Insulinotropin: glucagon-like peptide I (7-37) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas

This historic work, published by peptide chemist Svetlana Mojsov and endocrinologist Joel Habener at Harvard/Massachusetts General Hospital, was the seminal study that identified GLP-1(7-37) as the true incretin hormone encoded in the glucagon gene. Before this work, the glucagon gene was known to encode two forms of glucagon-like peptides (GLP-I), but the identity of the biologically active form remained unclear.

The authors chemically synthesized two GLP-I variants of different sizes: GLP-I(1-37), with 37 amino acids corresponding to the full sequence translated from the gene, and GLP-I(7-37), a 31-amino-acid truncated form resulting from post-translational processing. Both peptides were tested in the isolated perfused rat pancreas model, the gold standard of the era for evaluating pancreatic insulin secretion.

Results were dramatic: in the presence of physiological glucose (6.6 mM), GLP-1(7-37) potently stimulated insulin secretion at concentrations as low as 5 × 10⁻¹¹ M (50 picomolar), with 3- to 10-fold increases over baseline. In contrast, GLP-1(1-37) had no effect even at concentrations 10,000-fold higher (5 × 10⁻⁷ M). This extreme difference clearly established that proteolytic processing to remove the first 6 amino acids is essential for biological activity, and that GLP-1(7-37) was the sought-after active fragment.

This work laid the foundation for the entire era of GLP-1 analogs that revolutionized treatment of type 2 diabetes and obesity — exenatide, liraglutide, semaglutide, dulaglutide, tirzepatide. In 2024, Mojsov and Habener received the Lasker Prize for this discovery, a long-overdue recognition of the historic and clinical importance of GLP-1(7-37) in contemporary medicine.