1537-P: GPSM1-Mediated Astroctyte-Secreted IGFBP5 Regulates Glucose Metabolism via AgRP Neurons

Genome-wide association studies (GWASs) have identified that genetic variations in G-protein-signaling modulator 1 (GPSM1) are strongly associated with type 2 diabetes mellitus (T2DM) in Asians, but the specific mechanism remains largely unknown. Here, we found that GPSM1 is abundantly expressed in the hypothalamus, and its expression in astrocytes is significantly increased in HFD-fed mice. Mice with astrocyte-specific GPSM1 knockout (KO) protect against high-fat diet-induced glucose dysfunction by regulating whole-body glucose uptake and production, while mice with GPSM1 overexpression in astrocytes exhibit glucose and insulin intolerance. Mechanistically, GPSM1 in astrocytes promotes IGFBP5 secretion via the mTOR-HIF1α pathway. Subsequently, IGFBP5 blocks the effects of IGF1 on decreasing AgRP neuron activity, leading to sustained activation of AgRP neurons and ultimately resulting in T2DM.