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Whole Organism Chemical Screening Identifies Modulators of Pancreatic beta Cell Function

Abstract

beta cell loss and dysfunction play a critical role in the progression of type 1 and type 2 diabetes. Identifying new molecules and/or molecular pathways that improve beta cell function and/or increase beta cell mass should significantly contribute to the development of new therapies for diabetes. Using the zebrafish model, we screened 4640 small molecules to identify modulators of beta cell function. This in vivo strategy identified 84 stimulators of insulin expression which simultaneously reduced glucose levels. The insulin promoter activation kinetics for 32 of these stimulators were consistent with a direct mode of action. A subset of insulin stimulators, including the antidiabetic drug Pioglitazone, induced the coordinated upregulation of gluconeogenic pck1 expression, suggesting functional response to increased Insulin action in peripheral tissues. Notably, Kv1.3 inhibitors increased beta cell mass in larval zebrafish and stimulated beta cell function in adult zebrafish and in the STZ-induced hyperglycemic mouse model. In addition, our data indicate that cytoplasmic Kv1.3 regulates beta cell function. Thus, using whole organism screening, we have identified new small molecule modulators of beta cell function and glucose metabolism.

Type Journal
ISBN 1939-327X (Electronic) 0012-1797 (Linking)
Authors Matsuda, H.; Mullapudi, S. T.; Yang, Y. H.C..; Masaki, H.; Hesselson, D.; Stainier, D. Y. R.
Responsible Garvan Author Dr Daniel Hesselson
Publisher Name DIABETES
Published Date 2018-08-16
Published Pages pii: db171223
Status Always Electronic
DOI 10.2337/db17-1223
URL link to publisher's version https://www.ncbi.nlm.nih.gov/pubmed/30115653
OpenAccess link to author's accepted manuscript version https://publications.gimr.garvan.org.au/open-access/14597