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Glucose independent pleiotropic effects of a dipeptidyl peptidase-4 inhibitor on diabetic complications
DPP-4 억제제의 당뇨 합병증에서다양한 혈당 비의존성 기전 연구

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Authors
정은수
Advisor
조명행
Major
수의과대학 수의학과
Issue Date
2016-02
Publisher
서울대학교 대학원
Keywords
Diabetic mellitusDipeptidyl peptidase-4 inhibitorDiabetic complicationsDiabetic nephropathyDiabetic retinopathy
Description
학위논문 (박사)-- 서울대학교 대학원 : 수의과대학 수의학과, 2016. 2. 조명행.
Abstract
Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used as anti-diabetic agents in clinical practice. Gemigliptin, a new and selective DPP-4 inhibitor, has shown robust blood-glucose lowering effects in type 2 diabetic patients, but its effects on diabetic complications have not yet been reported.
This study evaluated the inhibitory effects of gemigliptin, a highly selective dipeptidyl peptidase-4 inhibitor, on the formation of advanced glycation end products (AGEs) and AGE cross-links with proteins in in vitro as well as in type 2 diabetic db/db mice. In in vitro assay, gemigliptin dose-dependently inhibited methylglyoxal-modified AGE-bovine serum albumin (BSA) formation (IC50 = 11.69 mM). AGE-collagen cross-linking assays showed that gemigliptin had a potent inhibitory effect (IC50 = 1.39 mM) on AGE-BSA cross-links to rat tail tendon collagen, and its activity was stronger than aminoguanidine (IC50 = 26.4 mM). In addition, gemigliptin directly trapped methylglyoxal in a concentration-dependent manner in vitro. To determine whether gemigliptin inhibits the in vivo glycation processes, gemigliptin (100 mg/kg/day) was orally administered into type 2 diabetic db/db mice for 12 weeks. Elevated serum levels of AGEs in db/db mice were suppressed by the administration of gemigliptin. These inhibitory effects of gemigliptin on the glycation process in both in vitro and in vivo suggest its therapeutic potential for ameliorating AGE-related diabetic complications.
Podocytes participate in the formation and regulation of the glomerular filtration barrier. Loss of podocytes occurs during the early stages of diabetic nephropathy and impairs glomerular filtration. Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used as anti-diabetic agents in clinical practice. In this study, we showed that gemigliptin, a novel DPP-4 inhibitor, reduced podocyte apoptosis in type 2 diabetic db/db mice without reducing hyperglycemia. Gemigliptin (100 mg/kg/day) was administered orally for 12 weeks in db/db mice. Blood glucose levels and albuminuria were measured. The renal cortex was collected for histological examination, and molecular assays were used to detect 8-hydroxydeoxyguanosine, advanced oxidation protein products (AOPP), the receptor for advanced glycation end products (RAGE), and integrin-linked kinase (ILK). Type 2 diabetic db/db mice exhibited albuminuria, renal histopathological changes, and podocyte loss. Administration of gemigliptin to db/db mice suppressed albuminuria, enzyme activity and expression of DPP-4, and podocyte apoptosis. The effect of gemigliptin on diabetes-induced podocyte loss was associated with the suppression of oxidative damage, AOPP accumulation, RAGE expression, and ILK expression. These results indicate the possible benefits of using gemigliptin in diabetes patients to treat renal impairment without affecting glycemic control.
Retinal pericyte loss and neovascularization are characteristic features of diabetic retinopathy. Gemigliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, has shown robust blood-glucose lowering effects in type 2 diabetic patients, but its effects on diabetic retinopathy have not yet been reported. We evaluated the efficacy of gemigliptin on retinal vascular leakage in db/db mice, which is an animal model for type 2 diabetes, and neovascularization in oxygen-induced retinopathy (OIR) mice, which is an animal model for ischemic proliferative retinopathy.
Gemigliptin (100mg/kg/day) was orally administered to the db/db mice for 12 weeks. C57BL/6 mice on postnatal day 7 (P7) were exposed to 75% hyperoxia for 5 days, followed by exposure to room air from P12 to P17 to induce OIR. Gemigliptin (50 mg/kg/day) was intraperitoneally injected daily from P12 to P17. Retinal neovascularization was analyzed in flat-mounted retinas on P17. We determined the efficacy and possible mechanism of gemigliptin on high glucose-induced apoptosis of primary human retinal pericytes. The oral administration of gemigliptin for 4 months significantly ameliorated retinal pericyte apoptosis and vascular leakage in the db/db mice. Gemigliptin also ameliorated retinal neovascularization in the OIR mice. Gemigliptin attenuated the overexpression of plasminogen activator inhibitor-1 (PAI-1) in the retinas of diabetic and OIR mice. Gemigliptin and PAI-1 siRNA significantly inhibited pericyte apoptosis by inhibiting the overexpression of PAI-1, which is induced by high glucose. Our results suggest that gemigliptin has potent anti-angiogenic and anti-apoptotic activities via suppressing DPP-4 and PAI-1, and the results support the direct retinoprotective action of gemigliptin.
Language
English
URI
https://hdl.handle.net/10371/120230
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College of Veterinary Medicine (수의과대학)Dept. of Veterinary Medicine (수의학과)Theses (Ph.D. / Sc.D._수의학과)
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