In 1921, a team of Canadian researchers including Frederick G. Banting, M.D., Charles H. Best, J.J.R. Macleod, Ph.D., and James B. Collip, Ph.D., isolated a newly discovered hormone they named “insulin” from calf pancreases (pancreata). They injected it into a teenage boy who had type 1 diabetes (T1D). The young man, Leonard Thompson, was confined to a bed in a diabetes ward of Toronto General Hospital and not expected to live long—like all people diagnosed with T1D at that time. Prior to the discovery of insulin, a diagnosis of T1D was a death sentence; without an effective treatment, the disease was always fatal. That first insulin injection failed. The preparation was too impure and caused an allergic reaction.
Rather than give up, the researchers went back to the laboratory to hone their purification process. Less than two weeks later, the team tried again. This time, the more refined insulin formulation was a success. Glucose levels in the boy’s blood and urine began dropping. Leonard, who had been weak and listless, became more active and mentally alert almost immediately. The new formulation was soon tested on other patients, who all showed dramatic improvements in their appearance, energy level, sense of well-being, and clinical measures. This landmark trial gave new hope and joy to Leonard, his fellow diabetes ward mates, their families, and everyone affected by T1D. Dr. Banting and Dr. Macleod were awarded the 1923 Nobel Prize in Physiology or Medicine for the discovery of insulin; they later shared their award with the other members of the team.
Although insulin does not cure T1D, its discovery, the radical transformation of diabetes life expectancy, and the therapy that it brought are widely considered to be among the most important and exciting medical breakthroughs of the 20th century. By 1923, within one year of those first successful insulin injections, Eli Lilly and Company was producing large quantities of highly purified insulin for widespread treatment of people with T1D. Insulin has ever since been the lifeline and essential treatment for T1D.
Insulin is a small protein produced by a specific class of cells in the pancreas, called beta cells. When the amount of glucose (sugar) in the bloodstream increases, such as after a meal, the beta cells release insulin into the blood. Insulin then acts as a hormone, or messenger, that tells other cells throughout the body that glucose is available and helps the cells use that glucose as an energy source.
Insulin therapy has come a long way from injections of those original calf pancreas extracts. Today, multiple insulin formulations and insulin analogs—modified forms of the insulin protein—are available for fine-tuning diabetes management, and JDRF is committed to driving research toward the goal of even safer, easier, and more effective insulin therapy.
Insulin formulations and insulin analogs
Nearly 60 years after Dr. Banting and colleagues made the first insulin injections, the discovery of the human insulin gene in 1980 opened the door to a new era in insulin therapy. By the early 1980s, recombinant (biosynthetic) human insulin was on the market. Recombinant insulin is grown in laboratory strains of bacteria or yeast, so the drug no longer needs to be purified from animal pancreases. This advance makes insulin less expensive to manufacture and reduces immune reactions that were once a common side effect of animal-derived insulins.
Having the insulin gene in hand also allowed researchers in the 1980s and 1990s to begin tinkering with the string of amino acids that are the building blocks of the insulin protein. By creating different versions, or analogs, of the protein, scientists are trying to resolve some of the differences between how recombinant insulin acts when it is injected into the body and how insulin acts when secreted by a person’s own pancreas.
Over the past several decades, many types of insulin and its analogs have been developed, each doing a part to help people with T1D achieve better glucose control. Classes of insulin formulations and insulin analogs offer at least three significant advantages: the speed of onset of glucose-lowering activity, the timing of peak activity, and the overall duration of activity.
Types of insulin that are currently available include:
Fast-acting insulin analogs, including NovoLog/NovoRapid (aspart), Humalog (lispro), and Apidra (glulisine), are modified forms of the insulin protein that cannot cluster into small groups or crystals like regular, or unmodified, human insulin does. This modification allows the analogs to be absorbed into the bloodstream and begin working more quickly. Fast-acting analogs start functioning to reduce blood glucose within 5 to 15 minutes after injection or infusion. Their activity peaks within 90 minutes and lasts for only three or four hours at most. Fast-acting forms of insulin are typically injected or infused immediately before meals to help control the rise in blood-glucose level caused by eating or drinking. Fast-acting insulins are used in insulin pumps for both basal infusion and premeal boluses (additional single dosages).
Regular insulin, such as Humulin R or Novolin R, is classified as short acting. This form of insulin begins working within 30 minutes, reaches a peak of activity in one to three hours, and remains active in a person’s bloodstream for up to eight hours. Short-acting insulin is usually taken about 30 minutes to an hour before a meal to control food-related increases in blood-glucose level.
Intermediate-acting insulin formulations, such as NPH insulin (for example, Humulin N, Novolin N, Novolin NPH, NPH Iletin II), are created by putting regular insulin into chemical solutions that cause the insulin proteins to cluster into larger groups or crystals than they otherwise would. These larger crystals cause intermediate-acting insulin to be absorbed more slowly by the body than regular insulin, thus extending the time course of its blood glucose–lowering action. Intermediate-acting insulin begins to work within one to three hours, reaching peak activity after 4 to 12 hours. By remaining active for up to 24 hours, intermediate-acting insulin helps control blood-glucose levels between meals.
