Insulin resistance can lead to a number of serious health complications, including type 2 diabetes, cardiovascular disease, metabolic dysfunction-associated steatotic liver disease (MASLD), and obesity-related cancers, among others. Despite its major influence on so many common health issues, the connections between insulin resistance and its downstream complications are not well understood. Joshua R. Cook, MD, PhD, an endocrinologist at NewYork-Presbyterian and Columbia, has a particular interest in regulation of hepatic glucose and lipid production in insulin resistant states and is now transitioning his research from animal models to human subjects.
Most recently, Dr. Cook and his NewYork-Presbyterian and Columbia colleagues conducted a study to evaluate the use of the phosphoinositide-3-kinase (PI3K) inhibitor alpelisib, approved by the FDA for treatment of certain types of breast cancer, as a tool to acutely induce insulin resistance in healthy volunteers. The double-blind, placebo-controlled, randomized trial tested the hypothesis that a single dose of the drug is sufficient to produce biochemical evidence of insulin resistance. Below, Dr. Cook discusses the findings from their study that support moving insulin resistance research from mouse models to human subjects.
Research Background
While insulin resistance has been studied in experimental models, it is very difficult to investigate the condition in humans due to many confounding factors. For example, insulin resistance develops over many years or even decades, it is usually associated with obesity or other medical problems, and can be affected by medications. So, it becomes a quite complicated chicken-or-egg problem. Due to the scarcity of methods for the clinical modeling of insulin resistance in human subjects, we sought to develop a novel approach to dealing with the causality conundrum by starting at a defined point in healthy volunteers.
Exploring A Cancer Drug to Induce Insulin Resistance
In the cancer space, specific drugs have been developed as targeted treatment for tumors with activating mutations in PI3K. The inhibitor drugs for these tumor mutations also affect insulin signaling. For example, PI3K is both a driver of cellular proliferation in certain breast tumors as well as a necessary mediator of insulin signaling. Alpelisib inhibits PI3K to block mitogenic signal transduction by PI3K in tumors but also has the on-target side effect of rendering people insulin resistant because it directly interferes with insulin signaling.
Alpelisib has several advantages:
- It can be taken orally
- It has a single, clearly defined mechanism of action
- Its metabolic impact is short lived with a half-life of 8 to 9 hours
Research Methods
Due to potential side effects and its cost, we chose to test the effect of only a single dose of alpelisib to determine if it could be tolerated and also produce the picture of insulin resistance that we were hoping to reproduce.
To achieve this, we assigned 11 healthy volunteers randomly to the alpelisib or placebo group. Five participants received alpelisib at the standard cancer treatment dose of 300 mg and six were given a placebo. Medication was taken at bedtime followed by an overnight fast with measurements of glucose, insulin, and C-peptide levels during a three-hour, 75-g oral glucose tolerance test the next morning.
This study clearly showed that a single dose of alpelisib produced evidence of insulin resistance in a tolerable way. Our goal is to now apply the model from this study to conduct more detailed metabolic research.
— Dr. Joshua Cook
Research Results
Participants did well with the drug, having only mild side effects such as slight nausea or headache. The single dose of alpelisib increased the fasting insulin level nearly five-fold compared to individuals who received the placebo. Interestingly, blood sugar did not increase significantly in the fasting state, as participants were able to mount a sufficient insulin response. Similarly, during the oral glucose tolerance test, we saw massive increases in insulin in the alpelisib-treated group relative to the control group but no statistically significant overall increase in blood sugar.
This study demonstrates that a single dose of alpelisib produced evidence of insulin resistance and was well tolerated. Our goal is to now apply the model from this study to conduct more detailed metabolic research.
Acute inhibition of PI3K with alpelisib can be used for mechanistic studies of insulin resistance in humans and will allow us to gain insight into how insulin resistance causes its complications.
— Dr. Joshua Cook
Future Implications
We concluded that acute inhibition of PI3K with alpelisib can be used for mechanistic studies of insulin resistance in humans, which we believe will allow us to gain insight into how insulin resistance leads to its complications. We are currently studying the dynamic metabolic effects of PI3K inhibition using stable isotope tracers, so that we're not only looking at the overall effect of the drug, but how that effect occurs. This is the mechanistic insight that we were hoping to achieve.
As an endocrinologist and physician-scientist, what I ultimately care about is, “How is this going to affect my patients?” Although basic-science research is obviously crucially important, it doesn't quite give that direct peek into human systemic physiology that you can only get by doing these human-subject studies. My goal is to repopularize mechanistic work in humans because I believe it is extremely valuable.
