Diversity in the effects of extracellular ATP and adenosine on the cellular processing and physiologic actions of insulin in rat adipocytes.

Hashimoto, Naoaki; Robinson, F W; Y, Shibata; Flanagan, J E; Kôno, Tetsuro

doi:10.1016/s0021-9258(18)48132-x

Cited by 26 publications

(4 citation statements)

References 40 publications

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“…Further, identifying P2Y 2 R as the anti-insulin signaling mediator advances early discoveries demonstrating potent inhibition of insulin signaling and hepatocyte glucose production by extracellular nucleotides. 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 All these shreds of evidence support our hypothesis that metformin improves hepatic insulin sensitivity by suppressing ATP release and signaling, consistent with a previous report utilizing insulin receptor-null mice concluding that "for metformin to have any effect, an operating insulin-signaling system in the liver is mandatory." 30 …”

Section: Resultssupporting

confidence: 90%

“… 31 It was reported that intravenous administration of adenine nucleotides stimulates HGP. 23 , 25 , 26 , 32 However, a nucleotide receptor controlling HGP remained elusive; therefore, we first stimulated hepatocyte P2Y 2 R with ATP and UTP, finding a dose-dependent reduction in glucose uptake ( Figures 3 A and 3B), suggesting a possible glucose release through GLUT2 in response to P2Y 2 R activation. We then monitored gluconeogenesis to determine if decreased glucose uptake was correlated with increased glucose production.…”

Section: Resultsmentioning

confidence: 98%

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A purinergic mechanism underlying metformin regulation of hyperglycemia

et al. 2023

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Section: Resultssupporting

confidence: 90%

Section: Resultsmentioning

confidence: 98%

A purinergic mechanism underlying metformin regulation of hyperglycemia

et al. 2023

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“…9,22 Therefore, it is speculated that the mechanism of inhibition of IDE associated with favoring the closed conformation (inactive). The insulin degradation inhibition by ATP in vivo was first reported in 1987 by Hashimoto 49 and subsequently induced by ATP plus aluminum fluoride. 50 In 2001, Camberos et al demonstrated that ATP in the presence of Mn 2+ (or Mg 2+ ) inhibits the activity of purified IDE (in vitro) in the degradation of insulin.…”

Section: ■ Discussionmentioning

confidence: 96%

Molecular Dynamics Simulations Reveal a Novel Mechanism for ATP Inhibition of Insulin Degrading Enzyme

Cruz

Seabra

2014

J. Chem. Inf. Model.

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Regulation of brain levels of the Amyloid-β 42 (Aβ42) polypeptide by IDE has recently been linked with possible routes for new therapies against Alzheimer's disease (AD). One important aspect is the regulatory mechanism of IDE by ATP, which is an IDE activator in degrading small peptides and an inhibitor in degrading larger peptides, such as Aβ42. This relationship was investigated in this study. We present molecular dynamics simulations of Aβ42 complexed with IDE, in the absence or presence of either ATP or excess Na(+) and Cl(-) ions. Results suggest a previously unreported inhibition mechanism that depends on charge-induced structural modifications in the active site and interactions simultaneously involving ATP, Aβ42, and IDE. Such interactions exist only when both ATP and Aβ42 are simultaneously present in the catalytic chamber. This mechanism results in allosteric, noncompetitive inhibition with apparent decrease of substrate affinity, in accordance with experiment.

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“…Unlike skeletal muscle and adipose tissues, the hepatic glucose transporter, GLUT2 activity is not dependent on insulin signaling, enabling the liver to take in and release glucose bidirectionally (17) during the fed and fasted state. It was reported that intravenous administration of adenine nucleotides stimulates HGP (18)(19)(20)(21). However, a nucleotide receptor controlling HGP remained elusive; therefore, we first stimulated hepatocyte P2Y2R with ATP and UTP, finding a dosedependent reduction in glucose uptake (Fig.…”

mentioning

confidence: 99%

A Purinergic Mechanism Underlying Metformin Regulation of Hyperglycemia

Senfeld

Peng

Shi

et al. 2022

Preprint

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Metformin, created in 1922, has been the first-line medication treating type 2 diabetes mellitus for almost 70 years; however, its mechanism of action has been heavily debated, partly because most prior studies used supratherapeutic concentrations exceeding 1mM. Here we report that at a clinically relevant concentration of 10 μM, metformin blocks high glucose-stimulated ATP secretion from hepatocytes mediating its antihyperglycemic action. Following glucose administration, mice demonstrate increased circulating ATP concentrations, which are prevented by metformin. Extracellular ATP through P2Y2 receptors (P2Y2R) compromises insulin-induced AKT activation and increases hepatic glucose production. In addition, metformin-dependent improvement in glucose tolerance is abolished in P2Y2R-null mice. Thus, removing the target of extracellular ATP, P2Y2R, mimics the effects of metformin, revealing a novel purinergic antidiabetic mechanism for metformin.

show abstract

Diversity in the effects of extracellular ATP and adenosine on the cellular processing and physiologic actions of insulin in rat adipocytes.

Cited by 26 publications

References 40 publications

A purinergic mechanism underlying metformin regulation of hyperglycemia

A purinergic mechanism underlying metformin regulation of hyperglycemia

Molecular Dynamics Simulations Reveal a Novel Mechanism for ATP Inhibition of Insulin Degrading Enzyme

A Purinergic Mechanism Underlying Metformin Regulation of Hyperglycemia

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