2. Academic Validation
  3. Identification of an Anti-diabetic, Orally Available Small Molecule that Regulates TXNIP Expression and Glucagon Action

Identification of an Anti-diabetic, Orally Available Small Molecule that Regulates TXNIP Expression and Glucagon Action

  • Cell Metab. 2020 Sep 1;32(3):353-365.e8. doi: 10.1016/j.cmet.2020.07.002.
Lance A Thielen 1,  Junqin Chen 1,  Gu Jing 1,  Omar Moukha-Chafiq 2,  Guanlan Xu 1,  SeongHo Jo 1,  Truman B Grayson 1,  Brian Lu 1,  Peng Li 3,  Corinne E Augelli-Szafran 2,  Mark J Suto 2,  Matt Kanke 4,  Praveen Sethupathy 4,  Jason K Kim 5,  Anath Shalev 6
Affiliations

Affiliations

  • 1 Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
  • 2 Drug Discovery Division, Southern Research, Birmingham, AL 35205, USA.
  • 3 School of Nursing, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
  • 4 Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
  • 5 Program in Molecular Medicine and Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.
  • 6 Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Alabama at Birmingham, Birmingham, AL 35294, USA. Electronic address: shalev@uab.edu.
PMID: 32726606 DOI: 10.1016/j.cmet.2020.07.002
Abstract

Diabetes is characterized by hyperglycemia, loss of functional islet beta cell mass, deficiency of glucose-lowering Insulin, and persistent alpha cell secretion of gluconeogenic glucagon. Still, no therapies that target these underlying processes are available. We therefore performed high-throughput screening of 300,000 compounds and extensive medicinal chemistry optimization and here report the discovery of SRI-37330, an orally bioavailable, non-toxic small molecule, which effectively rescued mice from streptozotocin- and obesity-induced (db/db) diabetes. Interestingly, in rat cells and in mouse and human islets, SRI-37330 inhibited expression and signaling of thioredoxin-interacting protein, which we have previously found to be elevated in diabetes and to have detrimental effects on islet function. In addition, SRI-37330 treatment inhibited glucagon secretion and function, reduced hepatic glucose production, and reversed hepatic steatosis. Thus, these studies describe a newly designed chemical compound that, compared to currently available therapies, may provide a distinct and effective approach to treating diabetes.

Keywords

diabetes; fatty liver; glucagon; glucose homeostasis; hepatic glucose production; islet; small molecule drug; thioredoxin-interacting protein.

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