Naloxone, but not valsartan, preserves responses to hypoglycemia after antecedent hypoglycemia: role of metabolic reprogramming in counterregulatory failure.
OBJECTIVE
Hypoglycemia-associated autonomic failure (HAAF) constitutes one of the main clinical obstacles to optimum treatment of type 1 diabetes. Neurons in the ventromedial hypothalamus are thought to mediate counterregulatory responses to hypoglycemia. We have previously hypothesized that hypoglycemia-induced hypothalamic angiotensin might contribute to HAAF, suggesting that the angiotensin blocker valsartan might prevent HAAF. On the other hand, clinical studies have demonstrated that the opioid receptor blocker naloxone ameliorates HAAF. The goal of this study was to generate novel hypothalamic markers of hypoglycemia and use them to assess mechanisms mediating HAAF and its reversal.


METHODS
Quantitative PCR was used to validate a novel panel of hypothalamic genes regulated by hypoglycemia. Mice were exposed to one or five episodes of insulin-induced hypoglycemia, with or without concurrent exposure to valsartan or naloxone. Corticosterone, glucagon, epinephrine, and hypothalamic gene expression were assessed after the final episode of hypoglycemia.


RESULTS
A subset of hypothalamic genes regulated acutely by hypoglycemia failed to respond after repetitive hypoglycemia. Responsiveness of a subset of these genes was preserved by naloxone but not valsartan. Notably, hypothalamic expression of four genes, including pyruvate dehydrogenase kinase 4 and glycerol 3-phosphate dehydrogenase 1, was acutely induced by a single episode of hypoglycemia, but not after antecedent hypoglycemia; naloxone treatment prevented this failure. Similarly, carnitine palmitoyltransferase-1 was inhibited after repetitive hypoglycemia, and this inhibition was prevented by naloxone. Repetitive hypoglycemia also caused a loss of hypoglycemia-induced elevation of glucocorticoid secretion, a failure prevented by naloxone but not valsartan.


CONCLUSIONS
Based on these observations we speculate that acute hypoglycemia induces reprogramming of hypothalamic metabolism away from glycolysis toward β-oxidation, HAAF is associated with a reversal of this reprogramming, and naloxone preserves some responses to hypoglycemia by preventing this reversal.
Poplawski
Michal M
MM
Fishberg Center for Neurobiology, Mount Sinai School of Medicine, New York, New York, USA.
Mastaitis
Jason W
JW
Mobbs
Charles V
CV
D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000235:genetics; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D051273:Glucose Transporter Type 2 / Q000235:genetics; D005993:Glycerolphosphate Dehydrogenase / Q000235:genetics; D006706:Homeostasis / Q000187:drug effects; D007003:Hypoglycemia / Q000139:chemically induced / Q000150:complications* / Q000209:etiology / Q000235:genetics; D007328:Insulin / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D009270:Naloxone / Q000494:pharmacology* / Q000627:therapeutic use; D009292:Narcotic Antagonists / Q000494:pharmacology; D000071229:Perilipin-4; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D054970:Pure Autonomic Failure / Q000209:etiology / Q000517:prevention & control; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012097:Repressor Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013777:Tetrazoles / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan
D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; C407088:Angptl4 protein, mouse; D000959:Antihypertensive Agents; D051017:Apoptosis Regulatory Proteins; D001786:Blood Glucose; D002352:Carrier Proteins; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051273:Glucose Transporter Type 2; C444643:Hif3a protein, mouse; D007328:Insulin; D008565:Membrane Proteins; D009292:Narcotic Antagonists; D000071229:Perilipin-4; C487119:Plin4 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012097:Repressor Proteins; C495682:Slc2a2 protein, mouse; D013777:Tetrazoles; D014157:Transcription Factors; D009270:Naloxone; D000068756:Valsartan; D005993:Glycerolphosphate Dehydrogenase; D017346:Protein Serine-Threonine Kinases; D014633:Valine
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