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Diabetes Treatment and Research at Yale: 30 Years of Progress

July 19, 2022
by Ashley P. Taylor

The New England Journal of Medicine reported an important finding in 2019 from a Yale-led clinical trial: for the first time, researchers showed that a drug, teplizumab, could delay the development of type 1 diabetes by two years.

Kevan Herold, MD, C.N.H. Long Professor of Immunology and professor of medicine (endocrinology), and the principal investigator of the trial, said teplizumab likely will be FDA-approved in mid-November for people who are at high risk of diabetes, not only those with a family history of the disease. Once approved, all children should be screened for diabetes risk so that those at high risk will have a chance to prevent or at least delay the disease, Herold said.

Any delay in the onset of a chronic disease is valuable, Herold said. “If you’re eight years old, and you delay diabetes by two years or longer, that’s a long time,” he said. “Kids become more mature. They’re better able manage the disease.”

The teplizumab trial is just one example of how Yale School of Medicine is a leader in the study and treatment of diabetes. At the Yale Diabetes Research Center, founded in 1993, researchers work to better understand type 1 and type 2 diabetes. At the Yale Diabetes Center, founded in 1994, physicians translate that knowledge into patient treatments.

An estimated 34.2 million people in the U.S., or 10.5% of the population, have diabetes. Characterized by abnormally high blood sugar levels, diabetes occurs when the body cannot make or becomes resistant to insulin, which the body’s cells need to take in and store blood sugar, called glucose. To manage their blood sugar, people with diabetes must take insulin and watch what they eat. Complications of type 1 and type 2 diabetes can include cardiovascular disease, as well as eye, foot, and kidney problems.

Preventing type 1 diabetes

The Yale Diabetes Research Center, funded by the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK), is one of 16 NIDDK-funded diabetes research hubs nationwide. Researchers investigate type 1 and type 2 diabetes in children and adults and gestational diabetes. They also study the immunobiology of diabetes, cell and vascular biology, and obesity. The center is the site of 23 NIH-funded diabetes clinical trials.

In people with type 1 diabetes, the body mounts an autoimmune attack against the pancreas cells that produce insulin. Teplizumab is an antibody that counteracts that response and will be the first drug that prevents an autoimmune disease. “We’re very excited about that,” said Herold, co-director of the Yale Diabetes Research Center.

In Herold’s trial, 76 participants who were at high risk for type 1 diabetes and had diabetic relatives, were randomly assigned to take teplizumab or a placebo for two weeks. They took periodic glucose tolerance tests until they developed diabetes, or the trial ended. By the trial’s end, 57% of participants who received teplizumab were diabetes free, compared with 28% of those who received the placebo.

The results of the trial represent a paradigm shift for autoimmune research, Herold said. If diabetes can be prevented, perhaps other autoimmune diseases, such as rheumatoid arthritis or multiple sclerosis, can be, too. Herold is hopeful that researchers “can begin to shift the way we think about these widespread diseases and find people who are going to develop them and stop the disease before it actually happens.”

Insulin Resistance in type 2 Diabetes

Gerald I. Shulman, MD, PhD, MACP, MACE, George R. Cowgill Professor of Medicine (endocrinology) and professor of cellular and molecular physiology, and co-director of the Yale Diabetes Research Center, has spent the past 30 years investigating what causes insulin resistance and type 2 diabetes.

Shulman and colleagues began investigating these findings using nuclear magnetic resonance spectroscopy (NMR), combined with stable isotopes as a noninvasive way to trace metabolic flux in an organ-specific fashion in humans and transgenic rodents. They found insulin resistance in muscle could be attributed to reduced insulin-stimulated glucose transport and that people with insulin resistance have fat stored in places in their body, such as the liver and muscle, where fat is normally not stored.

“It’s really not how much fat a person has that drives insulin resistance, it’s where the fat is stored,” Shulman explained. “When fat is stored ectopically, in liver and skeletal muscle, that’s what drives insulin resistance and leads to the development of metabolic syndrome, cardiovascular disease, and type 2 diabetes. The most striking example are patients with lipodystrophy. They have virtually no fat but are profoundly insulin-resistant due to fat accumulation in their liver and muscle cells. When we treat them with leptin, the fat in these organs disappears and their insulin resistance and diabetes resolves.”

As reported in a 2007 paper in the journal PNAS, a study led by Kitt Petersen, MD, professor of medicine (endocrinology), found that in lean people with insulin resistance -- but who did not yet have diabetes -- the liver accumulated unusually large amounts of fat. The study also found that fat built up in the blood of insulin-resistant subjects, setting the stage for cardiovascular disease. In 2022, Petersen published a paper in JCI Insight that showed that even lower liver fat content than previously believed is associated with insulin resistance and increased cardiometabolic risks.

However, the researchers also have found that diet and exercise can combat both ectopic fat storage and insulin resistance. A 2011 PNAS article from Shulman’s group found that in lean, insulin-resistant but non-diabetic people, 45 minutes of leg exercise led skeletal muscle to respond to insulin again and decreased liver fat storage after a meal. In a 2005 study led by Petersen and published in the journal Diabetes, obese, diabetic patients who lost about 10% of their body weight saw their diabetes and insulin resistance go away and their liver fat return to normal levels.

