Researchers at MIT have developed a computational model to predict the response of different versions of glucose-responsive insulin (GRI) in the human body. The model can also compare human responses to those of lab animals used in preclinical testing of GRIs. By using this model, researchers hope to design novel GRIs and obtain better predictions of their effectiveness in humans before conducting costly clinical trials.
In a recent study, the MIT team used the model to analyze the results of a GRI clinical trial that was discontinued due to its lack of effectiveness in humans. The researchers discovered that the GRI, which had demonstrated success in animal studies, acted differently in humans due to differences in the behavior of a sugar receptor that helps control the drug’s action.
Glucose-responsive insulins are designed to activate in response to high blood sugar levels. One GRI that underwent a phase I clinical trial, called MK-2640, demonstrated promising results in animal studies but showed little efficacy in humans. The drug was designed to bind to cell receptors normally bound to mannose, a type of sugar. When blood sugar levels rise, the GRI is blocked from binding to the receptors and remains in the bloodstream to help reduce sugar levels.
The computational model created by the MIT engineers accurately predicts how glucose and insulin behave in different compartments of the human body. It can anticipate blood glucose levels in organs such as the liver, stomach, and brain, and has been calibrated with extensive clinical and animal data.
Using the model, the researchers found that interspecies differences in the clearance capacity of the mannose receptor explained the weak performance of the GRI in human trials. If the human version of the receptor were tuned to behave similarly to that of the animal model, the drug would likely have performed better in clinical trials.
The MIT researchers have made their computational model open source, allowing others to use it to explore potential GRIs that may perform more effectively in humans. They are also collaborating with researchers at Indiana University to develop new glucose-responsive drugs.
Source: ACS Pharmacology and Translation – https://pubs.acs.org/doi/10.1021/acsactranspharm.1c00168