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Gerald I Shulman, MD, PhD, MACP, MACE, FRCP

George R. Cowgill Professor of Medicine (Endocrinology) and Professor of Cellular And Molecular Physiology; Co-Director, Yale Diabetes Research Center, Internal Medicine

Gerald Shulman, MD, PhD, has long been fascinated by diabetes and metabolism. As a young boy attending a summer camp for children with diabetes where his father was the camp physician, he was struck by his fellow campers lining up for their insulin shots. In college, while studying biochemistry and physiology, he got hooked on the intricacies of metabolism. He came to Yale in 1983 as a postdoctoral fellow in order to use NMR spectroscopy to study biochemistry in humans in real time.

Today, he is known for pioneering the use of in vivo NMR spectroscopy to study glucose and lipid metabolism in both humans and rodents. Leading an interdisciplinary team of chemists, NMR spectroscopists, cell biologists, clinical physiologists, electrical engineers, organic chemists, nutritionists and nurses, he is focused on understanding the mechanisms of insulin resistance. His research has led to the identification of fatty metabolites that build up in liver and muscle cells and trigger the insulin resistance that leads to type 2 diabetes. “It’s not so much how much fat we have that leads to insulin resistance and diabetes, it’s the intracellular accumulation that causes problems,” he said.

His research, which utilizes such CTSA-supported resources as the Hospital Research Unit and the Magnetic Resonance Research Center, has led to major advancements in our understanding of the mechanisms underlying diabetes. His team found that treatment with leptin, a hormone that controls feelings of fullness, reverses hyperglycemia in rats with poorly controlled type 1 and type 2 diabetes. While previous studies had shown that leptin lowered plasma glucagon, a hormone that raises blood sugar levels, Shulman’s group found that leptin actually inhibits the hypothalamic-pituitary-adrenal axis, a major neuroendocrine pathway that controls the body’s reaction to stress and regulates digestion, energy storage, and metabolism.

Dr. Shulman and his colleagues identified the molecular mechanism by which insulin inhibits glucose production by the liver and why this process stops working in patients with type 2 diabetes. They showed that acetyl CoA is a key molecule in regulating the conversion of amino acids and lactate to glucose and that reversal of this process, due to inflammation in fatty tissue, leads to increased hepatic glucose production in rats and humans. “None of the drugs we currently use to treat type 2 diabetes target the root cause,” he said. “By understanding the molecular basis for hepatic insulin resistance we now can design better and more effective drugs for its treatment.”

Studying the effects of mitochondrial protonophore 2,4-dinitrophenol (DNP), a weight loss agent that is known to be toxic, Dr. Shulman found that its toxicity was related to its peak plasma concentrations. He showed that reformulating it can safely reverse nonalcoholic fatty liver disease (NAFLD) and reduce blood glucose, triglyceride and insulin concentrations in rodents with NAFLD and type 2 diabetes. He went on to develop a new oral, controlled-release form of DNP known as CRMP, which is equally effective with no adverse effects. The next step will be to translate these findings so that this approach can be used to safely and effectively treat patients with diabetes.