Type 1: The Other Diabetes

The autoimmune disease is increasing at an alarming rate. Einstein and Montefiore scientists are addressing it on a number of fronts.

By Gary Goldenberg

Sam (not his real name) was diagnosed with type 1 diabetes in his early teens. He struggled to follow the insulin regimen needed to control his blood-glucose level, even after experiencing diabetes-related complications that required hospitalizations. Finally, in his late 20s, Sam started handling self-management for his diabetes, but his effort came too late to prevent permanent disability.

All too many people with type 1 diabetes (T1D)—especially adolescents and young adults—fail to reach target blood-glucose levels. The elevated glucose forms toxic compounds that damage tissues, leading to potentially devastating consequences that occur in T1D as well as type 2 diabetes: diabetic coma, blindness, heart disease, kidney failure, nerve damage, and amputations.

“People talk about the type 2 diabetes epidemic—and it is certainly a major public health issue,” says Yaron Tomer, M.D., who is the chair of medicine at Einstein and Montefiore and a professor of medicine and of microbiology & immunology and the Anita and Jack Saltz Chair in Diabetes Research at Einstein. “But type 1 diabetes is much more common than people think. Since World War II, the frequency of type 1 has doubled every 20 years in almost every population group, and nobody knows why (See “Type 1 Diabetes By the Numbers,” below).

Young people with type 1 diabetes must be vigilant about controlling their blood-sugar levels, which requires the daily use of insulin. This girl is being taught how to use a penlike syringe for injecting insulin.

Coming of Age with T1D

As Sam’s story suggests, controlling blood-glucose levels poses particular problems for young people with T1D. A key goal is keeping their A1C levels (the standard measure of long-term blood-glucose control) within certain parameters. Researchers, however, estimate that between 85% and 90% of teens and young adults with T1D nationwide do not regularly meet their target A1C levels—a red flag for complications to come.

“Managing type 1 diabetes requires constant vigilance—counting carbs, testing your blood sugar, and injecting insulin at every meal,” says Shivani Agarwal, M.D., M.P.H., assistant professor of medicine at Einstein and director of the Supporting Emerging Adults with Diabetes (SEAD) program at Montefiore. “That’s difficult for everyone, but especially teens and young adults. While some are ready to assume responsibility for their care, most need guidance along the difficult journey to adulthood.”

Dr. Agarwal created the year-old SEAD program (a part of the Fleischer Institute for Diabetes and Metabolism) to offer that guidance. It’s one of the first clinical services specifically designed for people with T1D on the cusp of adulthood (ages 18 to 25).

“Our philosophy at SEAD is to nurture young adults so that they’re ready to take over their care when they’re transferred to adult services,” Dr. Agarwal says. “Imaging studies show that the brain’s frontal lobe, which is responsible for executive functioning, doesn’t fully develop until the mid-20s. That’s when we see our patients taking responsibility. It’s like a switch is flipped.”

Shivani Agarwal, M.D., conducts a telemedicine visit with a patient via a mobile digital device. (Photo by Jason Torres)

All too often, when left to their own devices, young adults with T1D neglect self-care or are unable to make it a priority. By early adulthood, they may already have started experiencing significant complications. “But if we support these patients and push them toward independence, we can change that trajectory,” Dr. Agarwal says.

SEAD is staffed by an endocrinologist (Dr. Agarwal); a nurse practitioner with expertise in type 1 diabetes and advanced technologies such as insulin pumps; a nurse specializing in social work and community care; and, notably, a psychologist—a rare combination in diabetes clinics. The team also offers peer-support groups and a yearly group retreat where participants can discuss T1D-related psychosocial issues and learn about technologies for managing their care, such as continuous glucose monitors and insulin pumps.

“We’re not going to improve everyone’s glycemic control,” Dr. Agarwal admits. “But engaging patients in care is the most important thing we can do. When they’re lost to the healthcare system is when things really go wrong.”

One of Dr. Agarwal’s goals is to create a model of care that can be adopted by providers around the nation, even those with limited resources. “Second, we need to demonstrate that our approach makes sense financially to healthcare providers and payers,” she says.

SEAD is a product of a larger project to reduce disparities in T1D care among young racial/ethnic minorities, funded by a five-year, $988,000 award from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The project aims to identify modifiable factors that can reduce disparities and improve health outcomes, learn more about patient-provider relationships in these communities, and design and test interventions.

