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
Citation
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. (2018) Screening for insulin-independent pathways that modulate glucose homeostasis identifies androgen receptor antagonists. eLIFE. 7:.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping