Adenine nucleotide regulation in pancreatic β-cells: modeling of ATP/ADP-Ca2+ interactions

2005 ◽  
Vol 289 (5) ◽  
pp. E839-E848 ◽  
Author(s):  
Leonid E. Fridlyand ◽  
Li Ma ◽  
Louis H. Philipson
Keyword(s):  
Glucose Metabolism ◽  
Intracellular Calcium ◽  
Metabolic Flux ◽  
Cell Function ◽  
Adenine Nucleotide ◽  
Glucose Consumption ◽  
Calcium Flux ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Low Glucose

Glucose metabolism stimulates insulin secretion in pancreatic β-cells. A consequence of metabolism is an increase in the ratio of ATP to ADP ([ATP]/[ADP]) that contributes to depolarization of the plasma membrane via inhibition of ATP-sensitive K+ (KATP) channels. The subsequent activation of calcium channels and increased intracellular calcium leads to insulin exocytosis. Here we evaluate new data and review the literature on nucleotide pool regulation to determine the utility and predictive value of a new mathematical model of ion and metabolic flux regulation in β-cells. The model relates glucose consumption, nucleotide pool concentration, respiration, Ca2+ flux, and KATP channel activity. The results support the hypothesis that β-cells maintain a relatively high [ATP]/[ADP] value even in low glucose and that dramatically decreased free ADP with only modestly increased ATP follows from glucose metabolism. We suggest that the mechanism in β-cells that leads to this result can simply involve keeping the total adenine nucleotide concentration unchanged during a glucose elevation if a high [ATP]/[ADP] ratio exits even at low glucose levels. Furthermore, modeling shows that independent glucose-induced oscillations of intracellular calcium can lead to slow oscillations in nucleotide concentrations, further predicting an influence of calcium flux on other metabolic oscillations. The results demonstrate the utility of comprehensive mathematical modeling in understanding the ramifications of potential defects in β-cell function in diabetes.

scholarly journals PERK Activation at Low Glucose Concentration Is Mediated by SERCA Pump Inhibition and Confers Preemptive Cytoprotection to Pancreatic β-Cells

2011 ◽  
Vol 25 (2) ◽  
pp. 315-326 ◽  
Author(s):  
Claire E. Moore ◽  
Omotola Omikorede ◽  
Edith Gomez ◽  
Gary B. Willars ◽  
Terence P. Herbert
Keyword(s):  
Glucose Concentration ◽  
Cell Function ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor ◽  
Energy Status ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Β Cell Function ◽  
Low Glucose

Abstract Protein kinase R-like ER kinase (PERK) is activated at physiologically low glucose concentrations in pancreatic β-cells. However, the molecular mechanisms by which PERK is activated under these conditions and its role in β-cell function are poorly understood. In this report, we investigated, in dispersed rat islets of Langerhans and mouse insulinoma-6 (MIN6) cells, the relationship between extracellular glucose concentration, the free endoplasmic reticulum (ER) calcium concentration ([Ca2+]ER) measured directly using an ER targeted fluorescence resonance energy transfer-based calcium sensor, and the activation of PERK. We found that a decrease in glucose concentration leads to a concentration-dependent reduction in [Ca2+]ER that parallels the activation of PERK and the phosphorylation of its substrate eukaryotic initiation factor-2α. We provide evidence that this decrease in [Ca2+]ER is caused by a decrease in sarcoplasmic/ER Ca2+-ATPase pump activity mediated by a reduction in the energy status of the cell. Importantly, we also report that PERK-dependent eukaryotic initiation factor-2α phosphorylation at low glucose concentration plays a significant role in 1) the regulation of both proinsulin and global protein synthesis, 2) cell viability, and 3) conferring preemptive cytoprotection against ER stress. Taken together, these results provide evidence that a decrease in the ATP/energy status of the cell in response to a decrease in glucose concentration results in sarcoplasmic/ER Ca2+-ATPase pump inhibition, the efflux of Ca2+ from the ER, and the activation of PERK, which plays an important role in both pancreatic β-cell function and survival.

scholarly journals Regulation of voltage-gated K+channels by glucose metabolism in pancreatic β-cells

FEBS Letters ◽  
2009 ◽  
Vol 583 (13) ◽  
pp. 2225-2230 ◽  
Author(s):  
Masashi Yoshida ◽  
Katsuya Dezaki ◽  
Shiho Yamato ◽  
Atsushi Aoki ◽  
Hitoshi Sugawara ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
K Channels ◽  
Voltage Gated

scholarly journals Selenoprotein P as a significant regulator of pancreatic β cell function

