*Thomas Donner receives funding from Novo Nordisk as a principal investigator for a trial studying FIAsp insulin. **Mary Korytkowski received a two-year grant from Sanofi that ended Dec. 31, 2013

Insulin as a medication has come a long way, but its journey is far from complete. When it first came on the market in the 1920s, insulin was extracted from the pancreases of pigs and cows. Decades later, bioengineers figured out how to prod yeast and bacteria to make human insulin. Next came the insulin analogs, which allowed injected insulin to act more like insulin released by the pancreas. Today, scientists continue their efforts to improve the lives and health of people with diabetes by designing ever better varieties of insulin—including some that may not need to be injected.

More Human Than Human

Even though the human insulin taken as a medication is identical to the stuff the pancreas produces, it doesn’t work as well. That’s because the pancreas delivers insulin first to the liver and then to the bloodstream, while insulin taken as a medication is injected or pumped just under the skin. It takes time for that insulin to make its way into the circulatory system, where it can lower blood glucose.

By tinkering with the chemistry of insulin, scientists have developed a range of insulin analogs that are intended to work more like the insulin made by the pancreas. “What these insulins try to do is mimic normal insulin physiology,” says Thomas Donner*, MD, associate professor of medicine and director of the Johns Hopkins Comprehensive Diabetes Center. “That’s really difficult to attain.” Even with the analogs available today, blood glucose can still go high after a meal because the insulin isn’t working fast enough. Or, it can go low overnight because long-acting insulin doesn’t provide a stable background level of blood glucose control. These drawbacks are driving the development of insulin types that work faster or longer and more steadily than those available now.

Longer and More Level

Insulin for injection is bundled into clusters of six molecules. For insulin to make its way into the circulatory system, it must first separate itself into individual molecules. One strategy for making insulin last longer in the body is to make it even stickier, so the insulin slowly enters circulation.

Human insulin, a protein, is made of a chain of 51 amino acids, the precise order of which gives insulin its properties. Insulin glargine (Lantus) is made by adjusting the amino acid sequence of insulin to make the protein form into tiny crystals after injection, resulting in a slower release from the injection site into the bloodstream. Insulin detemir (Levemir) is human insulin, minus one amino acid and modified by the attachment of a small fatty acid molecule. The fatty acid makes insulin stick to a protein called albumin—it takes time for the albumin to let go and let insulin do its work. These approaches have extended insulin’s duration of action to as much as 26 hours, but now scientists want to make ultra-long-acting insulins that stay in the body for days.

Insulin degludec

Insulin degludec (Tresiba) looks a lot like its sister insulin, detemir, with one missing amino acid and an extra fatty acid chain. The chain’s chemistry is different, though. The result is that, in addition to sticking to albumin, insulin degludec forms larger clusters, keeping insulin tied up and prolonging the medication’s activity. Insulin degludec is reported to last up to 40 hours after injection and can be given daily or as few as three times a week. Research suggests that insulin degludec lowers A1C about as much as insulin glargine, but with fewer episodes of nighttime hypoglycemia (low blood glucose).

In February 2013, the Food and Drug Administration (FDA) ruled that it could not clear insulin degludec until its maker, Novo Nordisk, collected more heart safety data. That pushed back the release date to 2015 at the earliest. The medication is already cleared for sale in the European Union, Japan, and other markets.

Insulin LY2605541

The core of Eli Lilly’s experimental ultra-long-acting insulin LY2605541 is insulin lispro (Humalog), a rapid-acting insulin analog. In LY2605541, insulin lispro has been modified by the attachment of a large molecule called polyethylene glycol (PEG). The PEG part of the medication dwarfs insulin. The large size of the drug slows its absorption and its removal from the body through the kidneys, says Donner, resulting in a longer-lasting insulin. Based on the studies so far, LY2605541 reduces hypoglycemia rates. Plus, Donner says researchers see some weight loss in people who use the experimental drug compared with insulin glargine. As of March, Lilly was recruiting people with type 1 or type 2 diabetes for advanced studies of insulin LY2605541.

Concentrated insulins

U-500, which is five times more concentrated than U-100 insulin, has been around for a long time. It’s an option for people who require high doses of insulin. One interesting feature of U-500 is that it’s also more long-acting than U-100, according to Mary Korytkowski**, MD, professor of medicine in the division of endocrinology and metabolism at the University of Pittsburgh. The reason for the prolonged action isn’t well understood, but individual insulin molecules in concentrated solutions may cling to one another more tightly, slowing their absorption into the bloodstream, says Korytkowski.

