GLP-1: Forty Years of Evolution from Incretin Discovery to the Metabolic Disease Treatment Revolution

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This article focuses on the biological discovery and drug development history of glucagon-like peptide-1 (GLP-1), systematically elaborating its physiological function as a 31-amino-acid polypeptide that regulates insulin secretion through a glucose-dependent mechanism, and analyzing the three types of half-life extension strategies prompted by the extremely short half-life of native GLP-1, along with their representative molecular designs.

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GLP-1: Forty Years of Evolution from the Discovery of Incretin to the Revolution in Metabolic Disease Treatment

Brief Summary: This article focuses on the biological discovery and drug development history of glucagon-like peptide-1 (GLP-1), systematically describing its physiological function as a 31-amino-acid polypeptide that regulates insulin secretion through a glucose-dependent mechanism, and analyzing the three classes of half-life extension strategies prompted by the extremely short half-life of native GLP-1, along with their representative molecular designs.

I. The discovery of GLP-1 and the establishment of the incretin concept.

In the 1970s, researchers began with the glucagon gene and used the anglerfish as experimental material to study prohormone processing. In 1982, it was discovered that glucagon is encoded by a larger prohormone gene and is merely one of several polypeptide fragments cleaved from the prohormone protein through post-translational modification. In mammalian studies, the prohormone protein is processed in intestinal cells in a manner different from that in pancreatic cells, and two of these fragments are GLP-1 and GLP-2. GLP-1 is a polypeptide composed of 31 amino acids that finely regulates blood glucose by acting on pancreatic β cells, and it only takes effect when blood glucose rises after a meal.

The incretin effect was first proposed in the 1960s——oral and intravenous administration of the same dose of glucose produced similar rises in blood glucose, but oral administration induced more significant insulin secretion, suggesting that some gut-derived factor enhanced postprandial insulin release. The first incretin identified was glucose-dependent insulinotropic polypeptide, but it had almost no effect on insulin levels in diabetic patients and was disappointing as a drug. GLP-1 was the second incretin discovered. The contribution of GLP-1 and GIP to the insulin response in healthy individuals is estimated at 73%, but significantly decreases to 36% in patients with type 2 diabetes; in type 2 diabetes, postprandial GLP-1 concentrations decrease while GIP concentrations are normal or even elevated, making GLP-1 a more suitable candidate therapeutic approach.

II. The physiological advantages and druggability bottlenecks of GLP-1.

Compared with insulin, one major advantage of GLP-1 is that it only acts when blood glucose levels are high. When blood glucose levels are normal, GLP-1 does not stimulate insulin release, so it is unlikely to cause hypoglycemia, which is the most dangerous and most common side effect of insulin therapy. This glucose-dependent mechanism of action constitutes the core safety basis that distinguishes GLP-1 drugs from traditional glucose-lowering approaches.

But GLP-1 has a problem: its half-life in the body is only two minutes. After injection, GLP-1 is degraded before it reaches the pancreas, making it undruggable, and most pharmaceutical companies therefore abandoned the idea of developing GLP-1. The enzyme that degrades GLP-1 is dipeptidyl peptidase-4, and its cleavage site on GLP-1 is the second amino acid, alanine. This “two-minute half-life” bottleneck became the core challenge for all subsequent GLP-1 drug designs.

III. Three technical paths for half-life extension.

There are three main strategies for improving the pharmacokinetic properties of GLP-1. The first is systematic modification or chemical modification of the GLP-1 polypeptide to extend its in vivo half-life; the most intuitive change is to replace the alanine at position two with another amino acid, but this single change alone is far from sufficient. The second is to use DPP-4 inhibitors to reduce the rate at which GLP-1 is degraded. The third is to attach a “talisman” to GLP-1 so that it is protected from damage while circulating in the body——long-chain fatty acids can bind to serum albumin, and serum albumin has a half-life of about 21 days in humans, so polypeptide drugs anchored to albumin can have their duration of use extended.

The most typical achievement of the first path comes from a molecule of natural origin: exendin-4, discovered in the venom of the Gila monster, has numerous amino acid substitutions compared with GLP-1, with only about 50% homology; the greatest difference is an extra “tail” of 10 amino acids, and its second amino acid is glycine, thereby avoiding degradation by DPP-4. Like GLP-1, exendin-4 is not prone to causing hypoglycemia, and it does not degrade within hours in animals, giving it druggability that native GLP-1 lacks. The representative design of the third path is the covalent conjugation of lysine in the GLP-1 polypeptide with a palmitoyl fatty acid molecule to form a fusion molecule, anchoring the polypeptide to albumin through a fatty acid “hook.” This design went through setbacks such as purification difficulties and ultimately yielded a molecule with a half-life of 12 hours, namely liraglutide.

IV. The evolution of molecular design from single targets to dual targets.

The concept of dual-receptor agonists was first proposed and validated by researchers: designing a polypeptide that contains both GLP-1 and GIP sequences; this dual-receptor agonist exceeded single-receptor agonists in both glucose-lowering and weight-loss effects in animal models. The mechanistic basis is that hyperglycemia causes downregulation of the GIP receptor and thus resistance to GIP, and this resistance can be relieved by GLP-1, so that the combination of GIP and GLP-1 has synergistic effects on both glucose lowering and weight loss; in addition, GIPR signaling can prevent vomiting and alleviate other adverse side effects of GLP-1R activation.

VI. Conclusion.

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

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