Skip to main content

Advertisement

SpringerLink
Log in

Continuous hypothalamic KATP activation blunts glucose counter-regulation in vivo in rats and suppresses KATP conductance in vitro

  • Short Communication
  • Published:
Diabetologia Aims and scope Submit manuscript

Abstract

Aims/hypothesis

Acute systemic delivery of the sulfonylurea receptor (SUR)-1-specific ATP-sensitive K+ channel (KATP) opener, NN414, has been reported to amplify glucose counter-regulatory responses (CRRs) in rats exposed to hypoglycaemia. Thus, we determined whether continuous NN414 could prevent hypoglycaemia-induced defective counter-regulation.

Methods

Chronically catheterised male Sprague–Dawley rats received a continuous infusion of NN414 into the third ventricle for 8 days after implantation of osmotic minipumps. Counter-regulation was examined by hyperinsulinaemic–hypoglycaemic clamp on day 8 after three episodes of insulin-induced hypoglycaemia (recurrent hypoglycaemia [RH]) on days 5, 6 and 7. In a subset of rats exposed to RH, NN414 infusion was terminated on day 7 to wash out NN414 before examination of counter-regulation on day 8. To determine whether continuous NN414 exposure altered KATP function, we used the hypothalamic glucose-sensing GT1-7 cell line, which expresses the SUR-1-containing KATP channel.

Results

Continuous exposure to NN414 in the setting of RH increased, rather than decreased, the glucose infusion rate (GIR), as exemplified by attenuated adrenaline (epinephrine) secretion. Termination of NN414 on day 7 with subsequent washout for 24 h partially diminished the GIR. The same duration of exposure of GT1-7 cells to NN414 substantially reduced KATP conductance, which was also reversed on washout of the agonist. The suppression of KATP current was not associated with reduced channel subunit mRNA or protein levels.

Conclusions/interpretation

These data indicate that continuous KATP activation results in suppressed CRRs to hypoglycaemia in vivo, which in vitro is associated with the reversible conversion of KATP into a stable inactive state.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Abbreviations

CRR:

Counter-regulatory response

GIR:

Glucose infusion rate

GS:

Glucose sensing

KATP :

ATP-sensitive potassium channel

KIR :

Inward-rectifier K+ channel

RH:

Recurrent hypoglycaemia

SUR:

Sulfonylurea receptor

References

  1. McCrimmon RJ, Sherwin RS (2010) Hypoglycemia in type 1 diabetes. Diabetes 59:2333–2339

    Article  PubMed  CAS  Google Scholar 

  2. Beall C, Ashford ML, McCrimmon RJ (2012) The physiology and pathophysiology of the neural control of the counterregulatory response. Am J Physiol Reg I 302:R215–R223

    Article  CAS  Google Scholar 

  3. Borg MA, Borg WP, Tamborlane WV, Brines ML, Shulman GI, Sherwin RS (1999) Chronic hypoglycemia and diabetes impair counterregulation induced by localized 2-deoxy-glucose perfusion of the ventromedial hypothalamus in rats. Diabetes 48:584–587

    Article  PubMed  CAS  Google Scholar 

  4. Sanders NM, Taborsky GJ Jr, Wilkinson CW, Daumen W, Figlewicz DP (2007) Antecedent hindbrain glucoprivation does not impair the counterregulatory response to hypoglycemia. Diabetes 56:217–223

    Article  PubMed  CAS  Google Scholar 

  5. Song Z, Routh VH (2006) Recurrent hypoglycemia reduces the glucose sensitivity of glucose-inhibited neurons in the ventromedial hypothalamus nucleus. Am J Physiol - Reg I 291:R1283–R1287

    Article  CAS  Google Scholar 

  6. Dunn-Meynell AA, Rawson NE, Levin BE (1998) Distribution and phenotype of neurons containing the ATP-sensitive K+ channel in rat brain. Brain Research 814:41–54

    Article  PubMed  CAS  Google Scholar 

  7. Kang L, Routh VH, Kuzhikandathil EV, Gaspers LD, Levin BE (2004) Physiological and molecular characteristics of rat hypothalamic ventromedial nucleus glucosensing neurons. Diabetes 53:549–559

