The Future of Basal Insulin

Abstract

Diabetes has been known to mankind for hundreds of years and was considered a deadly disease before the advent of insulin. It was the discovery of insulin by Frederick Banting and Charles Best that revolutionized the management of diabetes. Early insulins were made from either bovine or porcine whole pancreata. These early insulins were rather crude and impure. Because they differ by two or three amino acids from human insulin, immunologic reactions resulted such as insulin allergy, immune-mediated lipoatrophy at the injection site, antibody-mediated insulin resistance, and significant hyperglycemia and hypoglycemia due to unpredictable dissociation of insulin from antibodies. The initial insulins including bovine and porcine insulins were short-acting, and therefore it was difficult for patients to take several injections per day. Patients were often unable to optimize glucose control because of difficulty in adjusting the frequent doses of insulin needed to achieve euglycemia without hypoglycemia. Over a period of time, we understood that, physiologically, there is a continuous small amount of insulin secretion from the b-cells in the pancreas called basal insulin. Therefore, it became necessary to look for a more pure and ideal insulin that had a duration of action of at least 24 h. The early development of insulin diverged in two directions; many researchers were working on the purification of existing insulins, while others were working on longeracting insulins. It was Sanger’s discovery of insulin’s amino acid sequence in 1950 that paved the way to manufacturing of human insulin. The task of manufacturing insulin on a larger scale was made possible with the use of recombinant technology in the 1970s. Currently available insulins are recombinant DNA-derived human insulins. Bovine and porcine insulins are no longer available worldwide. During the same time frame, researchers were working on prolonging the duration of insulin action, resulting in the development of the first long-acting insulin analog (LAIA) known as protamine zinc insulin in the 1930s. Use of protamine zinc insulin was limited by the great risk of sudden hypoglycemia, slow onset of action, and high interand intraindividual variability. Soon after, in 1946, Hans Hagedorn and colleagues introduced crystalline neutral protamine Hagedorn (NPH) insulin, which was a more stable protamine zinc insulin. This modification combined insulin and protamine in ‘‘isophane’’ proportions (no excess of insulin or protamine) at neutral pH in the presence of a small amount of zinc and phenol and/or phenol derivatives to form a tetragonal oblong-shaped hexamer. During the same time in 1950, Hallas-Moller developed the lente insulins: lente, semilente, and ultralente, of which ultralente was the longer-acting insulin. These long-acting insulins (NPH and ultralente) came on the market and quickly gained widespread popularity among physicians in the 1940s and 1950s. However, these LAIAs were still not ideal. The NPH insulin exhibited a highly variable absorption profile (especially if not properly mixed before injection) and had a peak action of approximately 6 h, resulting in poor glycemic control and unpredictable hypoglycemia, especially nocturnal.