Awardee Eric Appel, PhD

Award: Joint Pilot & Feasibility with the Stanford Diabetes Research Center (2018)

Total Award Amount: $25,000

MCHRI impact: Such a relatively modest sum has helped make possible two large contributions to diabetes research. With Pilot & Feasibility funding from SDRC and MCHRI, Dr. Appel’s lab created an insulin and amylin co-formulation and also fast-acting insulin with a shorter duration of action.

Doctoral student Caitlin Maikawa is responsible for most of the work, demonstrating improvements in insulin delivery when testing the new formulations in pigs (modeled for Type 1 diabetes).The lab’s pilot studies have laid the groundwork for future clinical trials in humans. Dr. Appel secured an R01 of $2,9700,00 from the National Institute of Diabetes and Digestive and Kidney Diseases to continue research efforts.

Improvements to insulin formulations have the potential to impact all people with diabetes, including children.

Co-formulation, insulin + amylin: The beta cells of the pancreas naturally produce insulin and amylin together, and the two compounds act synergistically to control blood glucose. Both hormones are deficient in people with diabetes.

To regulate blood glucose, people with diabetes inject insulin. Many miss out on the added benefit of amylin because it has to be injected separately. Dr. Appel estimates only 1.5 percent of eligible insulin users also use amylin because double dosing is a burden.

Understanding there was a need, Dr. Appel and his team have engineered a solution with a co-formulation of insulin and amylin. What’s more, by adding amylin to the dose of insulin, they’ve improved the efficacy of both. The time-frame of action for the two hormones overlaps by 70 percent when given together in a co-formulation, compared to only 40 percent when given separately. (Overlap is typically 100 percent in a normal functioning pancreas.)

“Because you’re improving insulin sensitivity with the co-formulation, we think that the increased synergy should reduce the amount of insulin you need to dose,” Dr. Appel says.

Faster-acting/short-duration insulin: After a person with diabetes injects insulin, there’s a lag in its activation. It also typically sticks around in the body for too long, which can result in hypoglycemia well after a meal.

Chemistry can explain why. Traditionally, insulin has been made up of hexamers to stabilize the drug since the insulin monomer, the only active form of the drug, is highly unstable. The catch—hexamers are also responsible for the delay in the onset of insulin action and slow depletion of insulin over time.

Dr. Appel and his team wanted to eliminate the need for hexamers by creating an excipient that can be added to the insulin to stabilize a formulation of monomers with shorter lag time and shorter duration. Their new formulations are roughly 80 percent monomers and 20 percent dimers—no hexamers to speak of.

They engineered an optimal amount of the special excipient that helps stabilize the system for up to 24 hours. That’s much longer than the stability of commercial insulin on the market today, which has a shelf life of about 10 hours.

“The excipient acts like a Saran Wrap around the molecule that protects it from aggregation,” says Dr. Appel. “It’s not locking the molecule in a box. It’s transient. As soon as you inject it in the body and it dilutes, the excipient just falls off and it leaves the standard authentic protein free to go do its job.”

A chemist’s approach to diabetes research: Dr. Appel consulted with Professor of Pediatrics Bruce Buckingham, MD, and Professor of Pediatrics and SDRC Associate Director David Maahs, MD, PhD, in order to understand what projects would have the most clinical impact.

In fact, it was at a lunch for new faculty in 2016 when Dr. Appel first met Dr. Maahs who wanted to know if the young investigator had ever worked with insulin. (He had.)

Dr. Appel explains that the goal of his lab isn’t to make new drugs, but rather to design systems that can more efficiently and effectively deliver active compounds to where they need to be in the body. Insulin, he found, is an old drug with a lot of potential for improvement.

BY LAURA HEDLI

Laura Hedli is a writer for the Division of Neonatal and Developmental Medicine in the Department of Pediatrics and contributes stories to the Stanford Maternal and Child Health Research Institute.