Insulin glargine

In plain language

Insulin glargine is a long-acting background insulin that lasts about a day. It is sold as Lantus, with follow-on versions such as Basaglar and Semglee.

Researchers changed one amino acid and added two more at the end of the molecule, making it slightly soluble in the slightly acidic vial but barely soluble at the body's pH. After injection it forms a small reservoir under the skin that dissolves slowly, releasing insulin steadily for about 24 hours.

For students

Insulin glargine (about 6,038 Da) substitutes glycine for asparagine at A21 and adds two arginines to the B-chain C-terminus (ArgB31-ArgB32). The isoelectric point shifts toward neutral, so the molecule precipitates at the physiological pH of the injection site and dissolves slowly from the microprecipitate.

The A21 change removes a deamidation-prone residue, improving stability. Metabolites M1 and M2 (arising from carboxypeptidase trimming of the added arginines) carry most of the circulating activity, which is why glargine's clinical profile is essentially that of a slowly released human insulin. The ORIGIN cardiovascular outcomes trial and extensive post-marketing data support its safety.

For researchers and instructors

Biochemistry. The solubility switch is purely pH-dependent: soluble at pH 4 in the vial, microprecipitating at pH 7.4 in tissue; activity is retained because the arginine tail is trimmed to human-insulin-like metabolites in vivo.

Pharmacology. Duration ~24 hours with no pronounced peak; U300 (Toujeo) further slows absorption by concentrating the same molecule into smaller precipitate particles.

Human evidence. Non-inferiority to NPH insulin in registration trials; ORIGIN (12,500+ patients) showed no excess cardiovascular or cancer signal; follow-on and biosimilar programs established interchangeability standards for peptide drugs.

Teaching point. The foundational example of using physical chemistry (isoelectric point and solubility) to build a basal insulin.