With the massive and ever-expanding market for diabetes medications, the pharmaceutical companies are burning the midnight oil to outdo each other in the race to develop more perfect insulins and delivery systems.
We have come a long way, baby, but not nearly as far as we would like. The insulins we have today are certainly better than those of twenty years ago, but none would win an “endogenous insulin” look a-like contest.
Even with a pump, drug inception and degradation, timing, and consistency of results is far from ideal. Hyper- and hypoglycemia are ever present realities and the ability to eat a meal with significant amount of carbohydrate or fatty foods without doing intricate mathematical calculations about the precise time to give the injection is still a gleam in a researcher’s eye. And, of course, insulin made in the body comes with an injection free delivery system.
So what’s on the way?
Insulins with better timing
One type of product in development is ultra-rapid-acting insulin. These emerging insulins are aiming to more closely mimic the pattern of the body’s own first-phase insulin release. Depletion of first phase insulin response is highly correlated with the development of type 2 diabetes.
A bit of path physiology is in order here. For those without diabetes, prandial insulin is released in two phases: the first occurs as glucose concentrations rise from carbohydrate consumption, triggering a cascade of electrolyte activity in the beta cell. When calcium levels in the beta cells become sufficiently elevated, preformed insulin is secreted from storage granules in the cell.
This first-phase secretion is key to determining the body’s use of the incoming nutrient load; it directs the uptake of glucose by the body’s cells, suppresses the liver from making glucose and blunts postprandial glucose excursions. And the key point is that all of this happens really fast. First-phase secretion starts with 2 minutes of eating and continues for about 10 to 15 minutes.
The second phase involves the de novo synthesis of new insulin and continues through the digestive process for 2 to 3 hours. Insulin is not secreted continuously during this phase but rather oscillates on and off.
Patients with type 1 diabetes have little or no insulin response; people with type 2 have lost their first phase response.
The goal for these ultra-rapids is to mimic as much as possible the speed of normal first phase insulin release. They will theoretically provide better coverage for food intake, suppress liver glucose output quicker and reduce the risk of hypoglycemia by leaving the body faster than the rapid insulins now on the market.
Insulins with longer coverage
Right now basal insulins last 24 hours, at the most. Sometimes people with type 1 have to take two injections of either Lantus® or Levemir® to maintain adequate control. But there are ultra-long-acting basal insulins in late stage development.
Instead of taking basal insulin once or twice a day, these insulins would allow you to take them three to four times a week. Researchers were able to achieve this longevity by altering the way the injected insulin dissolves into active insulin. (When insulin is injected into the fat tissue it is in the form of a hexamer- it needs to dissociate into a single molecule form to work properly.)
Part of the reason people are often distressed when told they have to go on insulin is that they have to inject it. Getting a flu shot once a year is no problem for most people; every day, several times a day for the rest of your life is tedious, no matter how painless the injections have become. Which is why, although it isn’t easy, the drug companies are pursuing oral, inhaled and transdermal alternate delivery systems.
To have an oral insulin work, it has to be encased in a protective type coating to allow it to escape digestion by our acidic gastric juices. This is a big problem, but progress is being made. The bet is that the obstacles won’t be insurmountable.
In addition to insulin by mouth, researchers are revisiting the possibility of inhaled insulin. And now instead of the mechanics of getting it into the lungs—that was worked out when it was previously on the market—late phase studies are concentrating on safety issues such as avoidance of late onset respiratory problems, and working out absorption profiles. (Exubera® was taken off the market in 2007 ostensibly due to lack of market share. However, there were reports of an increase in bronchial tumor rates in smokers who used the drug.)
If you can’t breathe it swallow it, perhaps you can absorb it through the skin. The patches under development are akin to nitroglycerin patches for people with heart disease, except they have an energy source to power ultrasonic wave transmission that would pulse the insulin through the skin pores.
It seems like there is a lot to look forward to: What modifications in insulin or insulin delivery would you like to see?