In Gerald Shulman’s Lab, Work Focuses on Reversing Insulin Resistance in Diabetes

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Insulin resistance causes type 2 diabetes, which is increasing worldwide. Insulin resistance is also a major factor in the pathogenesis of cardiometabolic diseases. According to the World Health Organization, diabetes is the most pressing non-communicable disease worldwide. Diabetes leads to high levels of 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, Dr. med. Gerald I. Shulman, PhD, MACP, MACE, studying the molecular basis for insulin resistance and developing goals for its treatment and healing. His lab at the Yale School of Medicine looked at lipid-induced insulin resistance in the liver, skeletal muscle and, more recently, in white adipose tissue (WAT) – fat.

Through this work, Shulman and his team have shown that fat cells become insulin resistant by a mechanism similar to that of lipid-induced insulin resistance in the liver and skeletal muscle. His results promise a reversal of insulin resistance not only in the liver and skeletal muscle, but also in the adipocytes. “I think that 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, and to young, lean, insulin-resistant people who are at high risk of developing type 2 diabetes. His team has also explored ways to reverse insulin resistance using agents that lower the lipids in the plasma membrane of the liver, skeletal muscle, and fat. Shulman recently published an article in JCI Insight explaining this study and the mechanism by which weight loss and liver-directed mitochondrial uncouplers reverse insulin resistance in mice and rats.

His research team is now investigating the same mechanisms that explain insulin resistance in the kidney, aorta and other tissues. “I think this will be a new paradigm for lipid-induced insulin resistance in multiple organs,” he said.

Diabetes is a leading cause of blindness, end-stage kidney disease, and non-traumatic limb loss. “One of the main drivers of type 2 diabetes pathogenesis is insulin resistance,” Shulman said. “We see this in young people with a family history of type 2 diabetes as well as in the elderly. And although obesity is strongly linked to insulin resistance in diabetes, we see insulin resistance in lean individuals, especially those with lipodystrophy who have no fat. ”

“I think one of the interesting things about this recent study is that it shows that the same mechanism for lipid-induced insulin resistance that we described in the liver and skeletal muscle also occurs in adipose tissue. “If we can figure out how to fix this step, we can reverse insulin resistance not only in the liver and muscles, but also in adipocytes.”

In previous studies, Shulman and his team identified these lipids in cells called diacylglycerol as key players in lipid-induced insulin resistance. “It’s the penultimate step in triglyceride synthesis,” he said.

His laboratory found that the key metabolite is a specific stereo isoform of diacylglycerol, the sn-1,2 isoform, which is responsible for mediating insulin resistance in the liver and skeletal muscle.

“Although most of the fat in the fat cell is in a lipid droplet, no one has really carefully studied the diacylglycerol content in the membrane that surrounds the fat droplet,” Shulman said. They found that only 1% of all diacylglycerols are in the plasma membrane. “But it turns out that those 1% cause 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 associated with WAT dysfunction, one aspect of which is insulin resistance,” he said.

His laboratory’s data show that this molecular pathway not only plays an important role in mediating lipid-induced WAT insulin resistance, but also indicates a potential therapeutic target for improving insulin sensitivity in WAT.

With regard to the liver, his laboratory is also working on ways to increase the energy consumption of the mitochondria. They have developed new agents to promote increased mitochondrial activity in a liver-related manner, “to metabolize these diacylglycerols and reverse insulin resistance in rodent and non-human primate models of non-alcoholic fatty liver disease and type 2 diabetes.”