Shulman’s group has elucidated the molecular basis for lipid-induced insulin resistance in liver, skeletal muscle, and white adipose tissues, which has led to several new drugs for NAFLD/NASH and type 2 diabetes. One of these new drugs rids the liver of its excess fat. The drug, a controlled-release mitochondrial protonophore (CRMP), revs up the mitochondria in the liver, causing them to burn more fat. Studies have shown that CRMP can totally reverse these conditions, and CRMP is undergoing IND enabling studies.

Improving Diabetes Treatments

The increased risk of cardiovascular problems for diabetes patients remains even when patients control their blood sugar, said Silvio Inzucchi, MD, professor of medicine (endocrinology) and medical director of the Yale Diabetes Center.

“Even though it's intuitive to think that good control of diabetes could mitigate those complications, that actually does not end up to be so,” Inzucchi said. “It's been a little bit of a conundrum as to why, if you fix the major underlying problem with diabetes, can't you decrease the rates of these complications. This has been one of my interest areas for many years.”

Two relatively new classes of type 2 diabetes drugs can mitigate cardiovascular symptoms while helping control blood sugar. In 2015, Inzucchi and colleagues reported in the New England Journal of Medicine that type 2 diabetes patients randomly assigned to the type 2 diabetes drug empagliflozin had a lower risk of dying from cardiovascular causes than those assigned to the placebo. Empagliflozin, which the FDA approved in 2014, is an SGLT2 inhibitor. SGLT2 inhibitors reduce blood sugar by causing the kidneys to release more glucose into the urine. The drug also decreases the risk of kidney problems, Inzucchi said.

A different class of type 2 diabetes drug, the GLP-1 receptor agonists, has also been associated with reductions in cardiovascular complications as well as significant weight loss, Inzucchi said. GLP-1 receptor agonists stimulate the body to produce more insulin but also do several other things like reducing appetite, leading to weight loss. William Tamborlane, MD, professor of pediatrics (endocrinology), led the study, published in the New England Journal of Medicine in 2019, leading to the pediatric indication of one such GLP-1 receptor agonist, liraglutide, for youth with type 2 diabetes.

“Between those two drug classes, we now have solid evidence that these medications can not only lower the glucose to help with diabetes control, but also prevent heart complications of diabetes,” Inzucchi said. With these multi-functional drugs, clinicians at the Yale Diabetes Center can tailor diabetes treatment regimens to patients’ needs, Inzucchi added. “That’s been a real sea change in our field.”

Additionally, a novel GIP/GLP-1 receptor agonist, tirzepatide, was recently shown to be extremely effective for weight loss. People with obesity treated with tirzepatide lost about 52 pounds on average, according to results of a study that were published in the New England Journal of Medicine. Ania Jastreboff, MD, PhD, associate professor of medicine (endocrinology) and pediatrics (pediatric endocrinology), was the lead author of the study.

Advances in Technology

Diabetes used to be a disease of daily shots: fingersticks to check blood sugar, then injections of insulin. But according to Inzucchi, the toolkit he and his colleagues have for helping type 1 and type 2 diabetes patients has expanded in recent years.

“For type 1 diabetes, I think the major advancement has been the technology,” Inzucchi said. In 2016, for example, the FDA approved a device that measures patients’ blood sugar levels every five minutes through a continuous glucose monitor and sends the information to a pump that delivers insulin accordingly. The system, called a hybrid closed loop insulin delivery system because the person with diabetes still needs to take a bolus of insulin before a meal, is connected to patients 24/7 and allows for more physiologic insulin delivery, Inzucchi said. Stuart Weinzimer, MD, professor (pediatric endocrinology and diabetes) and the interim chief of pediatric endocrinology, led the Yale site of the trial that led to this device’s approval. Tamborlane, chief of pediatric endocrinology for over 37 years, guided pioneering studies in the development of insulin pump therapy, continuous glucose monitors, and automated insulin delivery systems. Weinzimer also has conducted longitudinal studies characterizing the effects of diabetes on brain development in youth with type 1 diabetes.

Pediatric Partners

Jennifer Sherr, MD, PhD, professor in pediatrics (endocrinology), Michelle Van Name, MD, assistant professor of pediatrics (endocrinology), and Laura Marie Nally, MD, assistant professor of pediatrics and of pediatric endocrinology and diabetes, are national leaders in helping youth with type 1 diabetes to manage this chronic medical condition. They have conducted continued work on new automated insulin delivery systems and new treatments for type 1 diabetes. Sonia Caprio, MD, professor of pediatrics (endocrinology), has studied obesity and type 2 diabetes for 25 years, and her work has brought the magnitude of the childhood obesity problem to national attention. Stephanie Samuels, MD, instructor of pediatrics has also focused her work on the care of youth with type 2 diabetes.

Submitted by Jane E. Dee on July 19, 2022