    Article  PubMed  CAS  Google Scholar 

  8. Ashford ML, Boden PR, Treherne JM (1990) Tolbutamide excites rat glucoreceptive ventromedial hypothalamic neurones by indirect inhibition of ATP-K+ channels. Br J Pharmacol 101:531–540

    Article  PubMed  CAS  Google Scholar 

  9. McCrimmon RJ, Evans ML, Fan X et al (2005) Activation of ATP-sensitive K+ channels in the ventromedial hypothalamus amplifies counterregulatory hormone responses to acute hypoglycemia in normal and recurrently hypoglycemic rats. Diabetes 54:3169–3174

    Article  PubMed  CAS  Google Scholar 

  10. Evans ML, McCrimmon RJ, Flanagan DE et al (2004) Hypothalamic ATP-sensitive K + channels play a key role in sensing hypoglycemia and triggering counterregulatory epinephrine and glucagon responses. Diabetes 53:2542–2551

    Article  PubMed  CAS  Google Scholar 

  11. Fan X, Ding Y, Cheng H, Gram DX, Sherwin RS, McCrimmon RJ (2008) Amplified hormonal counterregulatory responses to hypoglycemia in rats after systemic delivery of a SUR-1-selective K(+) channel opener? Diabetes 57:3327–3334

    Article  PubMed  CAS  Google Scholar 

  12. Beall C, Hamilton DL, Gallagher J et al (2012) Mouse hypothalamic GT1-7 cells demonstrate AMPK-dependent intrinsic glucose-sensing behaviour. Diabetologia 55:2432–2444

    Article  PubMed  CAS  Google Scholar 

  13. Du Q, Jovanović S, Sukhodub A, Jovanović A (2010) Infection with AV-SUR2A protects H9C2 cells against metabolic stress: a mechanism of SUR2A-mediated cytoprotection independent from the KATP channel activity. BBA - Mol Cell Res 1803:405–415

    CAS  Google Scholar 

  14. Cook DL, Satin LJ, Ashford ML, Hales CN (1988) ATP-sensitive K+ channels in pancreatic b-cells. Spare channel hypothesis. Diabetes 37:495–498

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank Novo Nordisk for providing NN414.

Funding

This study was funded by: grants from the JDRF (to RJM), Diabetes UK (to MLJA, RJM); a JDRF Postdoctoral Fellowship to CB; and NIH grants DK 20495 and P30 DK 45375 (to RSS).

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

CB, EH, XF, QD, SJ, RSS and RJM contributed to the acquisition of data. CB, EH, MLJA and RJM made substantial contributions to the analysis and interpretation of data. RJM, CB, EH, RSS and MLJA contributed to the conception and design of the study. CB, EH, XF, QD, SJ, RSS, MLJA and RJM wrote or critically revised the manuscript. All authors approved the final version.

Author information

Authors and Affiliations

  1. Cardiovascular and Diabetes Medicine, Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, Scotland, UK

    Craig Beall, Elizabeth Haythorne, Qingyou Du, Sofija Jovanovic, Michael L. J. Ashford & Rory J. McCrimmon

  2. Department of Internal Medicine, Yale University, New Haven, CT, USA

    Xiaoning Fan & Robert S. Sherwin

Authors
  1. Craig Beall
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elizabeth Haythorne
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiaoning Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qingyou Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sofija Jovanovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Robert S. Sherwin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Michael L. J. Ashford
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Rory J. McCrimmon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rory J. McCrimmon.

Additional information

C. Beall and E. Haythorne contributed equally to this study.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM Fig. 1

(PDF 200 kb)

ESM Fig. 2

(PDF 410 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Beall, C., Haythorne, E., Fan, X. et al. Continuous hypothalamic KATP activation blunts glucose counter-regulation in vivo in rats and suppresses KATP conductance in vitro. Diabetologia 56, 2088–2092 (2013). https://doi.org/10.1007/s00125-013-2970-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00125-013-2970-5

Keywords

Search

Navigation