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Chronic exposure to KATP channel openers results in attenuated glucose sensing in hypothalamic GT1-7 neurons

Haythorne, Elizabeth, Hamilton, D. Lee, Findlay, John A., Beall, Craig, McCrimmon, Rory J. and Ashford, Michael L. J. 2016, Chronic exposure to KATP channel openers results in attenuated glucose sensing in hypothalamic GT1-7 neurons, Neuropharmacology, vol. 111, pp. 212-222, doi: 10.1016/j.neuropharm.2016.09.008.

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Title Chronic exposure to KATP channel openers results in attenuated glucose sensing in hypothalamic GT1-7 neurons
Author(s) Haythorne, Elizabeth
Hamilton, D. Lee
Findlay, John A.
Beall, Craig
McCrimmon, Rory J.
Ashford, Michael L. J.
Journal name Neuropharmacology
Volume number 111
Start page 212
End page 222
Total pages 11
Publisher Elsevier
Place of publication Amsterdam, The Netherlands
Publication date 2016-12
ISSN 1873-7064
Keyword(s) Diazoxide
Diazoxide (PubChem CID: 3019)
Glucose sensing
Hypoglycemia
K(ATP)
NN414
NN414 (Tifenazoxide) (PubChem CID 219048)
Type 1 diabetes
Action Potentials
Animals
Bridged Bicyclo Compounds, Heterocyclic
Cell Line
Cyclic S-Oxides
Glucose
Hypothalamus
KATP Channels
Mice
Neurons
Science & Technology
Life Sciences & Biomedicine
Neurosciences
Pharmacology & Pharmacy
Neurosciences & Neurology
K-ATP
ACTIVATED PROTEIN-KINASE
PANCREATIC BETA-CELLS
HORMONAL COUNTERREGULATORY RESPONSES
POTASSIUM CHANNEL
SULFONYLUREA RECEPTORS
RECURRENT HYPOGLYCEMIA
COUNTER-REGULATION
RATS
ADP
Summary Individuals with Type 1 diabetes (T1D) are often exposed to recurrent episodes of hypoglycaemia. This reduces hormonal and behavioural responses that normally counteract low glucose in order to maintain glucose homeostasis, with altered responsiveness of glucose sensing hypothalamic neurons implicated. Although the molecular mechanisms are unknown, pharmacological studies implicate hypothalamic ATP-sensitive potassium channel (KATP) activity, with KATP openers (KCOs) amplifying, through cell hyperpolarization, the response to hypoglycaemia. Although initial findings, using acute hypothalamic KCO delivery, in rats were promising, chronic exposure to the KCO NN414 worsened the responses to subsequent hypoglycaemic challenge. To investigate this further we used GT1-7 cells to explore how NN414 affected glucose-sensing behaviour, the metabolic response of cells to hypoglycaemia and KATP activity. GT1-7 cells exposed to 3 or 24 h NN414 exhibited an attenuated hyperpolarization to subsequent hypoglycaemic challenge or NN414, which correlated with diminished KATP activity. The reduced sensitivity to hypoglycaemia was apparent 24 h after NN414 removal, even though intrinsic KATP activity recovered. The NN414-modified glucose responsiveness was not associated with adaptations in glucose uptake, metabolism or oxidation. KATP inactivation by NN414 was prevented by the concurrent presence of tolbutamide, which maintains KATP closure. Single channel recordings indicate that NN414 alters KATP intrinsic gating inducing a stable closed or inactivated state. These data indicate that exposure of hypothalamic glucose sensing cells to chronic NN414 drives a sustained conformational change to KATP, probably by binding to SUR1, that results in loss of channel sensitivity to intrinsic metabolic factors such as MgADP and small molecule agonists.
Language eng
DOI 10.1016/j.neuropharm.2016.09.008
Field of Research 1109 Neurosciences
1115 Pharmacology And Pharmaceutical Sciences
1701 Psychology
HERDC Research category C1 Refereed article in a scholarly journal
Copyright notice ©2016, The Authors
Free to Read? Yes
Use Rights Creative Commons Attribution licence
Persistent URL http://hdl.handle.net/10536/DRO/DU:30112689

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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.