Protecting beta cells against stress may guard against type 1 diabetes

July 27, 2020

BOSTON - (July 27, 2020) - Type 1 diabetes occurs when a person's own immune system destroys insulin-producing beta cells in the pancreas. In recent years, scientists have learned how to grow large volumes of replacement beta cells, but the researchers are still trying out many options to protect these cells against the immune attack. Joslin Diabetes Center researchers now have found an unusual strategy that eventually may help to guard such transplanted beta cells or to slow the original onset of the disease.

Research in mouse models and in human cells has shown that targeting a protein called renalase may protect beta cells against autoimmune attack by strengthening them against stress, says Stephan Kissler, an investigator in Joslin's Section on Immunobiology, associate professor of medicine at Harvard Medical School, and co-senior author on a paper describing the work in Nature Metabolism.

Kissler, co-senior author Peng Yi, PhD, and their colleagues also demonstrated that an existing FDA-approved drug inhibits renalase and increases the survival of beta cells in those lab models.

The Joslin study joins a growing set of evidence suggesting that functional problems with beta cells themselves may help to trigger the autoimmune attack in type 1 diabetes, say Kissler and Yi, who is an assistant investigator in the Islet Cell and Regenerative Biology Section. "You might have genes that make the beta cell a little bit dysfunctional and more prone to becoming a target of the immune system," Kissler explains.

The research began with a casual hallway conversation between Kissler and Yi about potential ways to protect beta cells from autoimmune attack. The two ended up launching a bold gamble to try inhibiting genes across the genome, one at a time, using a screening technique based on the CRISPR gene-editing method with a beta cell line from a "non-obese diabetic" (NOD) mouse that models type 1 diabetes. "Whole genome CRISPR screening is a powerful tool for new target discovery and we hoped that it would help us find any mutations that protect the beta cell," Yi says.

The CRISPR screen for surviving beta cells produced a dozen genes of interest. The most striking was the gene for renalase, which previous research had shown is associated with type 1 diabetes.

Next, the researchers created NOD mouse beta cells, some with the renalase gene functionally "knocked out" and some not. They transplanted these cells to NOD mice with autoimmune diabetes.

Intact beta cells died off--but the renalase knock-out cells survived. "This was a very black-and-white research model," Kissler comments. "If the cells aren't protected, they're gone."

The investigators then looked to see if the cells that lacked the renalase gene provoked a diminished response from T immune cells (which spearhead the autoimmune assault) in a dish. The scientists found that one type of T cell was less likely to attack these knockout cells than to attack normal beta cells.

But what was slowing this autoimmune assault?

In earlier work to analyze beta cell survival, Yi had analyzed how the cells respond to a condition called endoplasmic reticulum (ER) stress. Now when the team tried three ways of introducing ER stress to mouse beta cells in a dish, the researchers saw that the renalase mutation was protecting against this condition.

In the next step, to see if the same mechanisms were at work in human cells, the team joined up with Douglas Melton of the Harvard department of Stem Cell and Regenerative Biology to create human beta cells for similar tests in a dish. "Again, we saw that the renalase knockout protected cells against ER stress," Kissler says.

The functions of renalase are not well understood, but Yi and Kissler knew that the protein is an enzyme (which often can be targeted by drug compounds) and that other scientists had produced a three-dimensional crystal structural map of the protein.

Wondering if this map would give clues to uncover a compound that could target renalase, the Joslin investigators began working with Celia Schiffer of the University of Massachusetts Medical School. Structural biologists at the university's structure-based drug design core facility soon noticed that renalase is very similar to another enzyme that is inhibited by existing drugs--including one drug known as pargyline that was approved by the Food & Drug Administration almost 60 years ago to treat hypertension.

Testing pargyline in their mouse transplant model, the Joslin researchers found that the drug protected beta cells extremely well, says Kissler. Studying it in the mouse beta cells themselves, the scientists demonstrated that pargyline indeed was protecting against ER stress. In experiments with human cells, pargyline also displayed a protective effect.

Kissler and Yi hope to test pargyline in a pilot clinical trial to see if it slows the progress of new onset type 1 diabetes in a small number of patients. "Since it's FDA-approved and the drug is safe, this would be the best approach to test if the protection we observed in mice and human cells will hold true in people," Kissler remarks. If research results continue to be positive, their next goal will be to find industry backing to develop a small molecule drug that provides even better protection than pargyline.
-end-
Joslin's Erica Cai, Yuki Ishikawa and Wei Zhang are co-lead authors on the paper. Other Joslin contributors include Jian Li, Badr Kiaf and Jennifer Hollister-Lock. Nayara Leite and Douglas Melton of the Harvard Stem Cell Institute also are co-authors, as are Shurong Hou, Nese Kurt Yilmaz and Celia Schiffer of the University of Massachusetts Medical School. The study was funded by Harvard Stem Cell Institute, JDRF and National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases).

Joslin Diabetes Center

Related Diabetes Articles from Brightsurf:

New diabetes medication reduced heart event risk in those with diabetes and kidney disease
Sotagliflozin - a type of medication known as an SGLT2 inhibitor primarily prescribed for Type 2 diabetes - reduces the risk of adverse cardiovascular events for patients with diabetes and kidney disease.

Diabetes drug boosts survival in patients with type 2 diabetes and COVID-19 pneumonia
Sitagliptin, a drug to lower blood sugar in type 2 diabetes, also improves survival in diabetic patients hospitalized with COVID-19, suggests a multicenter observational study in Italy.

Making sense of diabetes
Throughout her 38-year nursing career, Laurel Despins has progressed from a bedside nurse to a clinical nurse specialist and has worked in medical, surgical and cardiac intensive care units.

Helping teens with type 1 diabetes improve diabetes control with MyDiaText
Adolescence is a difficult period of development, made more complex for those with Type 1 diabetes mellitus (T1DM).

Diabetes-in-a-dish model uncovers new insights into the cause of type 2 diabetes
Researchers have developed a novel 'disease-in-a-dish' model to study the basic molecular factors that lead to the development of type 2 diabetes, uncovering the potential existence of major signaling defects both inside and outside of the classical insulin signaling cascade, and providing new perspectives on the mechanisms behind insulin resistance in type 2 diabetes and possibly opportunities for the development of novel therapeutics for the disease.

Tele-diabetes to manage new-onset diabetes during COVID-19 pandemic
Two new case studies highlight the use of tele-diabetes to manage new-onset type 1 diabetes in an adult and an infant during the COVID-19 pandemic.

Genetic profile may predict type 2 diabetes risk among women with gestational diabetes
Women who go on to develop type 2 diabetes after having gestational, or pregnancy-related, diabetes are more likely to have particular genetic profiles, suggests an analysis by researchers at the National Institutes of Health and other institutions.

Maternal gestational diabetes linked to diabetes in children
Children and youth of mothers who had gestational diabetes during pregnancy are at increased risk of diabetes themselves, according to new research published in CMAJ (Canadian Medical Association Journal).

Two diabetes medications don't slow progression of type 2 diabetes in youth
In youth with impaired glucose tolerance or recent-onset type 2 diabetes, neither initial treatment with long-acting insulin followed by the drug metformin, nor metformin alone preserved the body's ability to make insulin, according to results published online June 25 in Diabetes Care.

People with diabetes visit the dentist less frequently despite link between diabetes, oral health
Adults with diabetes are less likely to visit the dentist than people with prediabetes or without diabetes, finds a new study led by researchers at NYU Rory Meyers College of Nursing and East Carolina University's Brody School of Medicine.

Read More: Diabetes News and Diabetes Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.