Mathieu Di Miceli

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 study was 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 CRR 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 reduce 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.