Fig. 2

Proposed model of glucose-sensing mechanisms in the VMH. Glucose-sensing neurons can be classified into glucose-excited neurons (GE) and glucose-inhibited neurons (GI) in the VMH. GE neurons is activated by a high glucose (i.e., 5 mM), and GI neurons is activated in response to a low glucose (i.e., 1 mM). For GE neurons, it has been postulated that high glucose leads to an increase of the ATP-ADP ratio and the closure of the K_ATP channels (e.g., Abcc8), which leads to plasma membrane depolarization (i.e., increased action potential and firing frequency), and Ca²⁺ entry through voltage-gated channels, thereby increasing neuronal activity and neurotransmitter secretion. Activation of VMH GE neurons results in a reduction in hepatic glucose production and increased peripheral glucose utilization. The ionic mechanism by which GI neurons responds to a low glucose is still not fully understood. A reduction in ambient glucose leads to a decrease of the ATP-ADP ratio and induces an increase of AMP-activated protein kinase (AMPK), which triggers the production of nitric oxide (NO) via neuronal NO synthase (NOS). Activation of cyclic guanosine monophosphate (cGMP) by NO further stimulates AMPK, which induces the closure of chloride channel via cystic fibrosis transmembrane conductance regulator (CFTR), leading to membrane depolarization (i.e., increased action potential and firing frequency) of GI neurons. Meanwhile, anoctamin 4 (Ano4), which is a chloride channel, is opened during hypoglycaemia. Activation of VMH GI neurons leads to an increased in hepatic glucose production and decreased peripheral glucose utilization. Activation of GE or GI neurons by a high or low glucose will be able to trigger the release of relevant neurotransmitters from these neurons to influence downstream targets within glucoregulatory circuity in the brain. Astrocytes/tanycytes also exert glucose-sensing property in the brain. Glucose once taken up by hypothalamic astrocytes or tanycytes via glucose transporters 1/2 (GLUT1/2), it is catabolized into lactate, then exported via monocarboxylate transporters (MCT) to adjacent neurons, altering the formation of pyruvate in neurons. Gck, glucokinase. NT, neurotransmitter. The figure is created in BioRender.com