Received for publication November 1, 2005.
Revised April 3, 2006.
Accepted for publication April 4, 2006.

Preventive and Therapeutic Potential of p38 Selective MAPK Inhibitor in NOD 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 non-obese diabetic (NOD) mouse spontaneously develops T cell-mediated autoimmune pancreatic beta cell destruction that is similar to type-1 diabetes in humans. As p38 MAPKs have been shown to modulate T cell function, we studied the effects of a p38 MAPK-selective inhibitor, 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 immunohistochemistry of pancreatic beta islet tissue demonstrated significant reduction in CD5⁺ T cell infiltration in the SD-169 treatment group as compared to 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 sustained arrest of diabetes. In conclusion, we report that this p38 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 p38 selective inhibitors in the pre-diabetic period for children at high risk of type-1 diabetes, in the honeymoon period, and for adults with latent autoimmune diabetes.

Key words: HSP60, NOD mice, Pancreatic beta cells, T cells, Type 1 diabetes, p38 MAPK

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