University of Worcester Worcester Research and Publications

Serotonergic neurons are involved in the counter-regulatory response to hypoglycemia

Martin, H., Coursan, A., Lallement, J., Di Miceli, Mathieu ORCID:, Kandiah, J., Raho, I., Buttler, J., Guilloux, J-P., De Deurwaerdere, P., Layé, S., Routh, V.H., Guiard, B., Magnan, C., Cruciani-Guglielmacci, C. and Fioramonti, X. (2023) Serotonergic neurons are involved in the counter-regulatory response to hypoglycemia. Journal of Neuroendocrinology. ISSN Print: 0953-8194 Electronic: 1365-2826

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2023 - J Neuroendocrinology - Martin Fiormonti - Serotonergic neurons are involved in the counter-regulatory response to hypoglycemia.pdf - Accepted Version
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Objectives. Intensive insulin therapy provides optimal glycemic control in patients with
diabetes. However, intensive insulin therapy causes so-called iatrogenic hypoglycemia as a
major adverse effect. The ventromedial hypothalamus (VMH) has been described as the
primary brain area initiating the counter-regulatory response (CRR). Nevertheless, the VMH
receives projections from other brain areas which could participate in the regulation of the
CRR. In particular, studies suggest a potential role of the serotonin (5-HT) network. Thus, the
objective of this work is to determine the contribution of 5-HT neurons in CRR control.

Methods. Complementary approaches have been used to test this hypothesis in quantifying the level of 5-HT in several brain areas by HPLC in response to insulin-induced hypoglycemia, measuring the electrical activity of dorsal Raphe (DR) 5-HT neurons in response to insulin or decreased glucose level by patch-clamp electrophysiology; and measuring the CRR hormone glucagon as an index of the counterregulatory responseCRR to the modulation of the activity of 5-HT neurons using pharmacological or pharmacogenetic approaches.

Results. HPLC measurements show that the 5HIAA/5HT ratio is increased in several brain
regions including the VMH in response to insulin-induced hypoglycemia. Patch-clamp
electrophysiological recordings show that insulin, but not decreased glucose level, increases
the firing frequency of DR 5-HT neurons in the DR. In vivo, both the pharmacological inhibition of 5-HT neurons by intraperitoneal injection of the 5-HT1A receptor agonist 8-OH-DPAT or the chemogenetic inhibition of these neurons reduces glucagon secretion, suggesting an impaired CRR.

Conclusion. Taken together, these data highlight a new neuronal network involved in the
regulation of the CRR. In particular, this study shows that DR 5-HT neurons detect iatrogenic
hypoglycemia in response to the increased insulin level and may play an important role in the regulation of CRR.

Item Type: Article
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This is the peer reviewed version of the following article: [FULL CITE], which has been published in final form at This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited.

Uncontrolled Discrete Keywords: hypoglycemia, serotonin, glaucagon, insulin, chemogenetic
Subjects: Q Science > QH Natural history
Q Science > QH Natural history > QH301 Biology
Q Science > QP Physiology
R Medicine > RC Internal medicine
R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Divisions: College of Health, Life and Environmental Sciences > School of Science and the Environment
Related URLs:
Depositing User: Mathieu Di Miceli
Date Deposited: 18 Sep 2023 11:06
Last Modified: 06 Nov 2023 10:10

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