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Diabetes: Yale's tradition of transforming care

Yale Medicine Magazine, Autumn 2023 (Issue 171) Obesity Special Report
by Jenny Blair, MD


IN THE UNITED STATES, it’s highly likely that there is at least one person with diabetes on every bus and in every restaurant and workplace. This complex disorder of blood sugar regulation affects over 11% of the population. Both type 1 and type 2 diabetes can saddle people with a lifetime of thinking about blood sugars, navigating complex treatment regimens, and coping with dire complications.

“Diabetes is not part-time. It’s full-time,” said Kevan Herold, MD, C.N.H. Long Professor of Immunobiology and of Medicine (Endocrinology) at Yale School of Medicine. “If you have diabetes, there is nothing you do without thinking about it. You don’t go to sleep, you don’t wake up, you don’t eat anything, you don’t do any activity, you don’t go to school—diabetes is in every aspect of your life.”

Herold and his fellow immunology and endocrinology researchers at Yale have worked for decades to ease that burden. Through pioneering studies of insulin pumps, the development of a preventive drug, or elucidation of insulin resistance and its relationship—or not!—to obesity, advances made here have repeatedly changed how doctors and patients grapple with diabetes. Since 1993, investigators from diverse disciplines have received ongoing support for research focusing on diabetes and related metabolic and endocrine disorders at the Yale Diabetes Research Center.

Getting pumped

Insulin regulates blood sugar, and diabetes occurs when insulin is not doing its job. Either it’s absent, as in type 1 diabetes, in which the beta cells of the pancreas stop producing the hormone; or cells in the rest of the body stop responding to it normally, as in type 2 diabetes.

While insulin injections are just one among numerous treatment options for type 2, for type 1, they are absolutely necessary for survival—sometimes many a day.

This is no small task. Insulin is finicky and expensive, and getting the dose right can be tricky. In hopes of making insulin replacement easier on patients with diabetes, William Tamborlane, MD, professor of pediatrics (endocrinology), and his mentor, the late Robert S. Sherwin, MD, C.N.H. Long Professor Emeritus of Internal Medicine (Endocrinology), undertook pioneering work on insulin pumps. Their partnership spanned 40 years.

“For most of us, we don’t have to worry about how much insulin our body’s making,” Tamborlane said. Pumps can reduce that worry among people with diabetes by delivering a tailored response to glucose fluctuations; this feature can result in better glucose control and fewer long-term complications.

Tamborlane and Sherwin began working together in 1976. At the time, researchers were debating the roles played by insulin and the hormones glucagon and somatostatin in type 1 diabetes.

To untangle these relationships, Tamborlane suggested studying a multi-day infusion of somatostatin in children with type 1 diabetes. The researchers used a pump they had seen pediatrics colleagues use to treat children with iron overload. It had a button to deliver extra doses—handy at mealtimes for those with diabetes.

To be sure, researchers had been working on insulin pumps as long ago as the 1960s, but early versions were bulky and cumbersome. By the late ’70s, however, some, like the pediatricians who caught Tamborlane’s attention, had hit upon the expedience of adapting a pump designed to deliver hormones to animals. Grasping the possibilities, Tamborlane and Sherwin set out to study its use in humans with type 1 diabetes.

In 1979, they showed that a portable pump could reduce fluctuations in and normalize levels of blood glucose, normalize hormone responses to exercise, and improve cholesterol and triglyceride levels. They also examined its use within days after a child’s diabetes diagnosis and during pregnancy, among many other variables.

Lauded by Tamborlane in a eulogy as “one of the greatest of great diabetes investigators,” Sherwin was a celebrated researcher. He set the intellectual tone among Yale diabetes scientists with a well-attended weekly meeting that nourished many careers and lines of inquiry. Tamborlane has called the last quarter of the 20th century “Yale’s golden age of clinical diabetes research.”

And thanks in part to Sherwin’s legacy, that notable age continues. In recent years, Tamborlane and his colleagues have published prominent papers on pediatric diabetes drugs, treatment standards, and the holy grail of insulin pumps: automated closed-loop therapy, also known as the artificial pancreas.

“It’s still a challenge,” Tamborlane said of the disease, “but this pump makes it a little easier.”

