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Modulation of Glucose Production by Central Insulin Requires IGF-1 Receptors in AgRP Neurons

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posted on 20.07.2021, 13:43 by Gabriela Farias Quipildor, Kai Mao, Pedro J. Beltran, Nir Barzilai, Derek M. Huffman
Similar to insulin, central administration of insulin-like Growth Factor-1 (IGF-1) can suppress hepatic glucose production (HGP), but it is unclear if this effect is mediated via insulin receptors (InsRs) or IGF-1 receptors (IGF-1Rs) in the brain. To this end, we utilized pharmacologic and genetic approaches in combination with hyperinsulinemic-euglycemic clamps to decipher the role of these receptors in mediating central effects of IGF-1 and insulin on HGP. In rats, we observed that intracerebroventricular (ICV) administration of IGF-1 or insulin markedly increased the glucose infusion rate (GIR) by >50% and suppressed HGP (P<0.001). However, these effects were completely prevented by preemptive ICV infusion with an IGF-1R and InsR/IGF-1R Hybrid (HybridRs) blocking antibody. Likewise, ICV infusion of the InsR antagonist, S961, which also can bind HybridRs, interfered with the ability of central insulin, but not IGF-1 to increase the GIR. Furthermore, hyperinsulinemic clamps in mice lacking IGF-1Rs in AgRP neurons revealed ~30% reduction in the GIR in KO animals, which was explained by an impaired ability of peripheral insulin to completely suppress HGP (P<0.05). Signaling studies further revealed an impaired ability of peripheral insulin to trigger ribosomal S6 phosphorylation or PIP3 production in AgRP neurons lacking IGF-1Rs. In summary, these data suggest that attenuation of IGF-1Rs signaling in the MBH, and specifically in AgRP neurons, can phenocopy impaired regulation of HGP as previously demonstrated in mice lacking InsRs in these cells, suggesting a previously unappreciated role for IGF-1Rs and/or HybridRs in the regulation of central insulin/IGF-1 signaling on glucose metabolism.


This work was supported by R00 AG037574; and Einstein Startup Funds to D.M.H. DMH was also a recipient of an American Federation for Aging Research (AFAR) junior faculty award while conducting this work. This study was also supported by R37 AG018381 and the Einstein Nathan Shock Center (P30 AG038072) to N.B. and the Einstein-Sinai Diabetes Research Center (P30 DK020541). We would also like to acknowledge support from the NCI supported Einstein Cancer Center (P30 CA013330). Einstein Analytical Imaging Core use was supported by NIH SIG awards (#1S10OD019961-01; 1S10OD023591-01).