Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 116, Issue 6, Pages 1723-1730Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI27775
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Funding
- NIDDK NIH HHS [R01 DK055619, R01 DK064566, DK-20495, R01 DK020495, R37 DK020495, R56 DK055619, DK-55619, DK-64566] Funding Source: Medline
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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 (similar to 55-60%), whereas CRF, a predominantly CRFR1 agonist, amplified (similar to 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.
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