Sadly, SEAD came too late for Sam, who later in life became Dr. Agarwal’s patient. By his early 30s, he had gone blind from T1D. “It was heartbreaking when he told me he wished he’d had this program when he was younger,” Dr. Agarwal says. “Let’s hope we can prevent others from developing such devastating complications.”

We’re not going to improve everyone’s glycemic control. But engaging patients in care is the most important thing we can do.

— Dr. Shivani Agarwal

What Patients Want

For patients with T1D, a key goal is maintaining healthy A1C levels to avoid complications and hospitalizations. But that’s not all they want.

“If you ask patients what’s important to them, they’ll say they want a good A1C and a good quality of life,” says Jeffrey Gonzalez, Ph.D., professor of medicine and of epidemiology & population health and co-director of the New York Regional Center for Diabetes Translation Research. “For them, it’s not either/or—and it shouldn’t be for caregivers, either. There’s a lot of evidence that stress is associated with poor treatment adherence and poor glucose control, so we would do well to emphasize the psychological as well as the physiological aspects of diabetes care.”

Dr. Gonzalez is in the vanguard of health professionals bringing much-needed attention to the psychosocial aspects of diabetes, with a particular focus on “diabetes distress”—where patients experience feelings such as stress, guilt, or denial stemming from living with diabetes and the burden of self-management.

To the untrained eye, diabetes distress can look a lot like depression, which is also common among those with diabetes. But the two conditions are different. Depression is characterized by symptoms (such as persistent feelings of worthlessness or guilt, or lack of interest in normal activities) that don’t necessarily arise from a specific medical condition. Diabetes distress, by contrast, is an emotional response to having and managing the disease.

“It’s important to make this distinction,” Dr. Gonzalez says. “An antidepressant may not help a patient who is overwhelmed by diabetes. He or she might be better served by diabetes-specific interventions, such as teaching skills for coping with anxiety or for managing one’s illness.”

In 2016, the American Diabetes Association began recommending screening for both depression and diabetes distress. “This was an important step forward,” says Dr. Gonzalez, who contributed to the new treatment guidelines. “But we still have so much to learn before we can adequately address the problem. For example, we don’t really understand the relationship between stress and blood-glucose levels. Does a day of high stress precede a day of poorly controlled blood sugar? Or is it the other way around, or perhaps bidirectional?”

Clearly, we need to build a workforce that can deal with patients confronting the psychosocial aspects of diabetes care.

— Dr. Jeffrey Gonzalez

Dr. Gonzalez hopes to answer these and other questions in a study using smartphone apps and continuous glucose monitors (devices that are worn on the body that automatically and continuously measure blood-sugar levels).

“We usually ask patients to fill out paper-and-pencil questionnaires about their moods over a recent week and relate these to a single measure of A1C that may not overlap with that period,” he explains. “But memory is often imprecise and unreliable. With our app, we can query patients about their moods several times a day. Then we can correlate that info with data from continuous glucose monitors. This will give a better sense of how stress relates to blood glucose from moment to moment. We’ll also determine whether hyperglycemia and hypoglycemia are associated with changes in patients’ cognitive function, as has been suspected.

“We need to look beyond A1C,” he adds. “The long-term measure of blood sugar is important, but we also need to look at patients’ day-to-day experiences with diabetes, and at how those experiences can be improved.”

In the meantime, Dr. Gonzalez is also investigating how to make T1D care more patient-friendly and more accessible. Recent surveys show that most adults with T1D are seen not by endocrinologists but by primary care doctors, who are hard-pressed to give adequate time to patients with complex chronic diseases and may not be familiar with all the nuances of diabetes care.

“Smartphone apps are one approach; telehealth is another,” Dr. Gonzalez says. “Adding mental-health professionals to diabetes clinics, as we’ve done at the Fleischer Institute, would also be helpful. Unfortunately, it’s not financially rewarding to deliver mental-health care in this setting, at least in the short term. That’s part of the reason why it’s so hard to access. Part of my job as a researcher is to demonstrate to payers that this is an investment worth making.”

In sum, says Dr. Gonzalez, “clearly, we need to build a workforce that can deal with patients confronting the psychosocial aspects of diabetes care. But it’s also clear that we have a long way to go with that mission.”