The mysteries of insulin resistance

Diabetes has a complex relationship to obesity. Many people with high body weight also have insulin resistance, in which muscle tissue and the liver, normally sensitive to insulin, stop responding as usual. Beta cells buy time by producing more insulin but can’t keep up. The result of these derangements can be (but is not always) type 2 diabetes.

Though there is no causal relationship with type 1 diabetes, obesity can also occur in people with the condition—and when it does, the extra weight is associated with increased health risks. In fact, people with high body weights and type 1 diabetes may have the worst of both worlds. Not only do their beta cells no longer produce insulin, but their bodies often develop insulin resistance, resulting in a hard-to-treat condition called “double diabetes.”

But even type 2 diabetes is not inevitable among high body-weight people, and both insulin resistance and type 2 diabetes can occur in lean people, too.

A Yale husband-and-wife team have worked to illuminate the complex machinery that determines how insulin interacts with cells and how it can go wrong. What they’ve learned about insulin resistance challenges the notion that high body weight causes diabetes—and it opens the door to treatments that do more than reduce blood sugar.

“Insulin resistance is the strongest predictive factor for the development of type 2 diabetes, but it also promotes the development of heart disease, fatty liver disease, Alzheimer’s disease, and probably all obesity-associated cancers,” said Gerald I. Shulman, MD, PhD, George R. Cowgill Professor of Medicine (Endocrinology) and professor of cellular and molecular physiology, as well as co-director of the Yale Diabetes Research Center and Howard Hughes Medical Institute Investigator Emeritus.

“If you understand the molecular basis of insulin resistance, you can then go on to target the triggering factor and not only reverse type 2 diabetes, but then also slow down the progression of these other associated diseases,” he said.

Together with his wife, Kitt Falk Petersen, MD, professor of medicine (endocrinology), and colleagues, Shulman showed that reduced muscle glycogen synthesis, due to reduced insulin-stimulated transport of glucose across the cell membrane, is a key step in causing insulin resistance in skeletal muscle. What underlies this defect, the group then determined, is ectopic lipid—that is, fat stored in the wrong place (i.e., the liver and muscle).

In many people, the body stores fat not only in the usual subcutaneous depots, but also in muscle and the liver. “In our studies we have been able to dissociate obesity from insulin resistance and found that it is the ectopic lipid stored in the liver and muscle cells that causes the insulin resistance,” Shulman said. “This explains why even young, lean offspring of parents with type 2 diabetes and individuals with lipodystrophy [a rare group of syndromes that affect how a person stores fat], who have very little subcutaneous and visceral body fat, can become insulin-resistant.”

How does ectopic lipid do this? The Shulman lab has gone on to elucidate the molecular basis for the way in which ectopic lipid causes insulin resistance by identifying the intracellular fatty acid-derived lipid metabolite (sn-1,2-diacylglycerol) that causes insulin resistance in the liver, muscle, and adipose tissue. The metabolite does this by binding to a protein called protein kinase Ce, which in turn binds to and inhibits insulin receptor activity—a requirement to mediate insulin action.

This mechanism also provides a potential evolutionary basis for insulin resistance. During starvation, fat is mobilized from adipose tissue to deliver energy in the form of fatty acids to the liver and muscle tissue, as well as to other organs, and triggers insulin resistance in these organs through the same mechanism, Shulman explained.

“We have shown that the liver and muscle become insulin-resistant and therefore take up less glucose during starvation, thus preserving glucose in the bloodstream for the brain and other obligatory glucose utilizers, such as red blood cells and the renal medulla,” Shulman said. “This has obvious beneficial effects for survival during starvation. Now, in our toxic environment of highly processed food and sugary drinks, this same lipid pathway is being triggered to cause metabolic syndrome, metabolic dysfunctionassociated steatotic liver disease (MASLD) [formerly known as nonalcoholic fatty liver disease, or NAFLD], metabolic dysfunction-associated steatohepatitis (MASH) [formerly known as nonalcoholic steatohepatitis, or NASH], and type 2 diabetes.”

These insights suggest a new way to address type 2 diabetes at its foundations.

“Virtually all agents we have to date to treat type 2 diabetes do not get at the root cause of insulin resistance, which is ectopic lipid in the liver and muscle,” Shulman said. “What if we can rev up the mitochondria to burn the ectopic fat in the liver and muscle?”

