인크레틴 기반 치료법은 당뇨병에서 두 가지 미해결 문제에 대한 공들인 조사의 결과로 개발되었습니다. 첫 번째는 인크레틴 효과로서 경구 포도당이 정맥 내 포도당보다 더 큰 인슐린 반응을 자극하는 것이고, 두 번째는 장관 세포가 분비하는 다양한 글루카곤 유사 분자의 기능입니다. 이것은 GLP-1과 GIP가 경구 영양소에 반응하여 분비되며 췌장에서 인슐린 분비를 촉진(인크레틴 효과) 한다는 발견을 이끌었습니다. GLP-1 수치는 제 2 형 당뇨병에서 결핍되어 있고 치료 가능성을 시사합니다. 가장 큰 장애는 GLP-1이 혈액 순환에서 매우 짧은(1-2 분) survival을 보였다는 것입니다. 이를 극복하기 위해 두 가지 전략이 사용되었습니다. 첫 번째는 분해에 내성이있는 GLP-1 수용체 작용제의 개발이고, 두 번째는 자연적으로 생성된 호르몬의 전달을 delivery를 향상시키는 DPP4의 억제입니다.
Historical Background
The "incretin effect" describes a long-recognised phenomenon whereby oral glucose provokes a greater insulin secretory response than the same amount of insulin injected into a vein. This strongly suggested a mediating factor(s) which augments insulin secretion, but the nature of the stimulus was unknown.
It was also known that administration of an extract from the upper intestine could produce a fall in blood glucose, and In 1932 La Barre proposed the name "incretin" for the presumed hormone. Here matters rested until the identification of the gut peptides in the 1960s. Glucagon itself stimulates insulin secretion, but the role of a family of immunoreactive glucagon-related peptides in cells lining the intestine remained conjectural.
This family of glucagon-related molecules includes the 69 amino-acid glicentin and a truncated form known as oxyntomodulin. Gastric inhibitory peptide, identified in 1970, was renamed glucose-dependent insulinotrophic peptide (also GIP) when its ability to stimulate insulin was demonstrated, but evidence emerged that GIP alone could not be wholly responsible for the incretin effect.
Proglucagon was cloned and sequenced in 1983, with the surprising information that the molecule contained two additional glucagon-like sequences, coding for two glucagon-like peptides, subsequently known as GLP-1 and GLP-2. GLP-2 is an important gastrointestinal growth factor, and the 7-37 sequence within GLP-1 was found to be the most powerful insulinotropic agent yet known, thus explaining the incretin effect.
REF
https://www.diapedia.org/management/8104193110/history-and-development-of-incretin-therapy
