The discovery of insulin in 1921 by Banting and Best ushered in a new age of treatment—and hope—for patients with diabetes mellitus (DM). First administered to 14-year-old Leonard Thompson on January 11, 1922, insulin transformed the lives of patients with type 1 DM (T1DM). No longer were starvation diets the primary mode of treatment.1,2 Life saving in patients with T1DM, insulin has since become an important treatment option in patients with type 2 DM (T2DM) as well.
But as is often the case with medical breakthroughs, the discovery of the hormone that first reversed diabetic coma in dogs was only the beginning. Recognizing the crudeness of the pancreatic extract that he called isletin (after the islets of Langerhans, the insulin-producing tissue of the pancreas), Banting turned to chemist James Collip, also at the University of Toronto, who developed a process to remove the toxins and impurities from the pancreatic extract. Banting also recognized the limitation of using dogs as the source of isletin (the name of which was changed to insulin by the university) so he quickly turned to cattle as a more plentiful source. Not surprisingly, the demand for insulin skyrocketed within months of its first testing in humans by Banting and Best, so, in July 1922, licenses for the manufacture of insulin were given to several pharmaceutical companies.1,2
Evolution of Insulin
While the clinical effects of insulin in patients with T1DM were dramatic, such as waking people from diabetic coma, enabling them to consume a normal diet, and improving long-term prognosis, problems were encountered.2 One was the challenge of balancing normoglycemia without causing hypoglycemia. The early insulin preparations acted relatively quickly and had a peak effect, but they did not provide a continuous, low level of basal insulin in the same manner as did pancreatic β cells. The time-action profile was, therefore, far from physiologically similar to endogenous insulin. The second problem was allergic reactions since the source of the insulin was nonhuman.2 Resolving these issues was the focus of intensive research over many decades.
To better balance normoglycemia without causing hypoglycemia, intermediate- and long-acting insulins were subsequently developed as basal insulins to prolong the duration of effect. Discovered in 1936, neutral protamine Hagedorn (NPH) insulin was released in 1950 as an intermediate-acting basal insulin.3 Although NPH insulin remains widely used today, recent guidelines have recommended against its use since the availability of insulin analogs (detemir and glargine), which provide a relatively flat profile for 24 hours and “yield better reproducibility and consistency, both between patients and within patients, with a corresponding reduction in the risk of hypoglycemia.”4 Other basal insulins such as Lente and Ultralente were introduced in the 1950s and used extensively for many years,3 but they had important limitations, such as wide variability in absorption and duration of effect, which led to inconsistent blood glucose control.
Along with efforts to prolong the duration of action of insulin, much scientific work was undertaken to reduce the risk for the allergic reactions first encountered with canine insulin, and then with bovine and porcine insulins.3 While the purity of these formulations improved over time with advances in chromatography, allergic reactions remained a limitation for some patients. The use of animal-derived insulins eventually gave way to synthetic human insulins, first approved by the US Food and Drug Administration in 1982.5 Consisting of the same amino acid sequence as insulin secreted by the human pancreas, synthetic human insulins are less likely to cause allergic reactions and have a faster onset and shorter duration of action compared with animal-derived insulins. The short-acting regular human insulin has now been largely replaced by rapid-acting insulin analogs (aspart, glulisine, and lispro) because the analogs are more physiologically similar to endogenous insulin and provide improved safety and tolerability.4 While allergic reactions do occur with insulin analogs, the prevalence is low.6-17
Insulin Analogs
Some of the early insulin formulations included zinc for the binding of insulin to protamine to alter the pharmacokinetic properties of the drug. With the availability of recombinant DNA technology, it became possible to modify the insulin structure so as to yield analogs of human regular insulin with pharmacokinetic and pharmacodynamic properties that more closely mimic the effects of endogenous insulin secreted by the pancreas (FIGURE 1). Two groups of insulin analogs were developed: (1) those with an onset of action more rapid than that of regular human insulin (ie, the rapid-acting insulin analogs); and (2) those with a duration of action longer than that of NPH human insulin (ie, the long-acting basal insulin analogs) (TABLE 1).18-23 Premix insulin formulations are also available that combine a rapid-acting insulin analog with its intermediate-acting protamine suspension.
