• 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.

• 대한의생명과학회지
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• 제6권4호
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• pp.229-235
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• 2000

췌장에서 분비하는 인슐린과 글루카곤의 자극-분비 coupling 과정은 주로 혈당 농도와 중추신경계에 의하여 조절되어진다. 본 연구는 두부에 포도당이 결핍되었을 때에 중추신경계가 췌장에서 인슐린과 글루카곤이 분비되는 패턴을 Sprague-Dawley 흰쥐를 대상으로 하여 살펴보았으며, 실험 방법은 in situ 뇌-췌장 관류법을 이용하였다. 관류액은 100 mg/dL glucose와 20 mM arginine를 포함한 Krebs-Ringer 완충액 (pH 7.4)으로 하였으며, 95% $O_2$-5% $CO_2$ 가스를 계속적으로 주입시키면서 5 ml/min의 속도로 30분간 정주하였다. 대조군은 cephalic glucopenia가 일어나지 않는 군으로 하였고, 실험군은 두 군으로 나누어서 GLP1군은 cephalic glucopenia가 0분에 일어나도록 하였고, CLP2군은 16분에 일어나도록 하였다. 문맥으로 유출되는 췌장의 effluent액에서 인슐린과 글루카곤 농도를 RIA법으로 측정하였고 호르몬의 분비 속도를 산출하여 분비동태 양상을 분석하였다. 결과에서 인슐린 분비량은 GLP1군에서 가장 낮아서 cephalic glucopenia에 의하여 다소 감소하는 경향이었으나, 세 군간에 통계적으로 유의적인 차이는 없었다. 인슐린의 분비동태 양상을 살펴보면 이봉성의 정규 양상을 보였으나, GLP1군에서 첫번째 peak (4 min)가 다소 둔화되는 현상을 보였다. 글루카곤의 분비동태 양상도 이봉성의 정규 양상을 보였으며, 특히 GLP1군에 있어서 0~15분간의 글루카곤 분비량은 cephalic glucopenia에 의하여 유의성 있게 (p<0.05) 증가하였다. GLP2군에 있어서 글루카곤 분비량은 관류 후 15~30분 사이에 중가하는 경향을 볼 수 있었으나 통계적인 유의성은 없었다. 따라서 頭部의 포도당 결핍은 글루카곤의 분비를 증가시키는 것으로 나타났고, 이러한 현상은 특히 관류의 early period에서 현저하였다.

• Journal of Microbiology and Biotechnology
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• 제29권10호
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• pp.1644-1655
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• 2019

Saccharomyces cerevisiae (S. cerevisiae) and glucagon-like peptide-2 (GLP-2) have been employed to improve the intestinal development of weaned animals. The goal of this study was to determine whether either exogenous S. cerevisiae or GLP-2 elicits major effects on fecal microbiotas and cytokine responses in weaned piglets. Ninety-six piglets weaned at 26 days were assigned to one of four groups: 1) Basal diet (Control), 2) empty vector-harboring S. cerevisiae (EV-SC), 3) GLP-2-expressing S. cerevisiae (GLP2-SC), and 4) recombinant human GLP-2 (rh-GLP2). At the start of the post-weaning period (day 0), and at day 28, fecal samples were collected to assess the bacterial communities via sequencing the V1-V2 region of the 16S-rRNA gene, and piglets' blood was also sampled to measure cytokine responses (i.e., IL-$1{\beta}$, TNF-${\alpha}$, and IFN-${\gamma}$). This study revealed that, on the one hand, although S. cerevisiae supplementation did not significantly alter the growth of weaned piglets, it induced increases in the relative abundances of two core genera (Ruminococcaceae_norank and Erysipelotrichaceae_norank) and decreases in the relative abundances of two other core genera (Lachnospiraceae_norank and Clostridiale_norank) and cytokine levels (IL-$1{\beta}$ and TNF-${\alpha}$) (p < 0.05, Control vs EV-SC; p < 0.05, rh-GLP2 vs GLP2-SC). On the other hand, GLP-2 supplementation had no significant influence on fecal bacterial communities and cytokine levels, but it produced better body weight and average daily gain (p < 0.05, Control vs EV-SC; p < 0.05, rh-GLP2 vs GLP2-SC). Therefore, altered fecal microbiotas and cytokine response effects in weaned piglets were due to S. cerevisiae rather than GLP-2.

• 비만대사연구학술지
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• 제1권1호
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• pp.4-13
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• 2022

Currently, pharmacotherapy is becoming essential for obesity, owing to its expanding and increasing epidemiology. In this review, novel peptide-based drugs of four classes are covered: GLP-1 receptor agonist, GIP/GLP-1 receptor dual agonist, glucagon/GLP-1 receptor dual agonist, and a combination of amylin receptor agonist/GLP-1 receptor agonist. Semaglutide is a next-generation GLP-1 receptor agonist with a longer duration and stronger weight and glucose reduction effects than liraglutide and dulaglutide. In the STEP1 trial, semaglutide 2.4 mg reduced body weight by approximately 15% in people with obesity with similar or milder adverse events than liraglutide 3.0 mg. Tirzepatide, a GIP/GLP-1 receptor dual agonist, also has a long duration and strong weight- and glucose-lowering effect. According to SURPASS-2, 3, and 4, in patients with BMI≥25 kg/m² and type 2 diabetes mellitus (T2DM), tirzepatide 15 mg reduced the initial body weight by >13%. Cotadutide, a glucagon/GLP-1 receptor dual agonist, showed weaker weight-lowering effects than semaglutide and tirzepatide, while it was comparable to that of liraglutide in a phase 2 clinical trial for non-alcoholic fatty liver disease in patients with BMI≥25 kg/m² and T2DM. Additionally, its effect on the liver was noticeable. The long-acting amylin receptor agonist cargrilintide combined with semaglutide can be another effective option for obesity treatment. Even in a small phase 1 trial with a short study period of 20 weeks, cargrilintide 2.4 mg/semaglutide 2.4 mg reduced by 17% of initial body weight in people with BMI 27-39.9 kg/m². In coming several years, semaglutide, tirzepatide, and cargrilintide/semaglutide will become available for obesity treatment in Korea.

