part1 insulin history

Eighty years of insulin therapy: 1922-2002

Medicine and Health Rhode Island, Apr 2003 by Levinson, Paul D

Prior to the discovery of insulin, the life expectancy of a newly diagnosed juvenile-onset (type 1) diabetic was less than 12 months, with death usually resulting from inanition, ketoacidosis, and/or infection. At the start of the 20th century, the only treatment available for diabetic patients was a low-calorie, lowcarbohydrate diet. While this approach may have been effective for the typical obese, adult-onset (type 2) diabetic, it only briefly postponed the ultimate fatal outcome for persons with type 1 diabetes.

On January 23, 1922, at Toronto General Hospital, Leonard Thompson, a 14-year-old boy, became the first human to undergo successful treatment with insulin. About four months later, James Havens Jr. became the first patient treated with insulin in the United States. Thompson went on to work in a chemical factory, taking 85 units of insulin daily, until he died of pneumonia in 1935. Havens was 15 years old, a "73- pound skeleton living on 829 calories, barely able to lift his head from the pillow" at the time of his first insulin treatment. He subsequently married, had children, and became a successful artist before he died of cancer at age 59.(1)

By the end of 1922, commercial production of insulin was underway in the United States and Canada. Unmodified or regular insulin (also known as soluble, crystalline, or clear insulin) was processed from porcine and bovine pancreas and was the only type of insulin available for clinical use until the mid-1930s. Because regular insulin had a 6 - 8 hour duration of action, at least 2 daily injections were required to maintain blood glucose levels somewhat near normal and to keep the urine free of glucose. No data were available as to what constituted "good control;" and until the landmark intervention studies of the 1990s, there was no consensus regarding the appropriate objectives for glycemic control

To improve glucose control and also to promote patient convenience, researchers experimented with additives that would slow the absorption of regular insulin from its subcutaneous injection site into the circulation, thereby extending its duration of action.4 In the early 1930s, protamine (a basic protein) and zinc were mixed with insulin to produce protamine zinc insulin (PZI), a long-acting insulin with a duration of action of about 36 hours.

Although erratic absorption and frequent skin reactions limited its clinical use, other modified insulins were soon created. In the 1940s, neutral protamine Hagedorn (NPH or isophane) insulin was developed by Dr. H.C. Hagedorn and colleagues in Denmark. Its duration of action was midway between that of regular insulin and PZI, and it became a popular, intermediate-acting insulin. (Table 1) The Lente series of insulins, which utilized differences in zinc concentrations to define duration of insulin action, was developed in the 1950s. The major Lente insulins were short-acting semilente and long-acting ultralente. When combined in a mixture of 70% ultralente and 30% semilente, intermediate-acting lente insulin was the result

Although porcine and bovine insulin became available for clinical use in 1922, 30 years passed before Sanger characterized the amino acid sequence of human insulin. By the 1980s, insulin manufacturers were able to utilize the new tools of molecular biology to produce insulin with the same amino acid sequence and conformation as native human insulin. (Figure 1) Human insulin rarely caused immune-mediated reactions and its use eliminated dependence on animal sources for the production of insulin. Although beef and pork insulins were by now highly purified, they were gradually replaced by human NPH, regular, lente, and ultralente insulins. The human species insulins were equivalent in potency to the animal insulins but were absorbed slightly more rapidly, often requiring modest dose adjustments

In the 1980s, new technology coupled with innovative treatment concepts heralded a new era in diabetes therapy. Important new tools included the portable glucometer (for self-monitoring of blood glucose) and the hemoglobin AlC (HbA1C) assay (an indicator of average blood glucose during the previous 8-12 weeks). Frequent feedback from self-monitored glucose levels allowed patients to fine-tune their insulin regimens to a degree that was previously unachievable. HbA1C levels provided the "big picture" - an estimate of the patient's overall success at achieving an intended glycemic goal. (Table 2) Improvements in technology also made insulin injections more convenient and less painful. The improvements included disposable syringes and needles, ultra-fine needles, prefilled syringes (insulin pens), and insulin pumps, also known as continuous subcutaneous insulin infusion, (CSII).7 The pumps first became available in the late 1970s, and were worn on a belt or strap. They delivered a continuous 24-hour insulin infusion as well as on-command bolus insulin injections through a catheter and transcutaneous needle that was left in place for 48-72 hours at a time. Patients still had to self-monitor their glucose levels and instruct the pump to administer appropriate pre-meal bolus doses

At any one time, about 60% of patients in the DCCT administered their insulin using multiple daily injections and 40% used CSII.12 The most popular multiple injection regimen (used by about 60% of patients) included regular insulin before meals and lente or NPH at bedtime or at both bedtime and breakfast. About 40% of patients used once- or twice-daily ultralente and pre-meal regular insulin. The factors most predictive of success were frequent glucose self-monitoring, a high level of motivation, and willingness to maintain frequent contact with the diabetes support team. CSII has been the gold standard for the basal/ prandial approach to insulin therapy because it simulates normal insulin physiology more effectively than multiple-injection insulin regimens. Because of the cost, education, and maintenance issues associated with pump technology, however, patients must be particularly motivated to choose an insulin pump as their insulin delivery system. T

The first of these "designed" insulins to become available for clinical use were the shortacting analogs, insulin lispro (Humalog, Eli Lilly) and insulin aspart (Novolog, Novo Nordisk), which were approved for clinical use in the United States in 1996 and 2001, respectively. Insulin glargine (Lantus, Aventis), the first longacting insulin analog, was introduced in 2001.