PUBLICATION

Screening for insulin-independent pathways that modulate glucose homeostasis identifies androgen receptor antagonists

Authors
Mullapudi, S.T., Helker, C.S., Boezio, G.L., Maischein, H.M., Sokol, A.M., Guenther, S., Matsuda, H., Kubicek, S., Graumann, J., Yang, Y.H.C., Stainier, D.Y.
ID
ZDB-PUB-181207-26
Date
2018
Source
eLIFE   7: (Journal)
Registered Authors
Helker, Christian, Maischein, Hans-Martin, Matsuda, Hiroki, Stainier, Didier
Keywords
developmental biology, zebrafish
MeSH Terms
  • Androgen Receptor Antagonists/chemistry
  • Androgen Receptor Antagonists/metabolism
  • Animals
  • Disease Models, Animal
  • Gene Knockout Techniques
  • Glucose/metabolism*
  • Homeostasis
  • Hyperglycemia/genetics*
  • Hyperglycemia/metabolism
  • Hyperglycemia/pathology
  • Insulin/genetics*
  • Insulin Resistance/genetics
  • Receptors, Androgen/chemistry
  • Receptors, Androgen/genetics*
  • Signal Transduction/genetics
  • Zebrafish/genetics
PubMed
30520733 Full text @ Elife
Abstract
Pathways modulating glucose homeostasis independently of insulin would open new avenues to combat insulin resistance and diabetes. Here, we report the establishment, characterization and use of a vertebrate 'insulin-free' model to identify insulin-independent modulators of glucose metabolism. insulin knockout zebrafish recapitulate core characteristics of diabetes and survive only up to larval stages. Utilizing a highly efficient endoderm transplant technique, we generated viable chimeric adults that provide the large numbers of insulin mutant larvae required for our screening platform. Using glucose as a disease-relevant readout, we screened 2233 molecules and identified 3 that consistently reduced glucose levels in insulin mutants. Most significantly, we uncovered an insulin-independent beneficial role for androgen receptor antagonism in hyperglycemia, mostly by reducing fasting glucose levels. Our study proposes therapeutic roles for androgen signaling in diabetes and, more broadly, offers a novel in vivo model for rapid screening and decoupling of insulin-dependent and -independent mechanisms.
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