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Activation of the Na+/K+-ATPase by insulin and glucose as a putative negative feedback mechanism in pancreatic beta-cells

  • Signaling and Cell Physiology
  • Published:
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Abstract

Pancreatic beta-cells of sulfonylurea receptor type 1 knock-out (SUR1−/−) mice exhibit an oscillating membrane potential (V m) demonstrating that hyper-polarisation occurs despite the lack of KATP channels. We hypothesize that glucose activates the Na+/K+-ATPase thus increasing a hyper-polarising current. Elevating glucose in SUR1−/− beta-cells resulted in a transient fall in V m and [Ca2+]c independent of sarcoplasmic and endoplasmic reticulum Ca2+-activated ATPase (SERCA) activation. This was not affected by K+ channel blockade but inhibited by ATP depletion and by ouabain. Increasing glucose also reduced [Na+]c, an effect reversed by ouabain. Exogenously applied insulin decreased [Na+]c and hyper-polarised V m. Inhibiting insulin signalling in SUR1−/− beta-cells blunted the glucose-induced decrease of [Ca2+]c. Tolbutamide (1 mmol/l) disclosed the SERCA-independent effect of glucose on [Ca2+]c in wild-type beta-cells. The data show that in SUR1−/− beta-cells, glucose activates the Na+/K+-ATPase presumably by increasing [ATP]c. Insulin can also stimulate the pump and potentiate the effect of glucose. Pathways involving the pump may thus serve as potential drug targets in certain metabolic disorders.

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Abbreviations

[Ca2+]c :

Cytosolic free calcium concentration

V m :

Plasma membrane potential

KIR6.2:

Inward rectifying K+ channel type 6.2

SUR1:

Sulfonylurea receptor type 1

KATP channel:

ATP-dependent K+ channel

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Acknowledgements

This work was supported by grants from the DFG Dr225/6-3 (gd) and DU425/1-2 (md), the NIH grant DK044311 and JDRF 1-2005-750 (jb) and the Thrasher Foundation (lab).

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Authors and Affiliations

  1. Institute of Pharmacy, Department of Pharmacology and Toxicology, University of Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, Germany

    M. Düfer, D. Haspel, P. Krippeit-Drews & G. Drews

  2. Department of Medicine, Pacific Northwest Research Institute, Seattle, WA, 98122, USA

    L. Aguilar-Bryan & J. Bryan

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  1. M. Düfer
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  2. D. Haspel
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  3. P. Krippeit-Drews
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  4. L. Aguilar-Bryan
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  5. J. Bryan
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  6. G. Drews
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Correspondence to G. Drews.

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Düfer, M., Haspel, D., Krippeit-Drews, P. et al. Activation of the Na+/K+-ATPase by insulin and glucose as a putative negative feedback mechanism in pancreatic beta-cells. Pflugers Arch - Eur J Physiol 457, 1351–1360 (2009). https://doi.org/10.1007/s00424-008-0592-4

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