Autoimmunity and Destruction

T1D and other autoimmune diseases occur when the immune system—normally a bulwark against viruses and other microbial invaders—instead attacks a person’s own tissues. In the case of T1D, the pancreas is the target. Immune cells known as T cells mount the assault, causing inflammation that destroys pancreatic beta cells—the source of the insulin that enables the body’s tissues to use glucose as an energy source. Over time, the destruction of insulin-producing beta cells leaves the body unable to control its blood-glucose levels—the hallmark of T1D.

Variations in certain genes called HLA genes are associated with the misdirected T-cell attacks that cause autoimmune diseases. But gene variants aren’t sufficient, since fewer than 5% of people with HLA variants develop T1D. Additional factors—most likely environmental exposures of some kind—are believed to trigger T1D in genetically susceptible people.

“There’s a lot of debate about what those environmental triggers might be,” Dr. Tomer says. “I believe they’re viral infections, but they could be chemical exposures or even changes in the gut microbiome. Whatever the trigger, the result is a T-cell attack on the pancreas that stresses or kills insulin-making cells.” Dr. Tomer is working to prevent T1D caused by T cells known as CD4+ T cells, or “helper” T cells. He and his colleagues are trying to short-circuit instructions directing CD4+ T cells to target the pancreas.

The ‘Miseducation’ of T Cells

T cells such as CD4+ T cells aren’t born knowing what to hunt for. Just as bloodhounds require a scent to track and find a missing person, T cells rely on peptides—bits of protein from invading bacteria, for example—to tell them what to attack. Those immunity-arousing peptides are called antigens.

T cells get their marching orders, in the form of peptide antigens, from another type of immune cell called antigen-presenting cells (APCs). Transferring a peptide from an APC to a T cell resembles spoon-feeding. The APC’s “spoon” is present on its surface as a tangle of proteins dictated by HLA genes. This spoon contains grooves, known as “pockets,” which accommodate peptides that APCs then “feed” to T cells.

However, some HLA gene variants create APC spoons whose pockets mistakenly bind the body’s own peptides. T-cell receptors recognize these “self” peptides—prompting the T cells to attack the body’s own cells and tissues and leading to autoimmune diseases.

Illustration of an immunological synapse This illustration of an immunological synapse shows an antigen- presenting cell or APC (upper cell) interacting with a CD4+ T cell (lower cell). In the circular close-up of the synapse, an HLA protein (pink) on the APC’s surface is displaying a peptide (orange) that is being bound by a T-cell receptor (green). This interaction activates the T cell to attack cells containing that peptide. In type 1 diabetes, the display of peptides belonging to insulin-producing cells in the pancreas “miseducates” T cells to attack and destroy those pancreatic cells.

The Search for Pocket Protectors

Most T1D cases occur when APCs bind insulin peptides, causing T cells to attack insulin-rich beta cells of the pancreas. To halt T1D, Dr. Tomer and his colleagues in the Einstein–Mount Sinai Diabetes Research Center are pursuing a novel strategy: Find peptide drugs to block the binding pockets of APCs susceptible to causing T1D.

Using computer modeling to screen thousands of potential compounds, they found one highly promising pocket-blocking candidate that they are now modifying to boost its effectiveness. It’s called a retro-inverso peptide.

“We made a mirror image of the original peptide and then reversed its amino acid sequence,” Dr. Tomer explains. “This configuration stabilizes the peptide so it sits securely within the APC’s pocket.” The experimental peptide has shown encouraging results in inactivating APCs in a T1D mouse model and in cells taken from patients with T1D.

Dr. Teresa DiLorenzo at work in the lab.

We envision that this would be a personalized medicine for T1D.

—Dr. Teresa DiLorenzo

The Artificial Synapse

CD4+ T cells are not the only T cells implicated in T1D. To prevent T1D, another Einstein team is focusing on CD8+ T cells, or “killer” T cells. The strategy of researchers Steven Almo, Ph.D., and Teresa DiLorenzo, Ph.D., is to intercept misguided CD8+ T cells before they can reach and damage the pancreas. The researchers are testing a novel double-barreled immunotherapy that homes in on specific CD8+ T-cell populations and then inhibits their activity.

The immunotherapy’s ammo is a two-armed “fusion protein”: one arm docks specifically to CD8+ T cells genetically programmed to attack insulin-producing cells in the pancreas; the second arm puts the CD8+ T cells out of action by stimulating receptors on their surfaces. The double-armed protein is called a synTac, short for “artificial immunological synapse for T-cell activation.” The platform can also be tailored to fight other diseases, including cancers and AIDS.

