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

Martin, H., Coursan, A., Lallement, J., Di Miceli, Mathieu ORCID: https://orcid.org/0000-0003-3713-0370, 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

Text 2023 - J Neuroendocrinology - Martin Fiormonti - Serotonergic neurons are involved in the counter-regulatory response to hypoglycemia.pdf - Accepted Version Restricted to Repository staff only until 3 October 2024. Available under License Creative Commons Attribution Non-commercial. Download (1MB) | Request a copy

Abstract

Abstract
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.

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