• Molecules and Cells
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• 제47권1호
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• pp.100004.1-100004.11
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• 2024

Insulin is essential for maintaining normoglycemia and is predominantly secreted in response to glucose stimulation by β-cells. Incretin hormones, such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide, also stimulate insulin secretion. However, as obesity and type 2 diabetes worsen, glucose-dependent insulinotropic polypeptide loses its insulinotropic efficacy, whereas GLP-1 receptor (GLP-1R) agonists continue to be effective owing to its signaling switch from Gs to Gq. Herein, we demonstrated that endoplasmic reticulum (ER) stress induced a transition from Gs to Gq in GLP-1R signaling in mouse islets. Intriguingly, chemical chaperones known to alleviate ER stress, such as 4-PBA and TUDCA, enforced GLP-1R's Gq utilization rather than reversing GLP-1R's signaling switch induced by ER stress or obese and diabetic conditions. In addition, the activation of X-box binding protein 1 (XBP1) or activating transcription factor 6 (ATF6), 2 key ER stress-associated signaling (unfolded protein response) factors, promoted Gs utilization in GLP-1R signaling, whereas Gq employment by ER stress was unaffected by XBP1 or ATF6 activation. Our study revealed that ER stress and its associated signaling events alter GLP-1R's signaling, which can be used in type 2 diabetes treatment.

• BMB Reports
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• 제57권9호
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• pp.417-423
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• 2024

Glucose-dependent insulinotropic polypeptide (GIP), a 42-amino-acid hormone, exerts multifaceted effects in physiology, most notably in metabolism, obesity, and inflammation. Its significance extends to neuroprotection, promoting neuronal proliferation, maintaining physiological homeostasis, and inhibiting cell death, all of which play a crucial role in the context of neurodegenerative diseases. Through intricate signaling pathways involving its cognate receptor (GIPR), a member of the G protein-coupled receptors, GIP maintains cellular homeostasis and regulates a defense system against ferroptosis, an essential process in aging. Our study, utilizing GIP-overexpressing mice and in vitro cell model, elucidates the pivotal role of GIP in preserving neuronal integrity and combating age-related damage, primarily through the Epac/Rap1 pathway. These findings shed light on the potential of GIP as a therapeutic target for the pathogenesis of ferroptosis in neurodegenerative diseases and aging.

• 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.

• The Korean Journal of Medicine
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• 제99권2호
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• pp.78-83
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• 2024

Incretin-based obesity treatments are making remarkable progress, marking a new era in the field of obesity pharmacotherapy. These treatments not only meet the long-standing demands for safety and sustainability in obesity medications but also go beyond, significantly improving complications associated with obesity, such as cardiovascular diseases. This review explores the advancement in obesity treatments through the latest research findings on semaglutide and tirzepatide, two incretin-based obesity treatments currently receiving considerable attention.

• 식품과학과 산업
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• 제51권4호
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• pp.302-312
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• 2018

우유 단백질과 같은 식이 단백질은 분해되기 전에는 대사 조절을 위한 생물학적인 활성을 나타내지 않으나 장에서의 소화과정이나 단백질 분해 효소, 또는 미생물 발효 과정을 통하여 저분자의 펩타이드로 분해되어 수용체 결합을 통하여 생체조절기능을 발휘하거나, 체내 대사의 조절에 관여하는 다양한 효소의 활성을 억제함으로써 기능을 발휘하기도 한다. 우유단백질의 섭취에 의한 혈당 감소 효과는 여러 연구자에 의하여 확인되었으며, 그 작용 기전은 주로 분지사슬 아미노산에 의한 인슐린 분비촉진 기전과 음식물의 소화 과정 중 위장관에서 췌장에서 인슐린 분비 촉진, glucagon의 분비를 감소시켜 혈당을 감소시키는 역할을 담당하는 내분비 호르몬의 일종인 GLP-1의 작용에 영향을 미치는 기전을 생각할 수 있다. 생리적 환경에서 GLP-1은 GLP-1을 가수분해하여 불활성화시키는 DPP-4에 의하여 빠르게 분해되어 생물학적 활성을 소실하기 때문에 DPP-4 억제제는 제 2형 당뇨의 새로운 치료 방법으로써 주목을 받고 있다. DPP-4의 억제 효능을 가진 다수의 기능성 펩타이드가 우유단백질의 분해에 의하여 생성됨이 보고되었으며 그 효능이 in vitro 연구는 물론 동물 모델을 이용한 연구에서도 증명되었다. 이상의 연구 결과를 근거로 할 때 우유 단백질 유래 DPP-4 억제 펩타이드는 인체 적용 연구를 통하여 혈당 조절에 도움을 주는 기능성 소재로 개발될 수 있는 충분한 가능성을 가지고 있다고 판단된다.