• The Korean Journal of Physiology and Pharmacology
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• 제22권6호
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• pp.713-719
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• 2018

Dipeptidyl peptidase4 (DPP4) inhibitors such as gemigliptin are antidiabetic drugs elevating plasma concentration of incretins such as GLP-1. In addition to the DPP4 inhibition, gemigliptin might directly improve the functions of vessels under pathological conditions. To test this hypothesis, we investigated whether the acetylcholine-induced endothelium dependent relaxation (ACh-EDR) of mesenteric arteries (MA) are altered by gemigliptin pretreatment in Spontaneous Hypertensive Rats (SHR) and in Wistar-Kyoto rats (WKY) under hyperglycemia-like conditions (HG; 2 hr incubation with 50 mM glucose). ACh-EDR of WKY was reduced by the HG condition, which was significantly recovered by $1{\mu}M$ gemigliptin while not by saxagliptin and sitagliptin up to $10{\mu}M$. The ACh-EDR of SHR MA was also improved by $1{\mu}M$ gemigliptin while similar recovery was observed with higher concentration ($10{\mu}M$) of saxagliptin and sitagliptin. The facilitation of ACh-EDR by gemigliptin in SHR was not observed under pretreatment with NOS inhibitor, L-NAME. In the endothelium-denuded MA of SHR, sodium nitroprusside induced dose-dependent relaxation was not affected by gemigliptin. The ACh-EDR in WKY was decreased by treatment with $30{\mu}M$ pyrogallol, a superoxide generator, which was not prevented by gemigliptin. Exendin-4, a GLP-1 analogue, could not enhance the ACh-EDR in SHR MA. The present results of ex vivo study suggest that gemigliptin enhances the NOS-mediated EDR of the HG-treated MA as well as the MA from SHR via GLP-1 receptor independent mechanism.

• Molecules and Cells
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• 제41권3호
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• pp.234-243
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• 2018

In recent years, the interest towards the relationship between incretins and bone has been increasing. Previous studies have suggested that glucagon-like peptide-1 (GLP-1) and its receptor agonists exert beneficial anabolic influence on skeletal metabolism, such as promoting proliferation and differentiation of osteoblasts via entero-osseous-axis. However, little is known regarding the effects of GLP-1 on osteoblast apoptosis and the underlying mechanisms involved. Thus, in the present study, we investigated the effects of liraglutide, a glucagon-like peptide-1 receptor agonist, on apoptosis of murine MC3T3-E1 osteoblastic cells. We confirmed the presence of GLP-1 receptor (GLP-1R) in MC3T3-E1 cells. Our data demonstrated that liraglutide inhibited the apoptosis of osteoblastic MC3T3-E1 cells induced by serum deprivation, as detected by Annexin V/PI and Hoechst 33258 staining and ELISA assays. Moreover, liraglutide upregulated Bcl-2 expression and downregulated Bax expression and caspase-3 activity at intermediate concentration (100 nM) for maximum effect. Further study suggested that liraglutide stimulated the phosphorylation of AKT and enhanced cAMP level, along with decreased phosphorylation of $GSK3{\beta}$, increased ${\beta}-catenin$ phosphorylation at Ser675 site and upregulated nuclear ${\beta}-catenin$ content and transcriptional activity. Pretreatment of cells with the PI3K inhibitor LY294002, PKA inhibitor H89, and siRNAs GLP-1R, ${\beta}-catenin$ abrogated the liraglutide-induced activation of cAMP, AKT, ${\beta}-catenin$, respectively. In conclusion, these findings illustrate that activation of GLP-1 receptor by liraglutide inhibits the apoptosis of osteoblastic MC3T3-E1 cells induced by serum deprivation through $cAMP/PKA/{\beta}-catenin$ and $PI3K/Akt/GSK3{\beta}$ signaling pathways.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 2008년도 Proceedings of the Convention
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• pp.5-20
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• 2008

GLP 1 기반의 약(GLP-1 유도체와 DPP IV 저해제)과 인크레틴 유사체는 최근 가장 각광을 받는 2당뇨 치료제 계열 중 하나이다. GLP-1은 위장에서 분비되는 핍타이드 인크레틴 호르몬으로서 췌장으로부터의 당-의존적 인슐린 분비를 증진하고, 위장통과를 지연시키며, 췌장 베타세포의 증식을 촉진한다. DPP IV 저해제는 GLP-1 불활성화시키는 DPP IV 효소의 활성을 저해함으로써 인크레틴처럼 작용한다. LC15-0133은 경쟁적, 가역적 DPP IV 저해제 ($IC_{50}$ = 24 nM, Ki=0.247 nM)이며, DPP II, DPP 8, 엘라스타제, 트릴신, 유로키나제에 비해 DPPIV 에 대한 선택적 억제 효능이 우수하다. LC15-0133 랫과 개에서 긴 반감기와, 우수한 경구흡수율을 보였다. LC15-0133 랫과 개에서 각각 0.1 mg/kg 0.02 mg/kg 용량으로 경구투여하고 24시간이 지난 후에도 50%이상의 혈장 DPP IV 활성 억제효능을 유지하였다. C57BL/6 마우스에서 LC15-013301 경구당부하에 의한 혈당증가를 억제하는 최소유효용량은 0.01 mg/kg, 당에 의한 GLP-1 분비를 증가시키는 최소유효용량은 0.1 mg/kg 이다. Zucker 당뇨 랫에서 LC15-01331의 1개월간의 경구반복투여는 당뇨병으로의 진행을 지연시키고, 혈중 HbA1c 감소시켰다. 결론적으로, LC15-0133은 신규의 강력하고, 선택적인 경구 DPP IV 저해제이며, 여러가지 동물모델에서 탁월한 혈당강하효능을 보였다.