Corticotrophin-releasing factor receptors within the ventromedial hypothalamus regulate hypoglycemia-induced hormonal counterregulation.
Recurrent episodes of hypoglycemia impair sympathoadrenal counterregulatory responses (CRRs) to a subsequent episode of hypoglycemia. For individuals with type 1 diabetes, this markedly increases (by 25-fold) the risk of severe hypoglycemia and is a major limitation to optimal insulin therapy. The mechanisms through which this maladaptive response occurs remain unknown. The corticotrophin-releasing factor (CRF) family of neuropeptides and their receptors (CRFR1 and CRFR2) play a critical role in regulating the neuroendocrine stress response. Here we show in the Sprague-Dawley rat that direct in vivo application to the ventromedial hypothalamus (VMH), a key glucose-sensing region, of urocortin I (UCN I), an endogenous CRFR2 agonist, suppressed (approximately 55-60%), whereas CRF, a predominantly CRFR1 agonist, amplified (approximately 50-70%) CRR to hypoglycemia. UCN I was shown to directly alter the glucose sensitivity of VMH glucose-sensing neurons in whole-cell current clamp recordings in brain slices. Interestingly, the suppressive effect of UCN I-mediated CRFR2 activation persisted for at least 24 hours after in vivo VMH microinjection. Our data suggest that regulation of the CRR is largely determined by the interaction between CRFR2-mediated suppression and CRFR1-mediated activation in the VMH.
McCrimmon
Rory J
RJ
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8020, USA. rory.mccrimmon@yale.edu
Song
Zhentao
Z
Cheng
Haiying
H
McNay
Ewan C
EC
Weikart-Yeckel
Catherine
C
Fan
Xiaoning
X
Routh
Vanessa H
VH
Sherwin
Robert S
RS
D000818:Animals; D003345:Corticosterone / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D004837:Epinephrine / Q000378:metabolism; D005934:Glucagon / Q000378:metabolism; D006801:Humans; D007003:Hypoglycemia / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008845:Microinjections; D009474:Neurons / Q000378:metabolism; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000819:agonists / Q000378:metabolism*; D054832:Urocortins; D014697:Ventromedial Hypothalamic Nucleus / Q000166:cytology / Q000378:metabolism*
D018019:Receptors, Corticotropin-Releasing Hormone; D054832:Urocortins; D005934:Glucagon; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone; D004837:Epinephrine