For 35 years, Gerald I. Shulman, MD, PhD, FACP, MACE, and his research colleagues have maintained an intense focus on the idea that understanding the molecular basis for insulin resistance in the muscles and liver could lead to effective diabetes therapies.
Dr. Shulman, the 2018 Banting Medal for Scientific Achievement recipient, discussed his lab’s ongoing research after accepting the Banting Medal Sunday morning at the Scientific Sessions.
Understanding normal glucose metabolization is the first step toward understanding hyperglycemia’s cause, said Dr. Shulman, the George R. Cowgill Professor of Medicine and Cellular and Molecular Physiology at Yale University School of Medicine and Co-Director of the Yale Diabetes Research Center.
In type 2 diabetes, the glucose-insulin interplay becomes amiss when insulin cannot promote glucose uptake by muscle and suppress glucose production in the liver. This leads to a reduction of beta cell function along with subsequent fasting and postprandial hyperglycemia.
“In this regard, I think it’s fair to say that most of the drugs that we currently use to treat type 2 diabetes treat the symptom, which is hyperglycemia, but not the root cause, which is insulin resistance,” Dr. Shulman said.
Seeking to understand the role that muscle glycogen synthesis plays in the process, Dr. Shulman and his team use nuclear magnetic resonance spectroscopy, which allows for noninvasive assessment of intracellular metabolism, to gain a better understanding of insulin resistance in the liver and muscle.
“We found that insulin- stimulated muscle glycogen synthesis accounted for virtually all of the infused glucose in control subjects and that insulin-stimulated muscle glycogen synthesis was severely impaired in patients with type 2 diabetes,” Dr. Shulman said. “More importantly, we found that this defect in insulin-stimulated muscle glycogen synthesis was the major factor responsible for muscle insulin resistance in type 2 diabetes.”
Dr. Shulman shared his working model of how insulin regulates hepatic glucose metabolism. It starts with a direct effect of insulin through insulin signaling pathway activation to regulate hepatic glucose metabolism, mostly by glycogen synthesis stimulation.
Lipolysis suppression in the peripheral fat tissue, as well as in the liver, results in a reduction of hepatic acetyl CoA (acetyl coenzyme A) content. That leads to a reduction in hepatic pyruvate carboxylase activity and glucogenesis, he explained.
“If you’re studying insulin action following a relatively short-term fast, when hepatic glycogenolysis is the major contributor to hepatic glucose production, the direct effects of insulin on hepatic glycogen metabolism will predominate,” Dr. Shulman said. “In contrast, if you are studying insulin action following a longer-term fast or following high-fat feeding, when gluconeogenesis is the major contributor to glucose production, then the indirect effects of insulin action on hepatic glucose metabolism will predominate.”
Researchers are working to identify the specific molecular triggers responsible for the dysregulated hepatic glucose metabolism associated with type 2 diabetes in hopes of offering a roadmap to novel treatments.
“According to this model, the key mediators leading to hepatic insulin resistance and increased rates of gluconeogenesis are increased hepatic diacylglycerol content and acetyl CoA content,” Dr. Shulman said. “If we can find a way to reduce these metabolites, we should be able to reverse diabetes.”
One approach promotes increased rates of hepatic mitochondrial fat oxidation through liver-targeted mitochondrial uncoupling. By reducing liver fat, Dr. Shulman said, liver-targeted mitochondrial uncoupling also reversed liver inflammation in three rodent models of nonalcoholic steatohepatitis (NASH), along with liver fibrosis in a rat model of cirrhosis.
“Of course, the next step will be safety and efficacy studies in humans, but I am hopeful that this approach will lead to a new class of therapeutic agents for type 2 diabetes and NASH in the near future,” Dr. Shulman said.