title: Preventive and therapeutic potential of p38 alpha-selective mitogen-activated protein kinase inhibitor in nonobese diabetic mice with type 1 diabetes.
abstract: Mitogen-activated protein kinases (MAPKs) and heat shock proteins (HSPs) are ubiquitous proteins that function within T cells in both normal and stress-related pathophysiological states, including type 1 diabetes. The nonobese diabetic (NOD) mouse spontaneously develops T cell-mediated autoimmune pancreatic beta cell destruction that is similar to type 1 diabetes in humans. Because p38 MAPKs have been shown to modulate T cell function, we studied the effects of a p38alpha MAPK-selective inhibitor, indole-5-carboxamide (SD-169), on the development and progression of type 1 diabetes in the NOD mouse. In preventive treatment studies, SD-169 significantly reduced p38 and HSP60 expression in T cells of the pancreatic beta islets. Following treatment, the incidence of diabetes as determined by blood glucose levels was significantly lower, and immuno-histochemistry of pancreatic beta islet tissue demonstrated significant reduction in CD5+ T cell infiltration in the SD-169 treatment group as compared with untreated NOD mice. In therapeutic studies using mildly and moderately hyperglycemic NOD mice, SD-169 treatment lowered blood glucose and improved glucose homeostasis. Furthermore, following cessation of SD-169 treatment, NOD mice showed significant arrest of diabetes. In conclusion, we report that this p38alpha-selective inhibitor prevents the development and progression of diabetes in NOD mice by inhibiting T cell infiltration and activation, thereby preserving beta cell mass via inhibition of the p38 MAPK signaling pathway. These results have bearing on current prophylactic and therapeutic protocols using p38alpha-selective inhibitors in the prediabetic period for children at high risk of type 1 diabetes, in the honeymoon period, and for adults with latent autoimmune diabetes.
authors.affiliation: Scios Inc., 6500 Paseo Padre Parkway, Fremont, CA 94555, USA. smediche@scius.jnj.com
authors.forename: Satyanarayana
authors.initials: S
authors.lastname: Medicherla
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Protter
authors.forename: Jing Ying
authors.initials: JY
authors.lastname: Ma
authors.forename: Ruban
authors.initials: R
authors.lastname: Mangadu
authors.forename: Ramona
authors.initials: R
authors.lastname: Almirez
authors.forename: Bruce
authors.initials: B
authors.lastname: Koppelman
authors.forename: Irene
authors.initials: I
authors.lastname: Kerr
authors.forename: Tony A
authors.initials: TA
authors.lastname: Navas
authors.forename: Fabiola
authors.initials: F
authors.lastname: Movius
authors.forename: Mamatha
authors.initials: M
authors.lastname: Reddy
authors.forename: Yu-Wang
authors.initials: YW
authors.lastname: Liu
authors.forename: Gregory
authors.initials: G
authors.lastname: Luedtke
authors.forename: John
authors.initials: J
authors.lastname: Perumattam
authors.forename: Babu
authors.initials: B
authors.lastname: Mavunkel
authors.forename: Sundeep
authors.initials: S
authors.lastname: Dugar
authors.forename: George F
authors.initials: GF
authors.lastname: Schreiner
mesh_terms: D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000201:enzymology* / Q000517:prevention & control*; D005260:Female; D051379:Mice; D016688:Mice, Inbred NOD; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D047428:Protein Kinase Inhibitors; D048308:Mitogen-Activated Protein Kinase 14