Cellular Imaging Offers New Way of Understanding Insulin Action

Denmark-based pharmaceutical company Novo Nordisk recently awarded Diabetes Center faculty member Fred Schaufele, PhD, with a Diabetes Innovation Award to study the challenge of insulin resistance at the cellular level.  Dr. Schaufele seeks to understand why chronically elevated insulin found in patients with insulin resistance causes a dramatic change in insulin receptor structure, leading to even more insulin resistance and ultimately type 2 diabetes. His hope is that new drugs may be created that will improve overall diabetes management.

By Fred Schaufele, PhD

My research team at the University of California, San Francisco, works with protein signaling, historically in breast and prostate cancer. In particular, we are experts in a biophysical technology that measures energy exchange when molecules are close to each other. When a protein changes shape, the amounts of energy exchange also change. This allows us to ‘see’ how the shape of a given protein, such as the insulin receptor, changes during different states of insulin activation.

The research question being addressed

The insulin receptor is rapidly activated by insulin which initiates also the receptor’s subsequent deactivation. This deactivation avoids receptor over-stimulation during the time needed for insulin to have its physiologic effect. However, in individuals with ‘insulin resistance’, insulin remains elevated and the insulin receptor more poorly recovers from deactivation. Overall, we aim to find ways to stop the vicious cycle in which insulin resistance results in higher insulin levels and a prolonged deactivation that, in turn, leads to further insulin resistance, an ever-increasing demand for insulin and ultimately, pancreas failure and type 2 diabetes. This research has strong implications both for slowing the development of diabetes and for optimizing insulin delivery protocols to insulin-dependent patients.

Specific research objective

Our initial studies suggested that chronically elevated insulin, such as may be found in an insulin resistant patient, was associated with a change in shape of the insulin receptor. The Diabetes Innovation Award will allow us to fully investigate those preliminary findings. We aim to associate insulin resistance and the change in receptor structure with other modifications in the insulin receptor and to uncover insulin delivery protocols to minimize or counteract the formation of the insulin-refractory structure. These studies are conducted in cellular models. However, if our studies show how de-activation of the insulin receptor is abnormally prolonged or triggered in individuals with pre-diabetes, then the de-activation process becomes an interesting target for future treatment developments.

Role of Diabetes Innovation Award

I learned about the Novo Nordisk Diabetes Innovation Award Program from a mass email sent out by my university. I could see at once that this was a good fit for this side project. I had been discussing this project with my close collaborator, professor Ira Goldfine, for over six years now. But it is outside of the mainstream research in diabetes such that funding the studies was difficult. The studies also tend towards ‘translational’ without the exclusive mechanistic focus that academia is more keen to support.

Winning the Diabetes Innovation Award means that we can move forward with this project finally and put people on it full-time. If it leads to a drug-able venture, it is nice to know that Novo Nordisk has the capacity to develop it into a potential treatment for people with diabetes.