How to Reverse Insulin Resistance

Gerald I. Shulman, MD, PhD, George R. Cowgill Professor of Medicine (Endocrinology) and Cellular and Molecular Physiology, Investigator Emeritus of the Howard Hughes Medical Institute, and co-director of the Yale Diabetes Research Center, studies the molecular basis for insulin resistance, a condition found in approximately forty percent of U.S. adults.

“One of the major threats to global health in the 21st century, insulin resistance is a key factor in the development of type 2 diabetes, cardiovascular disease, fatty liver disease, neurogenerative disease, and obesity-associated cancers,” Shulman said. “Understanding the molecular basis for insulin resistance can lead to novel therapies that help prevent these diseases.”

Shulman is the recipient of numerous awards, including the American Diabetes Association’s Banting Medal for Scientific Achievement, the European Association for the Study of Diabetes-Lilly Centennial Anniversary Prize, the American Society of Clinical Investigation’s Stanley J. Korsmeyer Award, and the Endocrine Society’s Outstanding Clinical Investigator Award. Most recently, he was selected for the Bodil M. Schmidt-Nielsen Distinguished Mentor and Scientist Award, which recognizes a member of the American Physiological Society who has made outstanding contributions to research and to training the next generation of physiologists.

In a Q&A, Shulman discusses the basics of insulin resistance, how the condition impacts our health, and the steps we can take to reverse it.

The hormone insulin, which is produced by the pancreas, regulates blood glucose, or sugar from the food we eat, by allowing it to enter the body’s cells, where it is used for energy. Insulin resistance—found in both lean and overweight individuals—is when the body’s cells don’t effectively respond to insulin and take in glucose, leading to high blood sugar levels.

My lab has found that insulin resistance in liver and skeletal muscle, the organs where insulin normally promotes glucose storage as glycogen, is linked to increased ectopic lipid accumulation, or fat accumulation inside the liver and muscle cells.

Why has evolution preserved insulin resistance, something we think of as a deleterious process? It turns out insulin resistance is activated during starvation. During starvation, your body breaks down stored lipid in the white adipose tissue, which becomes mobilized and leads to fat accumulation in liver and muscle cells. These organs become insulin-resistant, which in turn preserves glucose in the bloodstream to fuel brain metabolism and other obligatory glucose-requiring cells in the body (e.g., red blood cells). In this way, insulin resistance is a normal physiological process that has promoted survival from starvation in mammals throughout evolution.

But now, insulin resistance is activated by overnutrition in our toxic food environment.

Insulin resistance is the major reason people go on to develop type 2 diabetes. The condition also results in metabolic dysfunction-associated steatotic liver disease, in which the body stores excess fat in the liver, and steatohepatitis, which can progress to end-stage liver disease and liver cancer. Muscle insulin resistance also leads to increased plasma triglycerides and LDL, the bad cholesterol, which are major contributors to heart disease.

Insulin resistance is also associated with obesity-related cancers. When you’re insulin resistant, your pancreas produces more insulin, which promotes tissue growth. In preclinical studies, my collaborators and I have shown that insulin resistance promotes the growth of breast and colon cancers.

Finally, insulin resistance is likely a major driver of Alzheimer’s disease.

Our research has shown that modest weight reduction due to caloric restriction to about 1,200 calories a day leads to a reduction of liver fat and reversal of liver insulin resistance and type 2 diabetes. You don’t have to get down to the weight you were in high school—a 10% weight reduction can make a big difference. This is also likely the major mechanism by which the new GLP-1 agonist medications are working to reverse type 2 diabetes.

We have also learned that exercise opens the door for glucose transport into the muscle cell, bypassing the block in insulin action. If you have muscle insulin resistance, you can normalize the storage of ingested carbohydrate into the muscle as glycogen, decreasing the conversion of carbohydrate to fat in the liver. This, in turn, leads to protection from the development of fatty liver disease and improvement in the plasma lipid profile, which will protect against the development of atherosclerosis.

I encourage my patients with diabetes or prediabetes to find a physical activity they like to do every day and stick with it.

As we deepen our understanding of the molecular basis of insulin resistance and develop new drugs to target this mechanism, I’m optimistic about the future of treating insulin resistance and improving cardiometabolic health.

Yale School of Medicine’s Section of Endocrinology and Metabolism works to improve the health of individuals with endocrine and metabolic diseases by advancing scientific knowledge, applying new information to patient care, and training the next generation of physicians and scientists to become leaders in the field. To learn more, visit Endocrinology & Metabolism.