Dipeptidyl Peptidase IV Inhibition With MK0431 Improves Islet Graft Survival in Diabetic NOD Mice Partially via T-Cell Modulation

被引:100
作者
Kim, Su-Jin [1 ,2 ]
Nian, Cuilan [1 ,2 ]
Doudet, Doris J. [3 ]
McIntosh, Christopher H. S. [1 ,2 ]
机构
[1] Univ British Columbia, Inst Life Sci, Dept Cellular & Physiol Sci, Vancouver, BC V5Z 1M9, Canada
[2] Univ British Columbia, Inst Life Sci, Diabet Res Grp, Vancouver, BC V5Z 1M9, Canada
[3] Univ British Columbia, Dept Med, Vancouver, BC V5Z 1M9, Canada
关键词
DEPENDENT INSULINOTROPIC POLYPEPTIDE; REPORTER GENE-EXPRESSION; PROTEIN-KINASE; IN-VIVO; RAC; STIMULATION; DEGRADATION; RECEPTORS; MIGRATION; EFFICACY;
D O I
10.2337/db08-1101
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
OBJECTIVE-The endopeptidase dipeptidyl peptidase-IV (DPP-IV) has been shown to NH2-terminally truncate incretin hormones, glucose-dependent insulinotropic polypeptide, and glucagon-like peptide-1, thus ablating their ability to potentiate glucose-stimulated insulin secretion. Increasing the circulating levels of incretins through administration of DPP-IV inhibitors has therefore been introduced as a therapeutic approach for the treatment of type 2 diabetes. DPP-IV inhibitor treatment has also been shown to preserve islet. mass in rodent models of type 1 diabetes. The current. Study was initiated to define the effects of the DPP-IV inhibitor sitagliptin (MK0431) on transplanted islet survival in nonobese diabetic (NOD) mice, an autoimmune type I diabetes model. RESEARCH DESIGN AND METHODS-Effects of MK0431 on islet graft survival in diabetic NOD mice were determined with metabolic studies mid micropositron emission tomography imaging, mid its underlying molecular mechanisms were assessed. RESULTS-Treatment of NOD mice with MK0431 before and after islet transplantation resulted in prolongation of islet. graft survival, whereas treatment after transplantation alone resulted in small beneficial effects compared with nontreated controls. Subsequent studies demonstrated that MK0431 pretreatment resulted in decreased insulitis in diabetic NOD mice and reduced in vitro migration of isolated splenic CD4(+) T-cells. Furthermore, in vitro treatment of splenic CD4(+) T-cells with DPP-IV resulted in increased migration mid activation of protein kinase A (PKA) and Rac1. CONCLUSIONS-Treatment with MK0431 therefore reduced the effect of autoimmunity on graft survival partially by decreasing the homing of CD4(+) T-cells into pancreatic beta-cells through a pathway involving cAMP/PKA/Rac1 activation. Diabetes 58: 641-651,2009
引用
收藏
页码:641 / 651
页数:11
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