TY - JOUR
T1 - Modulation of Glucose Production by Central Insulin Requires IGF-1 Receptors in AgRP Neurons
AU - Quipildor, Gabriela Farias
AU - Mao, Kai
AU - Beltran, Pedro J.
AU - Barzilai, Nir
AU - Huffman, Derek M.
N1 - Funding Information:
Acknowledgments. The authors thank Drs. Young-Hwan Jo and Gary Schwartz, both at the Albert Einstein College of Medicine and Fleischer Institute for Diabetes & Metabolism, for valuable input. The authors also acknowledge Vera DesMarais and Hillary Guzik for expert advice/assistance in microscopy and software analysis. The authors also acknowledge Zunju Hu, Hongqian Liang, and Ardijana Novaj for technical assistance. Funding. This work was supported by National Institutes of Health grant R00 AG037574 and Einstein Startup Funds to D.M.H. D.M.H. was also a recipient of an American Federation for Aging Research junior faculty award while conducting this work. This study was also supported by National Institutes of Health grant R37 AG018381 and the Albert Einstein College of Medicine Nathan Shock Center (P30 AG038072) to N.B. and the Einstein–Mount Sinai Diabetes Research Center (P30 DK020541). The authors also acknowledge support from the National Cancer Institute–supported Albert Einstein Cancer Center (P30 CA013330). Einstein Analytical Imaging Core use was supported by National Institutes of Health Shared Instrument Grant (SIG) Program awards (1S10OD019961-01 and 1S10OD023591-01). The authors thank Dr. Lauge Sch€affer (Novo Nordisk) for providing S961 material and Amgen Inc. for supplying IGF-1R mAb.
Funding Information:
This work was supported by National Institutes of Health grant R00 AG037574 and Einstein Startup Funds to D.M.H. D.M.H. was also a recipient of an American Federation for Aging Research junior faculty award while conducting this work. This study was also supported by National Institutes of Health grant R37 AG018381 and the Albert Einstein College of Medicine Nathan Shock Center (P30 AG038072) to N.B. and the Ein-stein–Mount Sinai Diabetes Research Center (P30 DK020541). The authors also acknowledge support from the National Cancer Institute–supported Albert Einstein Cancer Center (P30 CA013330). Einstein Analytical Imaging Core use was supported by National Institutes of Health Shared Instrument Grant (SIG) Program awards (1S10OD019961-01 and 1S10OD023591-01). The authors thank Dr. Lauge Schüaffer (Novo Nordisk) for providing S961 material and Amgen Inc. for supplying IGF-1R mAb.
Publisher Copyright:
© 2021 by the American Diabetes Association.
PY - 2021/10
Y1 - 2021/10
N2 - Similar to insulin, central administration of IGF-1 can suppress hepatic glucose production (HGP), but it is unclear whether this effect is mediated via insulin receptors (InsRs) or IGF-1 receptors (IGF-1Rs) in the brain. To this end, we used 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 (HybridR) 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 knockout 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 phosphati-dylinositol (3,4,5)-trisphosphate production in AgRP neurons lacking IGF-1Rs. In summary, these data suggest that attenuation of IGF-1R signaling in the medio-basal hypothalamus, 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 in glucose metabolism.
AB - Similar to insulin, central administration of IGF-1 can suppress hepatic glucose production (HGP), but it is unclear whether this effect is mediated via insulin receptors (InsRs) or IGF-1 receptors (IGF-1Rs) in the brain. To this end, we used 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 (HybridR) 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 knockout 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 phosphati-dylinositol (3,4,5)-trisphosphate production in AgRP neurons lacking IGF-1Rs. In summary, these data suggest that attenuation of IGF-1R signaling in the medio-basal hypothalamus, 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 in glucose metabolism.
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U2 - 10.2337/DB21-0028
DO - 10.2337/DB21-0028
M3 - Article
C2 - 34285117
AN - SCOPUS:85116397015
SN - 0012-1797
VL - 70
SP - 2236
EP - 2248
JO - Diabetes
JF - Diabetes
IS - 10
ER -
