| Recurrent hypoglycemia increases hypothalamic glucose phosphorylation activity in rats. | |
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MedLine Citation:
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PMID: 20667558 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The mechanisms underpinning impaired defensive counterregulatory responses to hypoglycemia that develop in some people with diabetes who suffer recurrent episodes of hypoglycemia are unknown. Previous work examining whether this is a consequence of increased glucose delivery to the hypothalamus, postulated to be the major hypoglycemia-sensing region, has been inconclusive. Here, we hypothesized instead that increased hypothalamic glucose phosphorylation, the first committed intracellular step in glucose metabolism, might develop following exposure to hypoglycemia. We anticipated that this adaptation might tend to preserve glucose flux during hypoglycemia, thus reducing detection of a falling glucose. We first validated a model of recurrent hypoglycemia in chronically catheterized (right jugular vein) rats receiving daily injections of insulin. We confirmed that this model of recurrent insulin-induced hypoglycemia results in impaired counterregulation, with responses of the key counterregulatory hormone, epinephrine, being suppressed significantly and progressively from the first day to the fourth day of insulin-induced hypoglycemia. In another cohort, we investigated the changes in brain glucose phosphorylation activity over 4 days of recurrent insulin-induced hypoglycemia. In keeping with our hypothesis, we found that recurrent hypoglycemia markedly and significantly increased hypothalamic glucose phosphorylation activity in a day-dependent fashion, with day 4 values 2.8 ± 0.6-fold higher than day 1 (P < .05), whereas there was no change in glucose phosphorylation activity in brain stem and frontal cortex. These findings suggest that the hypothalamus may adapt to recurrent hypoglycemia by increasing glucose phosphorylation; and we speculate that this metabolic adaptation may contribute, at least partly, to hypoglycemia-induced counterregulatory failure. |
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Authors:
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Mayowa A Osundiji; Paul Hurst; Stephen P Moore; S Pauliina Markkula; Chen Y Yueh; Ashwini Swamy; Shu Hoashi; Jill S Shaw; Christine H Riches; Lora K Heisler; Mark L Evans |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-07-29 |
Journal Detail:
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Title: Metabolism: clinical and experimental Volume: 60 ISSN: 1532-8600 ISO Abbreviation: Metab. Clin. Exp. Publication Date: 2011 Apr |
Date Detail:
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Created Date: 2011-03-22 Completed Date: 2011-05-23 Revised Date: 2011-07-27 |
Medline Journal Info:
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Nlm Unique ID: 0375267 Medline TA: Metabolism Country: United States |
Other Details:
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Languages: eng Pagination: 550-6 Citation Subset: IM |
Copyright Information:
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Copyright © 2011 Elsevier Inc. All rights reserved. |
Affiliation:
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Department of Medicine and Institute of Metabolic Science, University of Cambridge, Addenbrookes Hospital, Cambridge, UK. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Blood Glucose / metabolism Brain Chemistry / physiology Disease Models, Animal Epinephrine / blood Glucagon / blood Glucose / metabolism* Hypoglycemia / metabolism* Hypothalamus / metabolism* Male Phosphorylation Rats Rats, Sprague-Dawley Recurrence |
| Grant Support | |
ID/Acronym/Agency:
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081713//Wellcome Trust; R01DK065171/DK/NIDDK NIH HHS; //Wellcome Trust |
| Chemical | |
Reg. No./Substance:
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0/Blood Glucose; 50-99-7/Glucose; 51-43-4/Epinephrine; 9007-92-5/Glucagon |
| Comments/Corrections | |
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