Functional properties of Claramine: A novel PTP1B inhibitor and insulin-mimetic compound Zhaohong Qin a, 1 , Nihar R. Pandey a, 1 , Xun Zhou a , Chloe A. Stewart a, b , Aswin Hari a , Hua Huang a , Alexandre F.R. Stewart b, d , Jean Michel Brunel c, ** , Hsiao-Huei Chen a, b, * a Ottawa Hospital Research Institute, Canada b University of Ottawa, Canada c Aix-Marseille University, France d University of Ottawa Heart Institute, Canada article info Article history: Received 23 December 2014 Available online 24 January 2015 Keywords: Protein tyrosine phosphatase Trodusquemine Type 2 diabetes Food intake Body weight Energy expenditure abstract Protein tyrosine phosphatase 1B (PTP1B) inhibits insulin signaling, interfering with its control of glucose homeostasis and metabolism. PTP1B activity is elevated in obesity and type 2 diabetes and is a major cause of insulin resistance. Trodusquemine (MSI-1436) is a “first-in-class” highly selective in- hibitor of PTP1B that can cross the bloodebrain barrier to suppress feeding and promote insulin sensitivity and glycemic control. Trodusquemine is a naturally occurring cholestane that can be pu- rified from the liver of the dogfish shark, Squalus acanthias, but it can also be manufactured syn- thetically by a fairly laborious process that requires several weeks. Here, we tested a novel easily and rapidly (2 days) synthesized polyaminosteroid derivative (Claramine) containing a spermino group similar to Trodusquemine for its ability to inhibit PTP1B. Like Trodusquemine, Claramine displayed selective inhibition of PTP1B but not its closest related phosphatase TC-PTP. In cultured neuronal cells, Claramine and Trodusquemine both activated key components of insulin signaling, with increased phosphorylation of insulin receptor-b (IRb), Akt and GSK3b. Intraperitoneal administration of Clar- amine or Trodusquemine effectively restored glycemic control in diabetic mice as determined by glucose and insulin tolerance tests. A single intraperitoneal dose of Claramine, like an equivalent dose of Trodusquemine, suppressed feeding and caused weight loss without increasing energy expenditure. In summary, Claramine is an alternative more easily manufactured compound for the treatment of type II diabetes. © 2015 Elsevier Inc. All rights reserved. 1. Introduction The epidemic of obesity and diabetes is growing rapidly and has become a global problem affecting all age and socio-economic strata. The International Diabetes Federation has indicated that diabetes affects about 285 million people globally. This number is expected to climb to about 438 million by the year 2030 (http:// www.idf.org/). Current therapies including Metformin, DPP4 inhibitors and GLP1 mimetics are not without shortcomings [1] and novel therapeutics for the treatment of obesity and diabetes are still in great demand. Insulin, a hormone secreted by the pancreas after meals, is well known for its function to maintain glucose homeostasis. This is achieved by its actions at the central nervous system as well as at the peripheral tissues. Insulin signaling activates glucose uptake and storage into peripheral target tissues like skeletal muscle to lower blood glucose levels. At the same time, insulin signaling in the brain suppresses hepatic glucose production. This central effect of insulin depends upon activation of ATP-dependent potassium channels by phosphoinositide 3-kinase (PI3K) in orexigenic neu- rons of the hypothalamus, which in turn regulate efferent vagal innervation of the liver [2,3]. The hypothalamic action of insulin also regulates peripheral fat metabolism by modulating sympa- thetic innervation of white adipose tissue to inhibit lipolysis. This * Corresponding author. University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada. ** Corresponding author. Centre de Recherche en Canc erologie de Marseille (CRCM), Aix-Marseille University, F-13385, Marseille, France. E-mail addresses: bruneljm@yahoo.fr (J.M. Brunel), hchen@uottawa.ca (H.-H. Chen). 1 Equal contribution. Contents lists available at ScienceDirect Biochemical and Biophysical Research Communications journal homepage: www.elsevier.com/locate/ybbrc http://dx.doi.org/10.1016/j.bbrc.2015.01.040 0006-291X/© 2015 Elsevier Inc. All rights reserved. Biochemical and Biophysical Research Communications 458 (2015) 21e27