Gerald I. Shulman

Gerald I. Shulman, MD, PhD, MACP, MACE, FRCP, is an American physician-scientist specializing in endocrinology and metabolism. He is the George R. Cowgill Professor of Medicine (Endocrinology) and Professor of Cellular and Molecular Physiology at the Yale School of Medicine. Shulman also serves as Co-Director of the Yale Diabetes Research Center.

Shulman earned a Bachelor of Science degree in biophysics from the University of Michigan in 1974, graduating with high honors and distinction. He received both his M.D. and Ph.D. in physiology from Wayne State University in 1979. He completed his clinical and research fellowship in medicine at Massachusetts General Hospital from 1981 to 1984.^[1]

Shulman began his academic career at Harvard Medical School, where he served first as an instructor and then as an assistant professor of medicine from 1984 to 1987.

In 1987, he joined the faculty at Yale University as an assistant professor of medicine. He was promoted to associate professor in 1989 and, since 1996, has held a full professorship in both internal medicine and cellular and molecular physiology. Between 1987 and 1993, he also held a concurrent appointment as a lecturer in Yale's Department of Molecular Biophysics and Biochemistry.^[2]

In 2009, Shulman was named the inaugural George R. Cowgill Professor of Physiological Chemistry at Yale University,^[3] a position he continues to hold. He served as Associate Director of both the Yale Diabetes Endocrinology Research Center and the Yale Medical Scientist Training Program from 1992 to 2012.^[4] In 2012, he became Co-Director of the Yale Diabetes Research Center.

In addition to his academic roles, Shulman has served on the editorial boards of several prominent journals, including Journal of Clinical Investigation, Cell Metabolism,^[5] Science Translational Medicine,^[6] and Proceedings of the National Academy of Sciences.^[7] He was also an Investigator at the Howard Hughes Medical Institute, where he now holds the title of Investigator Emeritus.^[8][9]

In his research, Shulman has investigated the pathophysiology of type 2 diabetes (T2D),^[10][11] insulin resistance, and related metabolic conditions,^[12] with a focus on the use of in vivo nuclear magnetic resonance (NMR) and magnetic resonance spectroscopy (MRS). At Yale School of Medicine, Shulman has led investigations into glucose and lipid metabolism in humans and rodent models.

Shulman's laboratory applied NMR techniques to measure hepatic and muscular glucose metabolism in vivo, which enabled real-time, noninvasive assessments of metabolic processes. His early studies identified defects in insulin-stimulated muscle glycogen synthesis, attributed to reduced glucose transport activity, in individuals with T2D. Subsequent research extended these observations to individuals with prediabetes and indicated that exercise could improve insulin sensitivity.^[13][14]

He also reported that intramyocellular lipid content, as measured by 1H NMR, is associated with insulin resistance in both adults and children.^[15] His work proposed that insulin resistance is mediated by the accumulation of diacylglycerol (DAG) in the plasma membrane. This accumulation is associated with the activation of novel protein kinase C (nPKC) isoforms, including PKCθ in skeletal muscle and PKCε in the liver, which may impair insulin signaling pathways.^[16]

Shulman's group reported that hepatic insulin resistance in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) is similarly associated with increased DAG content and PKCε activation. His research suggested that sn-1,2-DAGs in the plasma membrane compartment may be mediators of insulin resistance across liver, skeletal muscle, and white adipose tissue.^[17]

Further studies from his laboratory examined therapeutic strategies to address insulin resistance. These included weight reduction and treatments with GLP-1 receptor agonists, thiazolidinediones, adiponectin, and mitochondrial protonophores. These interventions were observed to improve mitochondrial function and alter lipid metabolism, which supports a model where imbalances in fatty acid delivery and oxidation may lead to insulin resistance via DAG accumulation and nPKC activation.^[18]

To investigate mitochondrial contributions to metabolic dysfunction, Shulman developed NMR-based methods to assess ATP synthesis and mitochondrial oxidation in vivo. His studies observed age-related declines in mitochondrial fat oxidation, which were suggested to contribute to lipid accumulation and insulin resistance. He also identified similar impairments in lean, insulin-resistant individuals with a family history of T2D.

Using 13C NMR, Shulman quantified hepatic glycogenolysis and gluconeogenesis in humans. His research indicated that gluconeogenesis accounts for over half of hepatic glucose production after an overnight fast, differing from earlier estimates. He further investigated the respective roles of insulin and glucose in regulating glycogen metabolism and hepatic glucose output.^[19]

In studies examining hepatic fat oxidation using 13C MRS, Shulman observed no significant impairment in individuals with MASLD. Based on these findings, liver-targeted mitochondrial protonophores were developed, which were observed to reduce hepatic steatosis, insulin resistance, and fibrosis in rodent and nonhuman primate models. These compounds have entered clinical evaluation.^[20]

Shulman's work has also investigated the effects of adiponectin, leptin, fibroblast growth factors (FGF-1, FGF-19, FGF-21), and metformin on hepatic glucose metabolism. His group investigated mechanisms underlying selective hepatic insulin resistance and indicated that adipose tissue lipolysis and inflammation may increase hepatic acetyl-CoA concentrations, potentially enhancing gluconeogenesis in T2D.^[21]

More recently, his laboratory developed the Positional Isotopomer NMR Tracer Analysis (PINTA) method to assess hepatic mitochondrial fluxes in vivo. This method has been used to study the metabolic effects of caloric restriction, leptin signaling, the glucose-alanine cycle, and glucagon signaling through the IP3R1 receptor and CaMKII.^[22]

• Elected member of the American Society for Clinical Investigation (1990)^[23]
• Outstanding Scientific Achievement Award, American Diabetes Association (1997)^[24]
• Elected to the National Academy of Sciences (2007)^[25]
• Stanley J. Korsmeyer Award, American Society for Clinical Investigation (2008)^[26]
• AAAS Fellow (2009)^[27]
• Banting Medal for Lifetime Scientific Achievement, American Diabetes Association (2018)^[28]
• Elected to the American Academy of Arts and Sciences (2018)^[29]
• Samuel Eichold II Memorial Award, American College of Physicians (2020)^[30]
• Manpei Suzuki International Prize for Diabetes Research (2021)^[31]
• Master of the American College of Physicians (2021)^[32]
• Fellow of the Royal College of Physicians (2021)
• EASD-Lilly Centennial Anniversary Prize for Landmark Discoveries in Diabetes, European Association for the Study of Diabetes (2023)^[33]