• Asian-Australasian Journal of Animal Sciences
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• 제29권5호
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• pp.731-738
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• 2016

Glucagon-like peptide-2 (GLP-2) is important for intestinal barrier function and regulation of tight junction (TJ) proteins, but the intracellular mechanisms of action remain undefined. The purpose of this research was to determine the protective effect of GLP-2 mediated TJ and transepithelial electrical resistance (TER) in lipopolysaccharide (LPS) stressed IPEC-J2 cells and to test the hypothesis that GLP-2 regulate TJ and TER through the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt)-mammalian target of rapamycin (mTOR) signaling pathway in IPEC-J2 cells. Wortmannin and LY294002 are specific inhibitors of PI3K. The results showed that $100{\mu}g/mL$ LPS stress decreased TER and TJ proteins occludin, claudin-1 and zonula occludens protein 1 (ZO-1) mRNA, proteins expressions (p<0.01) respectively. GLP-2 (100 nmol/L) promote TER and TJ proteins occludin, claudin-1, and zo-1 mRNA, proteins expressions in LPS stressed and normal IPEC-J2 cells (p<0.01) respectively. In normal cells, both wortmannin and LY294002, PI3K inhibitors, prevented the mRNA and protein expressions of Akt and mTOR increase induced by GLP-2 (p<0.01) following with the significant decreasing of occludin, claudin-1, ZO-1 mRNA and proteins expressions and TER (p<0.01). In conclusion, these results indicated that GLP-2 can promote TJ's expression and TER in LPS stressed and normal IPEC-J2 cells and GLP-2 could regulate TJ and TER through the PI3K/Akt/mTOR pathway.

• Asian-Australasian Journal of Animal Sciences
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• 제27권5호
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• pp.733-742
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• 2014

The glucagon-like peptide 2 (GLP-2) that is expressed in intestine epithelial cells of mammals, is important for intestinal barrier function and regulation of tight junction (TJ) proteins. However, there is little known about the intracellular mechanisms of GLP-2 in the regulation of TJ proteins in piglets' intestinal epithelial cells. The purpose of this study is to test the hypothesis that GLP-2 regulates the expressions of TJ proteins in the mitogen-activated protein kinase (MAPK) signaling pathway in piglets' intestinal epithelial cells. The jejunal tissues were cultured in a Dulbecco's modified Eagle's medium/high glucose medium containing supplemental 0 to 100 nmol/L GLP-2. At 72 h after the treatment with the appropriate concentrations of GLP-2, the mRNA and protein expressions of zonula occludens-1 (ZO-1), occludin and claudin-1 were increased (p<0.05). U0126, an MAPK kinase inhibitor, prevented the mRNA and protein expressions of ZO-1, occludin, claudin-1 increase induced by GLP-2 (p<0.05). In conclusion, these results indicated that GLP-2 could improve the expression of TJ proteins in weaned pigs' jejunal epithelium, and the underlying mechanism may due to the MAPK signaling pathway.

• 한국임상약학회지
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• 제21권2호
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• pp.57-65
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• 2011

Incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide delay gastric emptying, increasing satiety, and enhance insulin secretion. Two new classes of treatments related to incretin hormones for the management of type 2 diabetes mellitus have emerged: GLP-1 receptor agonists (e.g., exenatide, liraglutide) and the dipeptidyl peptidase-4 (DPP-4) inhibitors (e.g., sitagliptin, saxagliptin, vildagliptin, alogliptin), which prevent the degradation of GLP-1. A MEDLINE search was conducted in order to evaluate the efficacy and safety of incretin-based therapies and publications were reviewed. Data from clinical trials indicated incretin-based treatment showed clinically significant reductions in hemoglobin A1c with low risk of hypoglycemia. Weight reductions were observed with GLP-1 receptor agonists where as DPP-4 inhibitors are weight neutral.

• 대한한방내과학회지
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• 제40권6호
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• pp.1294-1302
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• 2019

Objective: Glucagon-like peptide 1 (GLP-1), one of the gut peptide hormones, has an action to induce satiety, and its effect as an anti-obesity agent is known. Recently, it has been reported that many herbal medicines have an anti-diabetic effect through inhibition of DPP-4 enzyme and inducing of GLP-1 secretion. It is therefore suggested that GLP-1 may be effective for the treatment of obesity. In this study, we report a case of male obese patients treated with herbal medicine as a GLP-1 secretagogue. Methods: In this study, the patient took a fixed prescription of herbal medicine for 10 weeks and recorded his weight at each visit. Results: This prescription produced significant weight loss (BMI loss>5%). In the follow-up period after two weeks, the trend of weight loss was observed continuously. Conclusion: This prescription can be an alternative to ephedra herba-based obesity treatment.

• 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.

• 비만대사연구학술지
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• 제3권1호
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• pp.49-50
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• 2024