Mechanisms of glucose sensing in the pancreatic β-cell

Fridlyand, Leonid E.; Phillipson, Louis

doi:10.4161/isl.3.5.16409

Cited by 11 publications

(9 citation statements)

References 55 publications

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“…Redox shuttles and mitochondrial Ca 2+ handling were also modeled. We have performed a computational analysis of β-cell fuel metabolism to quantitatively assess how cytoplasmic ATP/ADP ratio can be controlled by mitochondrial and cytoplasmic processes 15 , 25 …”

Section: Components Of Glucagon Secretion Regulatory Mechanism Andmentioning

confidence: 99%

“…We have recently developed a mathematical model for regulated glucose sensing in pancreatic β-cells 15 , 25 and use it here to analyze α-cells. The cytoplasmic part of the model includes equations describing glucokinase, glycolysis, lactate dehydrogenase, NAD(P)H and ATP production and consumption ( Fig.…”

Section: Components Of Glucagon Secretion Regulatory Mechanism Andmentioning

confidence: 99%

“…The existence of specific mechanisms for β-cell glucose sensitivity itself, and particularly the increase of mitochondrial membrane potential with increased glucose, may underlie the increased sensitivity of these cells to injury (see for details, ref. 25 ). According to this hypothesis the absence of a significant increase of mitochondrial potential with glucose, as simulated in our model ( Fig.…”

Section: Computational Systems Analysis Of the Mechanisms Of Glucamentioning

confidence: 99%

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A computational systems analysis of factors regulating α cell glucagon secretion

Fridlyand

Philipson²

2012

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Glucagon, a peptide hormone secreted from the α-cells of the pancreatic islets, is critical for blood glucose homeostasis. We reviewed the literature and employed a computational systems analysis of intracellular metabolic and electrical regulation of glucagon secretion to better understand these processes. The mathematical model of α-cell metabolic parameters is based on our previous model for pancreatic β-cells. We also formulated an ionic model for action potentials that incorporates Ca2+, K+, Na+ and Cl- currents. Metabolic and ionic models are coupled to the equations describing Ca2+ homeostasis and glucagon secretion that depends on activation of specific voltage-gated Ca2+ channels. Paracrine and endocrine regulations were analyzed with an emphasis on their effects on a hyperpolarization of membrane potential. This general model simulates and gives insight into the mechanisms of regulation of glucagon secretion under a wide range of experimental conditions. We also reviewed and analyzed dysfunctional mechanisms in α-cells to determine key pharmacological targets for modulating glucagon secretion in type 1 and 2 diabetes.

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Section: Components Of Glucagon Secretion Regulatory Mechanism Andmentioning

confidence: 99%

Section: Components Of Glucagon Secretion Regulatory Mechanism Andmentioning

confidence: 99%

Section: Computational Systems Analysis Of the Mechanisms Of Glucamentioning

confidence: 99%

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A computational systems analysis of factors regulating α cell glucagon secretion

Fridlyand

Philipson²

2012

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“…This in turn leads to the closure of ATP-sensitive K + channels (K ATP channels) and results in cell membrane depolarization and opening of voltage-dependent calcium channels (VDCCs). Ca + influx triggers the release of insulin from β-cell insulin granules (3-5).…”

Section: Introductionmentioning

confidence: 99%

Loss of LAMTOR1 in pancreatic β‑cells increases glucose‑stimulated insulin secretion in mice

et al. 2019

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Insulin secretion from pancreatic β-cells regulates glucose metabolism and is related to various diseases including diabetes. The late endosomal/lysosomal adaptor MAPK and mTOR activator 1 (LAMTOR1) is one of the subunits of the 'Ragulator' complex and plays an important role in energy metabolism including glucose metabolism. The present study was designed to explore the role of LAMTOR1 in murine pancreatic β-cell function. A murine model with β cell-specific deficiency (βLamtor1-KO) was generated to assess β-cell function (insulin sensitivity paired with β-cell responses) by hyperglycemic clamp in vivo. Islet perfusion and mitochondrial functional analyses were performed to investigate the individual steps in the insulin secretion pathway. Results showed that glucose tolerance in vivo as well as glucose-stimulated insulin secretion in the hyperglycemic clamp and islet perfusion were higher in βLamtor1-KO mice compared to the control models. Although mitochondrial dysfunction was present, the deletion of Lamtor1 increased glutamate content in the mouse insulin granules as well as acetyl-CoA carboxylase 1 (ACC1) activity thus enhancing insulin secretion. Together, our data indicate that LAMTOR1 is important for maintaining mitochondrial function in mouse pancreatic β-cells, however deletion of Lamtor1 increases the amplification pathway induced by glutamate and ACC1, ultimately leading to increased insulin secretion. These findings suggest that knockout of Lamtor1 is a potential technique for improving pancreatic β-cell function and treating diabetes.

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“…4,5 Simulations of glucose-stimulated insulin secretion have shown that the ATP/ ADP ratio is most steeply coupled to glucose concentrations in the range of 5–10 mM, past the inflection point for GCK cooperativity, before plateauing above 10 mM glucose. 6 Given that an increase in the ATP/ADP ratio drives closure of the ATP-dependent K + channels leading to glucose-initiated action potentials and insulin secretion, the specific activity of GCK at 5–10 mM glucose is critical for the β -cell secretory response to the postprandial rise in the level of glucose. 7…”

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confidence: 99%

Nitric Oxide Activates β-Cell Glucokinase by Promoting Formation of the “Glucose-Activated” State

et al. 2018

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The release of insulin from the pancreas is tightly controlled by glucokinase (GCK) activity that couples β-cell metabolism to changes in blood sugar. Despite having only a single glucose-binding site, GCK displays positive glucose cooperativity. Ex vivo structural studies have identified several potential protein conformations with varying levels of enzymatic activity, yet it is unclear how living cells regulate GCK cooperativity. To better understand the cellular regulation of GCK activation, we developed a homotransfer Förster resonance energy transfer (FRET) GCK biosensor and used polarization microscopy to eliminate fluorescence crosstalk from FRET quantification and improve the signal-to-noise ratio. This approach enhanced sensor contrast compared to that seen with the heterotransfer FRET GCK reporter and allowed observation of individual GCK states using an automated method to analyze FRET data at the pixel level. Mutations known to activate and inhibit GCK activity produced distinct anisotropy distributions, suggesting that at least two conformational states exist in living cells. A high glucose level activated the biosensor in a manner consistent with GCK's enzymology. Interestingly, glucose-free conditions did not affect GCK biosensor FRET, indicating that there is a single low-activity state, which is counter to proposed structural models of GCK cooperativity. Under low-glucose conditions, application of chemical NO donors efficiently shifted GCK to the more active conformation. Notably, GCK activation by mutation, a high glucose level, a pharmacological GCK activator, or S-nitrosylation all shared the same FRET distribution. These data suggest a simplified model for GCK activation in living cells, where post-translational modification of GCK by S-nitrosylation facilitates a single conformational transition that enhances GCK enzymatic activity.

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Mechanisms of glucose sensing in the pancreatic β-cell

Cited by 11 publications

References 55 publications

A computational systems analysis of factors regulating α cell glucagon secretion

A computational systems analysis of factors regulating α cell glucagon secretion

Loss of LAMTOR1 in pancreatic β‑cells increases glucose‑stimulated insulin secretion in mice

Nitric Oxide Activates β-Cell Glucokinase by Promoting Formation of the “Glucose-Activated” State

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