Medicine and Translational Research, Physiology
Dr. Shulman is also George R. Cowgill Professor of Physiological Chemistry and a professor of internal medicine and of cellular and molecular physiology at Yale School of Medicine.
Cellular Mechanisms of Insulin Resistance
Gerald Shulman first became acquainted with diabetes as an eight-year-old attending summer camp in Michigan. The camp was devoted to children with diabetes, and his father was the camp physician.
"Watching my fellow campers line up for urine samples and insulin shots every morning, abstaining from sugar, and occasionally losing consciousness from hypoglycemia or ketoacidosis left an indelible impression on me regarding the lifelong struggle these individuals have living with this chronic disease," he says.
To better help those afflicted with diabetes, Shulman has spent the past 30 years identifying the biochemical steps that go awry in patients with this disease. His effort has led to new understanding of insulin resistance, a major factor in the development of type 2 diabetes mellitus (T2DM), the most common form of diabetes.
Insulin is a hormone that enables glucose to enter cells, where it is used for energy or stored in another chemical form, such as glycogen. Insulin resistance is a condition in which the body does not respond properly to insulin.
One of Shulman’s major contributions to understanding T2DM is his pioneering use of noninvasive nuclear magnetic resonance (NMR) spectroscopy to study intracellular glucose and fat metabolism and the pathogenesis of insulin resistance in patients with T2DM. Earlier methods to monitor the concentrations of biochemical metabolites inside patients' muscle cells typically required biopsies, which, besides being painful and invasive, did not provide real time information regarding the metabolic flux of substrate through a biochemical pathway.
With NMR spectroscopy, volunteers lie in a magnet and radio frequency waves are bounced off the organ (liver, muscle, brain) being examined. A surface coil picks up these radio frequency emissions, which are transformed by a computer into a chemical spectrum that yields the concentration of various biochemicals in the tissue.
Shulman used NMR sprectroscopy in combination with stable (nonradioactive) naturally occurring isotopes of glucose to measure the synthesis of muscle glycogen in humans in vivo for the first time. He found that defects in insulin-stimulated muscle glycogen synthesis are the major cause of insulin resistance in patients with T2DM. He also showed that a glucose transport problem is responsible for the lower insulin-stimulated muscle glycogen synthesis rates in these patients. If glucose cannot enter the cell, it builds up in the blood, leading to the chronic complications of diabetes, such as blindness, kidney disease, and heart disease.
Shulman then used NMR to try to understand the cause of the reduced insulin-stimulated glucose transport in skeletal muscle of T2DM patients. Using a proton NMR technique, he found a strong relationship between fat inside the muscle cells and insulin resistance in skeletal muscle in both adults and children. Earlier, animal-based in vitro studies had shown that levels of fatty acids, a component of fat, can lead to insulin resistance by inhibiting a key enzyme involved in glucose oxidation. Using a multinuclear NMR approach, Shulman made the paradigm-shifting observation that fatty acids cause insulin resistance in human skeletal muscle by working on an entirely different molecular pathway.
“Raising plasma fatty acids in humans causes insulin resistance by increasing intracellular diacylglycerol content, which leads to activation of a serine kinase cascade involving activation of novel protein kinase Cs, which in turn inhibits insulin signaling in muscle,” Shulman says. His group found that the same mechanism is responsible for causing fat-induced insulin resistance in the liver. This condition, referred to as nonalcoholic fatty liver disease (NAFLD), occurs in virtually all patients with poorly controlled T2DM.
The good news for patients with T2DM is that his group has shown that NAFLD is entirely reversible with modest weight reduction. Weight loss of just 15–20 pounds results in a reduction of excess fat deposition in the liver, leading to a reversal of liver insulin resistance and normalization of fasting plasma glucose concentrations.
His results led Shulman to propose a unifying hypothesis for fat-induced insulin resistance: The net accumulation of intracellular diacylglycerol, due to increased fatty acid delivery/synthesis and/or reduced mitochondrial/peroxisomal fatty acid oxidation, leads to activation of the nPKC serine kinase cascade and decreased insulin signaling and insulin action in liver and skeletal muscle.
This hypothesis, Shulman says, explains insulin resistance in both obesity and lipodystrophy as well as the insulin-sensitizing effects of thiazolidinediones, exercise, leptin, omega fatty acids, mitochondrial-uncoupling agents, adiponectin, and acetyl CoA carboxylase inhibitors. It has also led to the identification of several novel targets for the treatment and prevention of type 2 diabetes.
Recently, Shulman began exploring the pathogenesis of the metabolic syndrome, which is characterized by a clustering of risk factors for cardiovascular disease that include insulin resistance, abdominal obesity, hypertension, and atherogenic dyslipidemia.
Metabolic syndrome is estimated to afflict 50 million Americans, and approximately half of all Americans are predisposed to it. Abdominal obesity and insulin resistance each have been hypothesized to be the primary factors causing metabolic syndrome; however, the biologic mechanisms underlying metabolic syndrome are not fully understood.
Using NMR spectroscopy to measure changes in glycogen and fat content in liver and skeletal muscle of young, lean insulin-resistant and insulin-sensitive individuals, Shulman has shown that insulin resistance in skeletal muscle due to decreased insulin-stimulated muscle glycogen synthesis, leads to a redistribution of glucose away from muscle glycogen synthesis toward increased fat production in the liver, increased plasma triglyceride (fat) concentrations, and a reduction in concentration of plasma high-density lipoprotein (HDL), the "good" cholesterol. Shulman is now exploring ways to reverse muscle insulin resistance to determine whether these methods can prevent the atherogenic dyslipidemia that puts these young individuals at risk to develop cardiovascular and cerebrovascular disease later in life.
Much headway has been made in understanding diabetes since Shulman went to summer camp. He remains hopeful that continued research about the causes of metabolic syndrome and diabetes will lead to identification of new targets for treatment and prevention of these conditions.