title: Functional properties of Claramine: a novel PTP1B inhibitor and insulin-mimetic compound.
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 inhibitor of PTP1B that can cross the blood-brain barrier to suppress feeding and promote insulin sensitivity and glycemic control. Trodusquemine is a naturally occurring cholestane that can be purified from the liver of the dogfish shark, Squalus acanthias, but it can also be manufactured synthetically 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-β (IRβ), Akt and GSK3β. Intraperitoneal administration of Claramine 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.
authors.affiliation: Ottawa Hospital Research Institute, Canada.
authors.forename: Zhaohong
authors.initials: Z
authors.lastname: Qin
authors.affiliation: Ottawa Hospital Research Institute, Canada.
authors.forename: Nihar R
authors.initials: NR
authors.lastname: Pandey
authors.affiliation: Ottawa Hospital Research Institute, Canada.
authors.forename: Xun
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Ottawa Hospital Research Institute, Canada; University of Ottawa, Canada.
authors.forename: Chloe A
authors.initials: CA
authors.lastname: Stewart
authors.affiliation: Ottawa Hospital Research Institute, Canada.
authors.forename: Aswin
authors.initials: A
authors.lastname: Hari
authors.affiliation: Ottawa Hospital Research Institute, Canada.
authors.forename: Hua
authors.initials: H
authors.lastname: Huang
authors.affiliation: University of Ottawa, Canada; University of Ottawa Heart Institute, Canada.
authors.forename: Alexandre F R
authors.initials: AF
authors.lastname: Stewart
authors.affiliation: Aix-Marseille University, France. Electronic address: bruneljm@yahoo.fr.
authors.forename: Jean Michel
authors.initials: JM
authors.lastname: Brunel
authors.affiliation: Ottawa Hospital Research Institute, Canada; University of Ottawa, Canada. Electronic address: hchen@uottawa.ca.
authors.forename: Hsiao-Huei
authors.initials: HH
authors.lastname: Chen
mesh_terms: D000818:Animals; D002478:Cells, Cultured / Q000187:drug effects; D002776:Cholestanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D004435:Eating / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D013096:Spermine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015431:Weight Loss / Q000187:drug effects
chemical_list: C441128:3-N-1(spermine)-7, 24-dihydroxy-5-cholestane 24-sulfate; D002776:Cholestanes; D004791:Enzyme Inhibitors; D007328:Insulin; C000597478:claramine; D013096:Spermine; D011972:Receptor, Insulin; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; C516609:Ptpn1 protein, mouse; C516653:Ptpn2 protein, mouse
keywords: Body weight; Energy expenditure; Food intake; Protein tyrosine phosphatase; Trodusquemine; Type 2 diabetes