Corticotrophin-releasing factor receptors within the ventromedial hypothalamus regulate hypoglycemia-induced hormonal counterregulation
Rory J. McCrimmon, Zhentao Song, Haiying Cheng, Ewan C. McNay, Catherine Weikart-Yeckel, Xiaoning Fan, Vanessa H. Routh, Robert S. Sherwin
Rory J. McCrimmon, Zhentao Song, Haiying Cheng, Ewan C. McNay, Catherine Weikart-Yeckel, Xiaoning Fan, Vanessa H. Routh, Robert S. Sherwin
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Research Article Metabolism

Corticotrophin-releasing factor receptors within the ventromedial hypothalamus regulate hypoglycemia-induced hormonal counterregulation

Abstract

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 (~55–60%), whereas CRF, a predominantly CRFR1 agonist, amplified (~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.

Authors

Rory J. McCrimmon, Zhentao Song, Haiying Cheng, Ewan C. McNay, Catherine Weikart-Yeckel, Xiaoning Fan, Vanessa H. Routh, Robert S. Sherwin

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Figure 6

Effects of UCN I on VMN GE neurons.

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Effects of UCN I on VMN GE neurons. (A and C) Consecutive whole-cell cur...
(A and C) Consecutive whole-cell current clamp recordings in VMN GE neurons. (B) Segments from consecutive whole-cell current-clamp recordings in a VMN GE neuron illustrated in an expanded time scale. RMP is noted to the right of each trace in A–C. The downward deflections represent the membrane voltage response to a constant hyperpolarizing pulse. (A) Under control conditions, RMP, APF, and IR reversibly decreased when glucose levels decreased from 2.5 to 0.1 (upper trace) or 0.5 mM (lower trace). (B) Following treatment of the brain slice with 0.2 μM UCN, MP, APF, and IR reversibly decreased only when glucose levels decreased from 2.5 to 0.1 mM but not from 2.5 to 0.5 mM. (C) When the brain slice was pretreated with 0.2 mM UCN and 1 mM aSVG, MP, APF, and IR reversibly decreased when glucose levels were decreased to 0.1 (upper trace) and 0.5 mM (lower trace), as observed for control conditions.