To pursue this goal, his group has developed a series of liver-targeted mitochondrial uncoupling agents to promote increased fat oxidation by the liver mitochondria. Shulman’s group has now shown safety and efficacy for this approach to reverse insulin resistance, MASLD/MASH, and diabetes in rodent and nonhuman primate models of metabolic syndrome and type 2 diabetes.

In collaboration with Gilead Pharmaceuticals, Shulman has developed a third-generation liver-targeted mitochondrial uncoupling agent that is now marching its way through Phase 1 clinical trials. “I think liver-targeted mitochondrial uncouplers will be a very safe and effective approach to reverse liver and muscle insulin resistance as well as hyperlipidemia, and offer a novel and effective approach to treat our patients with MASLD, MASH, and cardiometabolic disease.”

Fending off a diagnosis

Most people with type 1 diabetes—the majority of them children—are neither obese nor insulin-resistant. It is an autoimmune process of beta-cell destruction that begins years before clinical diagnosis.

But what if we could block that destruction in at-risk people and delay or even prevent type 1 diabetes? That goal has motivated Herold since medical school, around the time that researchers were first realizing diabetes is an autoimmune disease.

Trained in both endocrinology and immunology, Herold was fascinated early in his career by news that researchers had used an antibody to reverse type 1 diabetes in a mouse model. He and colleagues at the University of Chicago began to test a new antibody to the T-cell CD3 receptor.

“CD3 is the business end of a T cell. As we began to understand that type 1 diabetes is largely driven by T cells, this became a likely thing to target,” Herold explained.

The drug doesn’t kill T cells. Rather, it delivers a partial agonist signal—one that seems to inactivate or exhaust the cells and keep them from attacking beta cells in the pancreas.

In 2002 at Columbia, Herold’s team showed that in people with newly diagnosed type 1 diabetes, a two-week course of the antibody, now called teplizumab, maintained or improved insulin production for least a year. That in turn improved chronic hyperglycemia and reduced the amount of insulin patients required.

By 2009, with Herold now at Yale, some of these patients had preserved insulin function for five years after the end of the two-year trial. The drug did not work as well for patients who had had diabetes for four to 12 months before treatment, suggesting that getting a jump start on the disease is important. That insight led to a key study.

Autoimmune destruction in type 1 diabetes begins long before symptoms. In stage 1, autoantibodies to pancreatic islets appear in the bloodstream, but blood sugars are normal. Already, though, the attack on insulin-producing beta cells has begun. In stage 2, abnormal blood sugars are found when the beta cells are challenged with glucose. At this time, the risk of being diagnosed with stage 3 or clinical diabetes, with classic signs like extreme thirst and urination or complications like diabetic ketoacidosis, is about 50% in two years. Although nearly all patients can still make insulin when they present with stage 3 diabetes, this ability is lost over time.

Herold and his team decided to see whether they could interrupt this process early. They conducted a placebo-controlled trial in 76 adults and children at high risk of developing type 1 diabetes; all of them also had a close relative with the disease. All of them were in asymptomatic stage 2 diabetes when they enrolled. The treatment group received a two-week teplizumab course; then all participants underwent periodic testing for outright stage 3 diabetes.

By 2019, the results were in. In the teplizumab group, full-blown diabetes arrived after a median of 48.4 months, while in the placebo group it took 24.4 months. One adolescent remained diabetes-free for 11 years. The drug had clearly delayed disease onset in high-risk participants. Combined with years of evidence showing that the drug preserved beta-cell function in every trial that had tested it, the study led to FDA approval in 2022.

“If you’re 10 years old and you’re not going to get diabetes until you’re 20, that’s a huge difference,” Herold said.

In the future, Herold said, screening could detect high-risk people with early signs of autoimmunity; they could then be treated with teplizumab or a similar drug, perhaps allowing them to dodge the disease altogether.

More work with teplizumab remains to extend its duration of activity and improve the frequency of responses. Herold expects it to one day become part of a combination-therapy approach, even in combination with beta-cell replacement therapy for patients who have already been diagnosed with stage 3 type 1 diabetes. Even absent full prevention, this approach could defend enough beta cells to reduce diabetes severity and make it easier to manage. Every partial advance helps lighten patients’ load.

“It’s better not to have diabetes than it is to have diabetes,” Herold said. “If we can identify someone who’s going to develop an autoimmune disease and stop it, why don’t we try to do just that?”

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