of peripheral insulin resistance at 6 months. Patients undergoing AB only exhibited reduction in peripheral insulin resistance at 6 months but no changes in insulin secretion.

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