A distinct hypothalamus-to-beta cell circuit modulates insulin secretion

The central nervous system has long been thought to regulate insulin secretion, an essential process in the maintenance of blood glucose levels. However, the anatomical and functional connections between the brain and insulin-producing pancreatic beta cells remain undefined. Here, we describe a functional transneuronal circuit connecting the hypothalamus to beta cells in mice. This circuit originates from a subpopulation of oxytocin neurons in the paraventricular hypothalamic nucleus (PVNOXT), and it reaches the islets of the endocrine pancreas via the sympathetic autonomic branch to innervate beta cells. Stimulation of PVNOXT neurons rapidly suppresses insulin secretion and causes hyperglycemia. Conversely, silencing of these neurons elevates insulin levels by dysregulating neuronal signaling and secretory pathways in beta cells and induces hypoglycemia. PVWOXT neuronal activity is triggered by glucoprivation. Our findings reveal that a subset of PVNOXT neurons form functional multisynaptic circuits with beta cells in mice to regulate insulin secretion, and their function is necessary for the beta cell response to hypoglycemia.