2019 ◽  
Author(s):  
Yoshiro Saito
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Insulin Signalling ◽  
Selenoprotein P ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Β Cell Function

Abstract Selenoprotein P (SeP; encoded by SELENOP) is selenium (Se)-rich plasma protein that is mainly produced in the liver. SeP functions as a Se-transport protein to deliver Se from the liver to other tissues, such as the brain and testis. The protein plays a pivotal role in Se metabolism and antioxidative defense, and it has been identified as a ‘hepatokine’ that causes insulin resistance in type 2 diabetes. SeP levels are increased in type 2 diabetes patients, and excess SeP impairs insulin signalling, promoting insulin resistance. Furthermore, increased levels of SeP disturb the functioning of pancreatic β cells and inhibit insulin secretion. This review focuses on the biological function of SeP and the molecular mechanisms associated with the adverse effects of excess SeP on pancreatic β cells’ function, particularly with respect to redox reactions. Interactions between the liver and pancreas are also discussed.

scholarly journals A Minimum of Fuel Is Necessary for Tolbutamide to Mimic the Effects of Glucose on Electrical Activity in Pancreatic β-Cells*

Endocrinology ◽  
1998 ◽  
Vol 139 (3) ◽  
pp. 993-998 ◽  
Author(s):  
Jean-Claude Henquin
Keyword(s):  
Membrane Potential ◽  
Electrical Activity ◽  
Slow Waves ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
K Channels ◽  
Low Concentrations ◽  
Low Glucose ◽  
Intracellular Microelectrodes

Glucose stimulation of pancreatic β-cells triggers electrical activity (slow waves of membrane potential with superimposed spikes) that is best monitored with intracellular microelectrodes. Closure of ATP-sensitive K+ channels underlies the depolarization to the threshold potential and participates in the increase in electrical activity produced by suprathreshold (>7 mm) concentrations of glucose, but it is still unclear whether this is the sole mechanism of control. This was investigated by testing whether blockade of ATP-sensitive K+ channels by low concentrations of tolbutamide is able to mimic the effects of glucose on mouse β-cell electrical activity even in the absence of the sugar. The response to tolbutamide was influenced by the duration of the perifusion with the low glucose medium. Tolbutamide (25 μm) caused a rapid and sustained depolarization with continuous activity after 6 min of perifusion of the islet with 3 mm glucose, and a progressive depolarization with slow waves of the membrane potential after 20 min. In the absence of glucose, the β-cell response to tolbutamide was a transient phase of depolarization with rare slow waves (6 min) or a silent, small, but sustained, depolarization (20 min). Readministration of 3 mm glucose was sufficient to restore slow waves, whereas an increase in the glucose concentration to 5 and 7 mm was followed by a lengthening of the slow waves and a shortening of the intervals. In contrast, induction of slow waves by tolbutamide proved very difficult in the absence of glucose, because the β-cell membrane tended to depolarize from a silent level to the plateau level, at which electrical activity is continuous. Azide, a mitochondrial poison, abrogated the electrical activity induced by tolbutamide in the absence of glucose, which demonstrates the influence of the metabolism of endogenous fuels on the response to the sulfonylurea. The partial repolarization that azide also produced was reversed by increasing the concentration of tolbutamide, but reappearance of the spikes required the addition of glucose. It is concluded that inhibition of ATP-sensitive K+ channels is not the only mechanism by which glucose controls electrical activity inβ -cells.

scholarly journals Src regulates insulin secretion and glucose metabolism by influencing subcellular localization of glucokinase in pancreatic β‐cells

2015 ◽  
Vol 7 (2) ◽  
pp. 171-178 ◽  
Author(s):  
Hiroki Sato ◽  
Kazuaki Nagashima ◽  
Masahito Ogura ◽  
Yuichi Sato ◽  
Yumiko Tahara ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Metabolism ◽  
Subcellular Localization ◽  
Β Cells ◽  
Pancreatic Β Cells

scholarly journals Optical control of GPR40 signalling in pancreatic β-cells

2017 ◽  
Vol 8 (11) ◽  
pp. 7604-7610 ◽  
Author(s):  
James Allen Frank ◽  
Dmytro A. Yushchenko ◽  
Nicholas H. F. Fine ◽  
Margherita Duca ◽  
Mevlut Citir ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Cell Function ◽  
Optical Control ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Β Cell Function

Fatty acids activate GPR40 and K+ channels to modulate β-cell function.

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