While insulin has recently been engineered to be more concentrated, faster acting, and overall more powerful, there is also a need for insulin that is weaker so that infants, people with a high sensitivity to insulin, and even pets can use it safely. Diluting insulin, however, is anything but simple.
“It’s a very niche use for insulin,” says Dr. Elvira Isganaitis, a pediatric endocrinologist at Joslin Diabetes Center who frequently prescribes diluted insulin for her youngest patients. “It’s meant for people whose insulin requirements are very low and, frankly, the tools to dilute insulin are not easy to come by, so we only use it when we really need to.”
Those people not only include infants and preschoolers, who have a low body weight and require micro-doses of insulin. It also includes people who are very sensitive to insulin, many of whom are recently diagnosed with type 1 diabetes or whose insulin requirements are unusually low. Additionally, pets with diabetes (who also weigh very little compared to human beings) also frequently require insulin that is not as concentrated as U-100 strength insulin.
U-100 is the standard concentration of insulin in the United States, and most of the world. That means there are 100 units of insulin for every milliliter of liquid. Recently, new, more concentrated insulin formulations have been hitting the market. In 2015, Eli Lilly launched a double-concentrated U-200 preparation of its fast-acting Humalog insulin, and they have had a U-500 intermediate-acting Humulin insulin on the market for many years. Meanwhile, in 2015, Sanofi launched a triple-concentrated U-300 preparation of its long-acting insulin glargine called Toujeo, and in 2016, Novo Nordisk released a double-concentrated U-200 version of insulin degludec (or Tresiba). These highly concentrated insulins are typically used in individuals with insulin resistance, which is a common feature of type 2 diabetes, but can occasionally be seen in individuals with type 1.
However, none of these new insulins help with the problem of low insulin requirements in young children or individuals with high sensitivity to insulin. In the past, a range of less concentrated insulins was available, including U-40 and U-80. However, a study in the 1970s found that so many varieties of concentrations led to an increase in people delivering wrong doses. In the 1980s most insulin concentrations were standardized to U-100 for uniformity and ease of use, and because of patient preference.
The recent launch of U-200 and U-300 insulins similarly poses a risk of unintentional overdoses by both patients and health professionals. It is essential that patients starting on these insulins be cautioned about the risks. These insulins, which typically come as insulin pens with dialable doses, should not be used with insulin syringes, which are intended for use with U-100 insulin. Thus, a patient who draws up Toujeo U-300 insulin into an insulin syringe may think they are taking 10 units, when in fact they are taking 3 times as much, with potentially devastating consequences.
Despite the risks posed by non-standard insulin concentrations, the fact remains that some patients require weaker concentrations of insulin. In preschoolers, it is not unusual for U-10 insulin to be used. But, if you have that need you need to master a difficult process. That’s because diluting insulin is not as simple as watering it down with saline solution or sterile water. The first step in the process is to get the proper diluent solution.
Only two companies, Novo Nordisk and Eli Lilly, manufacture diluent for use with their fast-acting insulin formulations. And Isganaitis says her clinic has to order the diluent directly from the manufacturer. No diluents are available for long-acting or basal insulin.
“Outside of the manufacturer it’s very hard to get,” she says. “I’ve had conversations with pharmacists at Walgreens and CVS and they don’t know what it is, or say they don’t have it, or that it doesn’t exist. It’s just not available at the corner drug store.”
Fortunately, Novo-Nordisk and Eli Lilly are usually able to provide free vials of Novolog and Humalog diluent, respectively, to diabetes clinics. However, once diluted, insulin solutions only last a couple of weeks so it’s an ongoing process to make sure patients have adequate supplies on hand.
But, even after getting the diluent, the insulin cannot simply be diluted. The nurses and certified diabetes educators at Joslin provide detailed training to parents of young children with diabetes on how to prepare diluted insulin correctly. Alternatively, the diluted U-10 insulin can be obtained through some pediatric hospital compounding pharmacies. Still, if a glass vial of diluted insulin breaks during a holiday weekend, it is very tricky for a family to get the diluent their child needs.
“Correct dosages are crucial when you’re talking about patients who require a quarter of a unit per kilo per day,” Isganaitis says. “It’s not something you can get almost right, or close to right. It’s got to be exact.”
“For my patients who have extremely low insulin requirements, I encourage them to consider an insulin pump,” Isganaitis says. “Insulin pumps can deliver minuscule insulin doses, as low as 0.01 units of insulin, and essentially eliminate the need for diluted insulin.” However, a small study from Poland suggests that even children on insulin pumps might benefit from the use of diluted insulin, as this might reduce glycemic variability.
Some people who are fully grown but who are very sensitive to insulin have a bit more leeway in experimenting with diluting their insulin than might an infant for whom low blood sugar can be very serious.
“I found out that even if I took just half a unit while I was running, it was way too much,” says Eric DiPietro, who has had diabetes for 45 years, or since he was five, and a seven-time marathoner. “Because of that, I had to come up with a new way to deliver insulin.”
If diabetes is a do it yourself condition, then DiPietro, a computer engineer, can be considered the MacGyver of diabetes. He tests his blood sugar up to 20 times a day. He has tried almost every kind of insulin ever invented. He has ordered and used diluent from both Lilly and Novo. And, after a lot of experimentation, DiPietro has retrofitted insulin pens to accommodate varying strengths of diluted insulin, which are color coded to indicate a range of concentrations, so he can run almost 50 miles a week and still receive the doses of insulin he needs.
“It’s kind of the poor man’s pump,” DiPietro says of his method of insulin delivery. “I’m not really a rule follower but, in this case, that works to my advantage. When it comes to diluting insulin, you kind of have to figure it out yourself. No one else is really going to.”
That necessity to figure it out on one’s own sometimes frustrates Isganaitis.
“Very young kids are sometimes forgotten when it comes to new diabetes products, even though new cases of type 1 diabetes are rising fastest among 0 to 6 year olds,” she says. “Maybe with more pets becoming diagnosed there will be an increased awareness about the need for diluted insulin. Wider access to insulin diluent, or the development of insulin pens that could deliver quarter-units of insulin would be great. Toddlers and preschoolers face a long life with diabetes, and whatever we can do to improve their health at the outset is welcome, and will benefit their health in the long run.”