title: Treatment of Obese Insulin-Resistant Mice With an Allosteric MAPKAPK2/3 Inhibitor Lowers Blood Glucose and Improves Insulin Sensitivity.
abstract: The prevalence of obesity-induced type 2 diabetes (T2D) is increasing worldwide, and new treatment strategies are needed. We recently discovered that obesity activates a previously unknown pathway that promotes both excessive hepatic glucose production (HGP) and defective insulin signaling in hepatocytes, leading to exacerbation of hyperglycemia and insulin resistance in obesity. At the hub of this new pathway is a kinase cascade involving calcium/calmodulin-dependent protein kinase II (CaMKII), p38α mitogen-activated protein kinase (MAPK), and MAPKAPK2/3 (MK2/3). Genetic-based inhibition of these kinases improves metabolism in obese mice. Here, we report that treatment of obese insulin-resistant mice with an allosteric MK2/3 inhibitor, compound (cmpd) 28, ameliorates glucose homeostasis by suppressing excessive HGP and enhancing insulin signaling. The metabolic improvement seen with cmpd 28 is additive with the leading T2D drug, metformin, but it is not additive with dominant-negative MK2, suggesting an on-target mechanism of action. Allosteric MK2/3 inhibitors represent a potentially new approach to T2D that is highly mechanism based, has links to human T2D, and is predicted to avoid certain adverse effects seen with current T2D drugs.
authors.affiliation: Department of Medicine, Columbia University, New York, NY lo2192@columbia.edu iat1@columbia.edu.
authors.forename: Lale
authors.initials: L
authors.lastname: Ozcan
authors.affiliation: Department of Medicine, Columbia University, New York, NY.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Medicine, Columbia University, New York, NY.
authors.forename: Shi-Xian
authors.initials: SX
authors.lastname: Deng
authors.affiliation: Department of Medicine, Columbia University, New York, NY.
authors.forename: Devram S
authors.initials: DS
authors.lastname: Ghorpade
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, NY Irving Institute for Clinical and Translational Research, Columbia University, New York, NY.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Thomas
authors.affiliation: Department of Medicine, Columbia University, New York, NY Department of Pathology and Cell Biology, Columbia University, New York, NY Irving Institute for Clinical and Translational Research, Columbia University, New York, NY.
authors.forename: Serge
authors.initials: S
authors.lastname: Cremers
authors.affiliation: Tabomedex Biosciences, Boxford, MA.
authors.forename: Brian
authors.initials: B
authors.lastname: Hubbard
authors.affiliation: Tabomedex Biosciences, Boxford, MA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Serrano-Wu
authors.affiliation: Department of Biochemistry, Hannover Medical School, Hannover, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Gaestel
authors.affiliation: Department of Medicine, Columbia University, New York, NY.
authors.forename: Donald W
authors.initials: DW
authors.lastname: Landry
authors.affiliation: Department of Medicine, Columbia University, New York, NY Department of Pathology and Cell Biology, Columbia University, New York, NY Department of Physiology and Cellular Biophysics, Columbia University, New York, NY lo2192@columbia.edu iat1@columbia.edu.
authors.forename: Ira
authors.initials: I
authors.lastname: Tabas
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007333:Insulin Resistance; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D001786:Blood Glucose; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C098416:MAP-kinase-activated kinase 3