The synTac concept was developed by Dr. Almo, professor and chair of biochemistry, professor of physiology & biophysics, the Wollowick Family Foundation Chair in Multiple Sclerosis and Immunology, and director of the Einstein Macromolecular Therapeutics Developmental Facility. His synTac work with Dr. DiLorenzo is supported by NIDDK.

The Einstein team is producing a variety of synTacs for T1D, designed to target T cells known to interact with the most-common insulin peptides. “We envision that this would be a personalized medicine for T1D,” says Dr. DiLorenzo, who is a professor of microbiology & immunology and of medicine and the Diane Belfer, Cypres & Endelson Families Faculty Scholar in Diabetes Research. “We would test the patient’s blood for insulin peptides and then choose the appropriate molecules from a whole panel of synTac immunotherapy molecules.”

SynTacs could overcome a major drawback of conventional immunotherapies, which indiscriminately affect all T cells—not just the harmful ones—and therefore can cause serious and even fatal side effects. SynTacs, by contrast, should have fewer unintended effects, since they’re aimed only at those CD8+ T cells with autoimmune potential.

The search for some way to prevent T1D has gone on for decades. Research by Einstein scientists could potentially achieve that goal. For all the young “Sams” of this world, that would be good news indeed.


Diabetes and COVID-19: A Confusing Combination

Early in the COVID-19 pandemic, doctors at Montefiore observed that about 40% of people hospitalized with the disease also had type 1 or type 2 diabetes. It was a striking observation but not a total surprise. People with diabetes are no more susceptible than others to viral infections, but they are more vulnerable to serious complications once infections occur. Factor in the high prevalence of diabetes in the Bronx, and the 40% figure makes sense.

What didn’t make sense were other aspects of the coronavirus-diabetes connection. Some patients with diabetes had well-controlled blood-glucose levels pre-COVID-19, but those levels became dangerously high and fluctuated wildly following infection.

Even stranger, COVID-19 may actually cause diabetes. Patients with no history of diabetes were showing up on the COVID-19 wards with ketoacidosis, a potentially deadly condition usually associated with type 1 diabetes (T1D). Ketoacidosis (the buildup of acidic substances called ketones) occurs when cells lack sufficient glucose for energy and burn fat instead.

“There are many interesting things about this virus—some more interesting than we’d like,” says Jill Crandall, M.D., professor of medicine, the Jacob A. and Jeanne E. Barkey Chair in Medicine, and chief of the division of endocrinology at Einstein and Montefiore.

As yet, clinicians have no definitive guide for caring for COVID-19 patients who have diabetes, so they’re learning by doing—and by sharing. Einstein and Montefiore’s endocrinologists are now contributing to a nationwide population health–surveillance study of individuals with T1D who contract COVID-19.

“We’re focusing this surveillance effort on type 1 diabetes, but we’re also interested in the effects of COVID-19 on type 2, the more-common form,” Dr. Crandall adds. She notes that patients will also be monitored after they return home, to see if COVID-19 has caused long-term changes to their diabetes.



Improving Patient Care

Meanwhile, Dr. Shivani Agarwal (introduced earlier in article) is coordinating two pilot projects aimed at improving care for people with diabetes who develop COVID-19.

One project is assessing how well continuous glucose monitors (tiny devices that automatically measure glucose levels) will work on hospitalized patients.

“The monitors are approved for outpatients but not for the inpatient setting, where finger sticks are used,” Dr. Agarwal says. “But with nurses so busy and to reduce use of personal protective equipment and exposure to COVID-19, it would be better to automate this process and not use up protective gear just to take a glucose measurement. However, several factors could affect the accuracy of these monitors in the inpatient setting, and so we need to rigorously test this approach.”

A second project is evaluating whether subcutaneous insulin injections can replace intravenous insulin drips for managing patients with diabetic ketoacidosis.

“Insulin drips allow for fine-tuning of insulin to control blood sugar but are labor intensive since a lot of monitoring is needed, including hourly finger sticks,” Dr. Agarwal says. “In this context, periodic insulin injections may be the better alternative, especially because of COVID-19. Our number one priority is to maintain patient safety and optimize clinical outcomes, but we also need to reduce the burden on our nursing staff. We hope this approach will achieve both goals.”

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