Long-acting insulin analogs, such as Lantus (glargine) and Levemir (detemir), are modified forms of the insulin protein that either cluster together more than regular insulin or attach themselves to a protein in blood called albumin. The interactions among insulin molecules or between insulin and albumin slowly fall apart, gradually releasing the long-acting insulin analogs to do their work in the bloodstream. These insulins start to work within one to two hours after injection. In general, long-acting insulins do not have a strong peak in activity but work steadily for about 24 hours. This provides a basal level of insulin in the blood at all times. The uniform pattern of insulin activity may reduce the risk of nighttime hypoglycemia (low blood glucose) for some people compared to intermediate-acting insulins. Like intermediate-acting insulins, long-acting insulins are often used once per day to help maintain blood-glucose levels between meals and during sleep.
The precise timing of the onset, peak, and duration of activity for each class of insulin varies among individuals with T1D. Like any drug, all forms of insulin have the potential for side effects. Each person should choose the appropriate types, dosages, and combinations of insulins for himself or herself in consultation with a qualified diabetes healthcare team.
The JDRF Insulin Initiative
Individuals with T1D have more insulin options than ever before for managing their blood-glucose levels throughout the day. People can also choose between two delivery methods—multiple daily injections or an insulin pump, both of which deliver insulin subcutaneously, or beneath the skin. Yet Sanjoy Dutta, Ph.D., sees room for further improvement in modern insulin therapy.
Dr. Dutta, who is JDRF’s senior director of treat therapies, identifies two major limitations of today’s insulins and insulin-delivery systems, when compared to physiologic insulin secretion from the pancreas of a person without T1D. First, the action profiles of even the best insulins available today are slow relative to insulin made by the pancreas. As a result, people on insulin therapy often experience hyperglycemia (high blood glucose) during or immediately after meals. The second major concern is that it takes a long time for insulin to be cleared from the body, which can cause delayed hypoglycemia hours after a meal is finished. These extreme swings in glucose levels can happen despite the most careful attention to carbohydrate counting, exercise management, and other elements of good T1D management. As a result, many people with T1D can spend a major part of the day outside the desirable range of blood-glucose values.
To tackle these issues and find better insulins for treating people with T1D, JDRF launched its Insulin Initiative in 2009. The initiative is a multipronged effort to support research on new insulin molecules with enhanced properties, novel formulations of current insulins to improve their activity, and new ways to deliver insulin that better replicate insulin release from the pancreas.
First, the Insulin Initiative focuses on developing an ultrafast-acting insulin or insulin-delivery system. The benefits of ultrafast-acting insulin include the reduction or elimination of the need for premeal boluses of insulin, as well as reduction of extreme swings in glucose levels throughout the day. The development of this type of insulin is also an essential step toward a fully automated, closed-loop artificial pancreas. JDRF supports a number of promising research projects on ultrafast-acting insulin development.
The second focus area of the Insulin Initiative comes with more risk but a much higher potential pay-off: the development of glucose responsive insulin. The goal of glucose responsive insulin is to deliver exactly the right amount of insulin in response to blood-glucose levels 24 hours per day in a tissue-specific pattern. In theory, insulin that responds instantly to the precise amount of glucose in the blood would lead to a major reduction of, or even eliminate, hyperglycemia and hypoglycemia without the need for multiple finger sticks or continuous glucose monitoring. This form of insulin could greatly improve the health-related quality of life of all individuals with T1D by relieving much of the daily burden of T1D management.
Because research on glucose responsive insulin will require out-of-the-box thinking, JDRF’s strategy for this phase of the Insulin Initiative includes its first-ever prize competition. The Glucose Responsive Insulin Grand Challenge Prize was launched to spark innovative thinking from any member of the public who wanted to propose a new theoretical solution that could lead to the discovery and development of glucose responsive insulin. In September 2012, JDRF selected three winning solutions submitted by one individual researcher and two teams of scientists (see the JDRF press release here). Experimental plans are now being drawn up to determine whether the proposed ideas can be developed into safe and effective new drugs.
Undoubtedly, the development of glucose responsive insulin is a tall order, and one that will require a substantial research effort. “This is a very difficult problem to crack,” Dr. Dutta points out. “This is not a short-term project. It will require patience, resources, and many people working together to resolve this complex problem.”
A commitment to the future of insulin therapy
Insulin therapy for T1D is not a cure, but it has given life and hope to millions of people since that first injection in a Toronto hospital 90 years ago. Yet, more can be done to improve the effectiveness of insulin therapy and alleviate the treatment burden associated with T1D. Through its Insulin Initiative, JDRF is taking the lead on the development of new insulin formulations and innovative insulin analogSs that represent the future of T1D therapy.
“As a champion for people with T1D, JDRF has pushed the boundaries of research on difficult topics, including the development of new insulins. We know that this is a high-risk program and that much more needs to be done,” Dr. Dutta says. “But we also know that enhanced insulins have the potential to transform the daily lives and health of people with T1D.” For that reason, JDRF is committed to supporting and accelerating insulin research to the benefit of all those living with T1D.
The information in this article is offered for general educational purposes and is not intended to replace professional medical advice. You should not make any changes to the management of type 1 diabetes without first consulting your physician or other qualified medical professional.