Insulin resistance causes type 2 diabetes, which is on the rise worldwide. Insulin resistance is also is a major factor in the pathogenesis of cardiometabolic disease. According to the World Health Organization, diabetes is the most urgent non-communicable disease across the globe. Diabetes leads to high LDL cholesterol, which in turn leads to heart disease, the leading cause of death for an estimated 17.9 million people worldwide each year.
For the past three-and-a-half decades, Gerald I. Shulman, MD, PhD, MACP, MACE, has been investigating the molecular basis for insulin resistance and developing targets for its treatment and cure. His lab at Yale School of Medicine has looked at lipid-induced insulin resistance in the liver, skeletal muscle, and recently in white adipose tissue (WAT) – the fat.
Through this work, Shulman and his team have shown that fat cells become insulin resistant through a similar mechanism to lipid-induced insulin resistance in the liver and skeletal muscle. His findings present the promise of reversing insulin resistance, not only in the liver and skeletal muscle, but also in the adipocytes. “I think this has important implications,” he said.
This general paradigm for lipid-induced insulin resistance applies to people with obesity, a common factor associated with type 2 diabetes, as well as in young, lean, insulin-resistant individuals who have a high likelihood of developing type 2 diabetes. His team also has investigated ways to reverse insulin resistance with agents that lower the lipids in the plasma membrane of the liver, skeletal muscle, and fat. Shulman recently published a paper in JCI Insight explaining this study as well as the mechanism by which weight loss and liver-targeted mitochondrial uncouplers reverse insulin resistance in mice and rats.
His research team is now looking at the same mechanisms for explaining insulin resistance in the kidney, the aorta and other tissues. “I think this will be an emerging paradigm for lipid-induced insulin resistance in multiple organs,” he said.
Diabetes is a leading cause of blindness, end-stage renal disease, and non-traumatic loss of limbs. “One of the major factors responsible for the pathogenesis of type 2 diabetes is insulin resistance,” Shulman said. “We see this in young individuals with a family history of type 2 diabetes as well as in the elderly. And even though obesity is strongly associated with insulin resistance in diabetes, we observe insulin resistance in lean individuals, especially in patients with lipodystrophy, who have no fat.
“I think one of the interesting aspects of this recent study is that it shows that the same mechanism for lipid-induced insulin resistance that we have described in liver and skeletal muscle also occurs in the adipose tissue. “If we can figure out how to fix this step, we can reverse insulin resistance, not only in liver and muscle, but in adipocytes.”
In previous studies, Shulman and his team identified these lipids within cells called diacylglycerol as important players in lipid-induced insulin resistance. “It's the penultimate step in triglyceride synthesis” he said.
His lab found that the key metabolite is a specific stereo-isoform of diacylglycerol, the sn-1,2 isoform, that is responsible for mediating insulin resistance in liver and skeletal muscle.
“Even though most of the fat in the fat cell is in a lipid droplet, no one really carefully looked at diacylglycerol content in the membrane which surrounds the fat droplet,” Shulman said. They found that only 1% of all the diacylglycerols is in the plasma membrane. “But it turns out that this 1% is what is causing insulin resistance in the fat cell,” he said.
“Obesity-related metabolic diseases, such as type 2 diabetes and non-alcoholic fatty liver disease, are often accompanied by WAT dysfunction, one aspect of which is insulin resistance,” he said.
His lab’s data demonstrate that this molecular pathway not only plays an important role in mediating lipid-induced WAT insulin resistance, but reveals a potential therapeutic target to improve insulin sensitivity in WAT.
Regarding the liver, his lab is also working on ways to increase energy expenditure of the mitochondria. They have developed new agents to promote increased mitochondrial activity in a liver-targeted manner “to metabolize these diacylglycerols and reverse the insulin resistance in rodent and non-human primate models of non-alcoholic fatty liver disease and type 2 diabetes.”