Novel ultrafast insulin may help control blood sugar during mealtimes
The development of human insulin has provided tighter control of blood sugar in diabetic patients. A substantial progress has been made in insulin preparations, from early animal insulins to human insulins in the 1980s to insulin analogues.
Patients with type 1 diabetes require exogenous insulin to regulate blood sugar, but current insulin formulations can take as long as 90 minutes to peak in activity, making them less than ideal for patients who need quick and effective blood sugar control during mealtimes.
Researchers at Stanford University are developing a new monomeric insulin a formulation that begins to take effect almost immediately upon injection, potentially working four times as fast as current commercial fast-acting insulin formulations. This ultrafast action will take care of mealtimes excursions of blood sugar.
Their research has been published in Science Translational Medicine. The researchers are now conducting additional tests in hopes of qualifying for clinical trials in humans.
The new insulin has a molecular structure that, according to theory, should allow it to act faster than other forms of insulin. But new monomeric insulin is too unstable for practical use.Therefore the researchers used a high-throughput screen to evaluate various excipients, and integrated the top-performing candidate into an insulin formulation named UFAL.
After screening and testing a large library of additive polymers, the researchers found one that could stabilize monomeric insulin for more than 24 hours in stressed conditions. The researchers then confirmed the ultrafast action of their formulation in diabetic pigs.
Current commercial formulations of insulin contain a mix of three forms: monomers, dimers and hexamers. Scientists have assumed monomers would be the most readily useful in the body but, within vials, the insulin molecules are drawn to the surface of the liquid where they aggregate and become inactive. (Hexamers are more stable in the vial but take longer to work in the body because they first have to break down into monomers to become active.) This is where the "magic fairy dust" – a custom polymer that is attracted to the air/water interface – comes in.
Illustration depicting how fast different forms of insulin absorb in the bloodstream, and how the polymer developed by these researchers helps stabilize ultrafast-absorbing insulin in the vial. (Image credit: Joseph Mann and Caitlin Maikawa)
Finding just the right polymer with the desired properties was a long process that involved a three-week trip to Australia, where a fast-moving robot created approximately 1500 preliminary candidates. This was followed by processing and testing individually by hand at Stanford to identify polymers that successfully exhibited the desired barrier behavior. The first 100 candidates didn't stabilize commercial insulin in tests but the researchers pressed on. They found their magic polymer only weeks before they were scheduled to run experiments with diabetic pigs.
In commercial insulin – which typically remains stable for about 10 hours in accelerated aging tests – the polymer drastically increased the duration of stability for upwards of a month. The next step was to see how the polymer affected monomeric insulin, which on its own aggregates in 1-2 hours. It was another welcome victory when the researchers confirmed that their formulation could remain stable for over 24 hours under stress.
"In terms of stability, we took a big step backward by making the insulin monomeric. Then, by adding our polymer, we met more than double the stability of the current commercial standard," said Caitlin Maikawa, a graduate student in the Appel lab and co-lead author of the paper.
The monomeric insulin also finished its action sooner. Both beginning and ending activity sooner makes it easier for people to use insulin in coordination with mealtime glucose levels to appropriately manage their blood sugar levels.
Because their insulin formulation activates so quickly – and, therefore, more like insulin in a person without diabetes – the researchers are excited by the possibility that it could aid the development of an artificial pancreas device that functions without the need for patient intervention at mealtimes.
These ultrafast kinetics make an ultrafast-absorbing insulin lispro (UFAL) a promising candidate for improving blood sugar control and reducing burden for patients with diabetes.
For further reference log on to:
More information: J.L. Mann el al., "An ultrafast insulin formulation enabled by high-throughput screening of engineered polymeric excipients,"
Science Translational Medicine.
DOI: 10.1126/scitranslmed.aba6676
