GLP-1: The incretin signaling axis and a core molecule in metabolic disease therapy

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This article focuses on the molecular characteristics and physiological functions of glucagon-like peptide-1 (GLP-1), systematically elaborating its mechanism as an incretin secreted by intestinal L cells in regulating insulin secretion and glucagon release in a glucose concentration-dependent manner, analyzing the druggability bottlenecks faced by native GLP-1 due to its extremely short half-life and the structural modification strategies of receptor agonists, and discussing the multiple glucose-lowering mechanisms conferred by the multi-organ distribution of GLP-1 receptors.

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GLP-1: The Incretin Signaling Axis and a Core Molecule in Metabolic Disease Therapy

Brief Introduction: This article focuses on the molecular characteristics and physiological functions of glucagon-like peptide-1 (GLP-1), systematically elaborating on its mechanism of action as an incretin secreted by intestinal L cells that regulates insulin secretion and glucagon release in a glucose concentration-dependent manner, analyzing the druggability bottleneck faced by native GLP-1 due to its extremely short half-life and the structural modification strategies of receptor agonists, and discussing the multiple glucose-lowering mechanisms conferred by the multi-organ distribution of GLP-1 receptors.

I. The Discovery Origins of GLP-1 and the Establishment of the Incretin Concept.

The discovery of GLP-1 is rooted in the exploration of the processing mechanism of the glucagon precursor. Studies have shown that glucagon may originate from a larger precursor molecule that is cleaved after translation into several fragments of different sizes and functions. In the pancreas, this precursor is cleaved to produce mature glucagon and a fragment lacking the glucagon sequence; in the intestine, the same precursor is processed differently to produce incretins including GLP-1. This discovery of tissue-specific processing revealed the molecular logic by which the same gene product generates functionally distinct molecules in different tissues.

The incretin effect was first proposed in the 1960s——oral and intravenous administration of the same dose of glucose caused similar blood glucose elevation, but oral administration induced more significant insulin secretion, suggesting that some gut-derived factor enhanced postprandial insulin release. GLP-1 is precisely the core executor of this effect, secreted mainly by L cells in the ileum and colon. From a physiological localization perspective, GLP-1 is a key signaling bridge connecting intestinal nutrient sensing with pancreatic endocrine regulation.

II. The Glucose-Dependent Mechanism of Action of GLP-1.

GLP-1 promotes insulin secretion from 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 characteristic has important physiological and 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——on one hand increasing glucose utilization and storage, on the other hand reducing hepatic glucose output, jointly maintaining postprandial blood glucose stability from two directions. Delaying gastric emptying further smooths postprandial blood glucose peaks by slowing the rate at which nutrients enter the small intestine.

III. The Half-Life Bottleneck of Native GLP-1 and Structural Modification Strategies.

The half-life of GLP-1 secreted by the human body is very short, only 1 to 2 minutes, and after secretion into the bloodstream it is easily degraded by dipeptidyl peptidase-4 and loses its insulin secretion-promoting activity. This extremely short half-life stems from the specific cleavage of the second alanine residue at the N-terminus of GLP-1 by DPP-4, and the cleaved product loses receptor agonist 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 while avoiding degradation and loss of activity, thereby prolonging the duration of action and exerting effects in regulating blood glucose and treating diabetes.

From a technical pathway perspective, strategies for extending the half-life of GLP-1 mainly include three categories: first, amino acid substitutions that alter the DPP-4 recognition site so that the N-terminal sequence is no longer effectively cleaved by DPP-4; second, covalent attachment of long-chain fatty acids so that the peptide binds to serum albumin in circulation, achieving sustained release through the long half-life of albumin; third, fusion of GLP-1 analogs with human antibody Fc fragments, utilizing the long circulation characteristics of Fc fragments in vivo to extend half-life. The common goal of these three pathways is to overcome the druggability bottleneck of the native molecule's "two-minute half-life" while retaining receptor agonist activity.

IV. 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, including besides the pancreas, the central nervous system, gastrointestinal tract, cardiovascular system, liver, adipose tissue, and muscle, so 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.

From an organ-level perspective, this mechanistic network can be summarized as follows: the pancreatic level is the core——promoting β cell insulin secretion and protecting β cell mass, which is the main source of the glucose-lowering effect of GLP-1 drugs; the hepatic level reduces hepatic glucose output, forming synergy with increased insulin secretion; the central nervous system level suppresses appetite and increases satiety, and this mechanism also serves as the physiological basis for GLP-1 drugs' expansion into the weight management field; the gastrointestinal level delays gastric emptying and gastrointestinal motility, smoothing postprandial blood glucose fluctuations. This "one receptor, multiple organs, multiple mechanisms" action pattern distinguishes GLP-1 receptor agonists from traditional single-target glucose-lowering drugs; their efficacy derives from the synergistic integration of multiple physiological links, which also explains why this class of drugs can demonstrate additional benefits such as cardiovascular protection beyond glucose lowering.

V. Conclusion.

GLP-1, as an incretin secreted by intestinal L cells, through its physiological functions of promoting insulin secretion in a glucose concentration-dependent manner, inhibiting glucagon release, and delaying gastric emptying, the three structural modification strategies of amino acid substitution, fatty acid chain modification, and Fc fusion prompted by the native molecule's only 1 to 2 minute half-life, and the multiple glucose-lowering mechanisms brought about by receptor distribution across multiple organs including the pancreas, central nervous system, liver, and gastrointestinal tract, has become one of the most influential molecules in the field of metabolic disease therapy.

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

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