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Turning the tide on type 2 diabetes

Medicine@Yale, 2010 - May June


Work on insulin resistance sparks researcher’s hopes for prevention and a cure

Gerald I. Shulman, M.D., Ph.D., a world-renowned authority on diabetes, says he can’t remember a time when he wasn’t interested in science and medicine. He was partly inspired by his father, a Detroit physician who occasionally took the younger Shulman on hospital rounds. But as a biophysics major at the University of Michigan, Shulman “fell in love with physics and biochemistry,” he says, and knew that research would figure prominently in his career.

After his second year of medical school at Wayne State University, Shulman took a break to study in the laboratory of Alan D. Cherrington, Ph.D., at Vanderbilt University School of Medicine. There, Shulman administered the newly discovered hormone somatostatin to animals to suppress the pancreatic secretion of glucagon and insulin, allowing him to eliminate the effects of these two hormones and show that the amount of glucose produced by the liver can be affected by changes in blood glucose levels alone.

Following a residency in internal medicine at Duke University Medical Center, Shulman did his endocrine fellowship training at Massachusetts General Hospital. During the research portion of the fellowship, he studied the insulin receptor but he was keen to return to studies of metabolism in animals, such as those he had done at Vanderbilt.

Fortuitously, magnetic resonance spectroscopy (MRS) was just beginning to blossom. Based on the same principles as MR imaging, MRS allows scientists to noninvasively create precise, real-time chemical profiles of small regions of tissue in live animals, including humans. For Shulman, who was searching for a noninvasive method to study intracellular metabolism in living systems, MRS was the answer. In 1984 he persuaded his Mass General mentors to let him travel to Yale to complete his fellowship, since Robert G. Shulman, Ph.D. (no relation), an MRS pioneer, had just joined the faculty. “It’s been 25 years,” jokes Shulman, who has been at Yale ever since, and is now the George R. Cowgill Professor of Physiological Chemistry. “And they keep asking me when I’m coming back.”

In two decades of research that has earned him election to the National Academy of Sciences and many other honors, Shulman, also professor of medicine and of cellular and molecular physiology, and a Howard Hughes Medical Institute investigator, has combined MRS studies of patients with experiments using transgenic mice to elucidate the mechanisms of insulin resistance, the metabolic dysfunction at the core of type 2 diabetes.

His group has found that insulin resistance in muscle is mainly caused by defective insulin-stimulated glucose transport, which reduces glycogen synthesis. On the other hand, increased synthesis of glucose from amino acids and lactate in the liver is the main cause of the fasting hyperglycemia seen in type 2 diabetes.

In a novel unifying hypothesis of insulin resistance, Shulman and colleagues have proposed that an imbalance between the delivery and oxidation of fatty acids in liver and muscle cells causes biochemical changes that block insulin signaling. Recently his group identified two common genetic variants that predispose individuals to nonalcoholic fatty liver disease (NAFLD) and insulin resistance, providing new insights into gene–environment interactions that promote the development of type 2 diabetes. His work is revealing new drug targets and exercise and dietary strategies to “melt fat away” from liver and muscle, which will reverse insulin resistance and prevent type 2 diabetes.
Shulman is optimistic that type 2 diabetes—an illness that is the leading cause of blindness, end-stage renal disease, and nontraumatic loss of limbs in the U.S., currently costing the U.S. economy more than $180 billion annually—will be beaten. “Just about every drug that we currently have to treat type 2 diabetes was discovered serendipitously,” he says, “and just treats the symptom of diabetes: hyperglycemia. Now that we are beginning to understand the cellular mechanisms of insulin resistance, which is at the root of type 2 diabetes, we have better therapeutic targets, and I’m quite excited about it.”