GLP-1: From a Processing Product of Proglucagon to the Core Molecule of Incretin Therapy

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This article focuses on the discovery origins and physiological functions of glucagon-like peptide-1 (GLP-1), systematically elaborating the molecular mechanisms by which the glucagon precursor undergoes tissue-specific processing in the pancreas and intestine to produce different products, analyzing the incretin effects of GLP-1 in promoting insulin secretion in a glucose concentration-dependent manner, inhibiting glucagon release, and delaying gastric emptying, and exploring the structural modification strategies for receptor agonists driven by the short half-life of native GLP-1, as well as the multiple glucose-lowering mechanisms arising from the distribution of its receptors across multiple organs.

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GLP-1: From a Proglucagon Processing Product to the Core Molecule of Incretin Therapy

Brief introduction: This article focuses on the discovery origins and physiological functions of glucagon-like peptide-1 (GLP-1), systematically elaborating the molecular mechanisms by which proglucagon undergoes tissue-specific processing in the pancreas and intestine to produce different products, analyzing the incretin effects of GLP-1 in promoting insulin secretion, inhibiting glucagon release, and delaying gastric emptying in a glucose concentration-dependent manner, and discussing the structural modification strategies for receptor agonists prompted by the short half-life of native GLP-1, as well as the multiple glucose-lowering mechanisms brought about by the distribution of its receptors across multiple organs.

I. The discovery of glucagon and confirmation of the secretory function of pancreatic α cells.

In 1923, Charles Kimball and John Murlin discovered in the pancreas a certain secretory factor that could produce a strong hyperglycemic effect. This factor antagonized the glucose-lowering effect of insulin, so it was named the “glucose agonist” or “glucagon.” In the early 1950s, Rarl Sutherland and Christian de Duve demonstrated that pancreatic α cells could secrete glucagon, whereas pancreatic β cells did not have this function. This discovery established glucagon as a specific secretory product of pancreatic α cells and also laid the foundation for subsequently distinguishing glucagon-like active substances of pancreatic versus intestinal origin.

II. The discovery of intestinal L cells and the proposal of the concept of proglucagon.

In 1968, Unger demonstrated that in the duodenum, glucose administration could elicit a glucagon-like peptide immunoreaction, meaning that the intestine could secrete glucagon. Further studies confirmed that the glucagon secreted by the intestine and the pancreas differed in nature. Immunohistochemical studies showed that the morphology and ultrastructure of intestinal glucagon-secreting cells differed from those of pancreatic α cells, and these intestinal cells were termed “L cells.” Subsequently, glucagon-immunoreactive substances larger than glucagon were detected in islets isolated from the pancreata of dogs, birds, and guinea pigs. These studies indicated that glucagon may originate from a larger precursor molecule of approximately 18 kDa, which is cleaved after translation into several fragments of different sizes and functions; this precursor was classified as proglucagon. In the pancreas, proglucagon can be cleaved to produce two fragments, mature glucagon and a 10 kDa protein that lacks the glucagon sequence and was named MPGF. The discovery of this tissue-specific processing revealed the molecular logic by which the same precursor molecule produces functionally distinct products in different tissues——the pancreas mainly produces glucagon, whereas the intestine mainly produces incretins such as GLP-1.

III. The secretory source of GLP-1 and the physiological functions of incretins.

Glucagon-like peptide-1 receptor agonists belong to the class of incretin drugs. GLP-1 is mainly secreted by L cells in the ileum and colon. It promotes insulin secretion by pancreatic β cells in a glucose concentration-dependent manner, participates in the regulation of blood glucose homeostasis, reduces glucagon secretion, delays gastric emptying, and improves peripheral insulin resistance. This glucose-dependent action characteristic has important clinical value——when blood glucose levels are normal, GLP-1 does not excessively stimulate insulin release, so compared with exogenous insulin, its risk of causing hypoglycemia is significantly lower. At the same time, the inhibitory effect of GLP-1 on glucagon and its insulin-promoting effect form a bidirectional synergy, jointly maintaining stable postprandial blood glucose from two directions.

IV. The degradation bottleneck of native GLP-1 and structural modification strategies for receptor agonists.

The half-life of GLP-1 secreted by the human body is very short, only 1 to 2 minutes. After being secreted into the bloodstream, it is readily rapidly degraded by dipeptidyl peptidase 4 and loses its insulin secretion-promoting activity. To fully exploit the “natural” effects of GLP-1, drug developers have modified its structure and developed a series of GLP-1 receptor agonists. GLP-1 receptor agonists can exert the same biological effects as native GLP-1 and can also avoid degradation and loss of activity, thereby prolonging the duration of action and exerting effects in regulating blood glucose and treating diabetes. From the perspective of technical routes for structural modification, these mainly include amino acid substitutions that alter DPP-4 recognition sites, prolonging the circulating half-life through binding of fatty acid chains to albumin, and fusing GLP-1 analogs with human antibody Fc fragments. The common goal of these strategies is to overcome the druggability bottleneck of the native molecule’s “two-minute half-life” while retaining GLP-1 receptor agonist activity.

V. The multi-organ distribution of GLP-1 receptors and multiple glucose-lowering mechanisms.

GLP-1 receptors are widely distributed in multiple organs or tissues throughout the body. In addition to the pancreas, these include the central nervous system, gastrointestinal tract, cardiovascular system, liver, adipose tissue, and muscle. Therefore, GLP-1 receptor agonists have multiple glucose-lowering mechanisms. These mechanisms include promoting insulin biosynthesis and secretion; increasing insulin sensitivity; inhibiting glucagon secretion; inhibiting β cell apoptosis and promoting β cell proliferation; reducing hepatic glucose output; suppressing appetite and increasing satiety; and delaying gastric emptying and gastrointestinal motility. When organized at the organ level, the effect at the pancreatic level is core——promoting insulin secretion by β cells and protecting β cell number; the effect at the hepatic level is reducing hepatic glucose output; the effect at the central nervous system level is suppressing appetite; and the effect at the gastrointestinal level is delaying gastric emptying. This “one receptor, multiple organs, multiple mechanisms” pattern of action distinguishes GLP-1 receptor agonists from traditional single-target glucose-lowering drugs, and their efficacy derives from the coordinated integration of multiple physiological links.

VI. Conclusion.

GLP-1, as an incretin produced by tissue-specific processing of proglucagon in intestinal L cells, has become one of the most influential molecules in the field of diabetes treatment by virtue of its physiological functions of promoting insulin secretion, inhibiting glucagon release, and delaying gastric emptying in a glucose concentration-dependent manner, as well as the structural modification strategies prompted by the native molecule’s half-life of only 1 to 2 minutes and the multiple glucose-lowering mechanisms brought about by the distribution of its receptors in multiple organs such as the pancreas, central nervous system, liver, and gastrointestinal tract.

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This article is reviewed and published by the technical expert team of UA

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