Diabetes_Appendix_6-25-21.pdf (186.07 kB)
Modulation of Glucose Production by Central Insulin Requires IGF-1 Receptors in AgRP Neurons
figure
posted on 2021-07-20, 13:43 authored by Gabriela Farias Quipildor, Kai Mao, Pedro J. Beltran, Nir Barzilai, Derek M. HuffmanSimilar 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.