Sanofi is working on a U-300 formulation of insulin glargine. Evidence suggests that this formulation may lower the risk of nighttime hypoglycemia because it provides longer and more steady glucose control compared with current long-acting insulins. Novo Nordisk is developing a U-200 version of insulin degludec for people who require higher insulin doses. One drawback of U-500 is that a user may accidentally inject an insulin overdose if a vial of U-500 is confused for the much more common U-100 insulin, but developers plan to make that less likely. “With these newer preparations in development, they’ll be available in their own pen device,” says Korytkowski. When a given number of units are selected using the pen, it delivers the proper amount of concentrated insulin.

Faster and Shorter

The key to making a faster-acting insulin is to speed its entry into the circulatory system. Breaking down the insulin clusters that form after injection under the skin helps the body absorb insulin more rapidly. Researchers are racing to develop new ways to hustle insulin into the bloodstream.

Biodel

At the core of each cluster of six insulin molecules is an atom of zinc, which helps hold the whole thing together. Researchers at Biodel Inc. are developing insulin formulations that include a chemical, EDTA, that strips the zinc away from the insulin, releasing the individual proteins for faster absorption. Their initial attempt, a product named Linjeta, tended to cause irritation at the injection site, says Donner. “Now, they have a product in development that includes calcium and magnesium to lower site discomfort,” he adds.

Insulin plus hyaluronidase

The area just beneath the skin is a jungle of biological molecules, which can physically block insulin’s path to the circulatory system. One molecule that’s particularly obstructive is called hyaluronan. To help clear the way for insulin, Halozyme Therapeutics mixes insulin with an enzyme called hyaluronidase that

cuts through the hyaluronan like a machete through the brush. The FDA has already approved the use of hyaluronidase with other drugs, says Donner, which may help speed this product to market.

Faster-acting insulin aspart

The medication FIAsp is a combination of rapid-acting insulin aspart (NovoLog), nicotinimide, and arginine. Nicotinimide, which is related to niacin, “seems to be what leads to more rapid-acting absorption,” says Donner, while arginine may improve stability. Novo Nordisk announced in December 2013 that it would begin to collect data for the final phase of research on FIAsp.

Now for Something Completely Different

Insulin is a protein and, like the protein in food, is digested when it enters the body through the mouth. That’s why, even 92 years after the first insulin injection, insulin remains a medication that requires a needle. But many scientists and people with diabetes hope that the needle may soon be out of work. Quite a few studies have tested alternative avenues of insulin delivery, including the nose, under the tongue, inside the cheek, the lungs, and the digestive tract. Here’s an update on two delivery systems that are working their way through clinical trials toward FDA clearance.

Inhaled insulin

You may think this is old news, and you’d be partly right. Inhaled insulin (Exubera) was available in the United States starting in September 2006, but it was removed from the market in October 2007 because of poor sales. That wasn’t the end of the story for inhaled insulin, though. MannKind Corp. has developed an inhaled insulin, Afrezza, that delivers insulin to the lungs in microparticles. It uses a smaller, more convenient inhaler than the cumbersome one that came with Exubera, raising inhaled insulin’s chances of commercial success.

When the microparticles enter the lungs, they dissolve to release insulin. The insulin is more quickly absorbed into the circulatory system than current injected rapid-acting insulins, offering a different route for ultra-rapid-acting insulin. An advisory committee recommended that the FDA clear Afrezza for sale. At press time, MannKind awaited the FDA’s decision.

Insulin pill

Oral insulin is often called the “Holy Grail” for diabetes medications. An insulin pill would mean no need for injections. Another advantage of taking insulin orally, according to Miriam Kidron, PhD, chief scientific officer at Oramed, is that it hits the liver after being absorbed through the intestines and before it enters the bloodstream, similar to insulin produced by the pancreas. Insulin in the liver helps ensure that the right amount of glucose gets into the bloodstream, so an insulin pill may improve glucose control.

Many have tried and failed to create versions of insulin that can be taken by mouth, says Kidron. Currently, three companies—Oramed, Novo Nordisk, and Biocon—are racing toward the first insulin pill. The Oramed version, which is being tested in people with either type 1 or type 2 diabetes, protects insulin from digestive enzymes by combining insulin with drugs that block the enzymes from working. While the medication could be taken alone in people with type 2 diabetes, Kidron says Oramed’s product is intended to complement insulin injections in people with type 1 diabetes. It aims to reduce how many injections are needed per day and curb blood glucose fluctuations.

With many new insulins in development, this decades-old wonder drug may soon offer more benefits to people with diabetes. The insulins of the future havethe potential to cause fewer blood glucose lows and highs, which means fewer short- and long-term complications. And reducing or eliminating the need to inject insulin may help take the sting out of diabetes.