Nav: Home

Cellular sickness linked to type 1 diabetes onset

February 21, 2019

A UC San Francisco study of human and mouse pancreatic tissue suggests a new origin story for type 1 (T1) diabetes. The findings flip current assumptions about the causes of the disease on their head and demonstrate a promising new preventative strategy that dramatically reduced disease risk in laboratory animals.

T1 diabetes is an autoimmune disorder that usually begins in childhood or adolescence, and has generally been attributed to the body's immune system mistakenly attacking the insulin-producing beta cells of the pancreas. Scientists still don't understand what triggers this autoimmune response, and so far, attempts to develop therapies to protect or restore beta cells have not been successful.

Now, in a study published February 21, 2019 in Cell Metabolism, UCSF Diabetes Center professor Anil Bhushan, PhD, and his team show that pancreatic beta cells themselves may play a much more active role in T1 diabetes than previously appreciated, opening the door to a totally new avenue for therapy.

Bhushan, who has long studied the biology of pancreatic beta cells, said that he has never been completely satisfied with the dominant model of the origins of type 1 diabetes: "Why does the immune system attack just those cells, while leaving neighboring cells of other types untouched?"

Dysfunctional Beta Cells Linked to Autoimmunity in Mice, Humans with T1 Diabetes

To understand whether beta cells might be contributing to early stages of T1 diabetes, a team led by Bhushan lab postdoctoral researchers Peter J. Thompson, PhD, and Ajit Shah, PhD, looked for changes in these cells during the early stages of disease development in so-called non-obese diabetic (NOD) mice, a commonly used animal model of the human disorder.

The researchers found that well before immune cells began to attack the pancreatic islets where beta cells reside, the beta cells began exhibiting signs of "secretory senescence," a type of cellular decline caused by DNA damage in which cells stop functioning properly and begin producing molecules that harm nearby cells and attract the attention of the immune system.

The new findings contrast sharply with the prevalent belief that T1 diabetes is caused by an overly aggressive immune system attacking healthy beta cells. The new data suggest instead that inherent problems with DNA repair in some beta cells triggers senescence, which patrolling immune cells first fail to recognize and clear out. As a result, these cells accumulate and spread so widely within the pancreas that by the time the immune system eventually recognizes the problem, it essentially has to raze the whole insulin-producing system, leading to the onset of diabetes.

"This is a paradigm shift for T1 diabetes therapy," Bhushan said. The main approach to date has been to dampen the immune system's attack on beta cells, but these data suggest the problem may not be an immune system gone awry. Instead, perhaps therapies should find a way to do the job the immune system is failing to do: clear the senescent cells early on."

To determine whether beta cell senescence plays a role in the onset of T1 diabetes in humans, the researchers studied pancreas tissue from deceased donors, sourced from the Network for Pancreatic Organ Donors with Diabetes, based at the University of Florida.

In line with their animal findings, the authors identified clear signs of DNA damage and secretory senescence in the beta cells of six donors with early-stage T1 diabetes, compared to six non-diabetic donors. The researchers also found signs of beta cell senescence in six donors without a diabetes diagnosis, but whose blood showed early signs of an immune reaction against beta cells, corroborating the idea that senescence is an early part of the chain of events leading to the disease.

"Seeing this data was an incredible moment," said Thompson. "Many results from these diabetic mouse lines have not panned out in humans, but the fact that we were seeing the very same markers of senescence in human pancreas tissue indicated that the same process is occurring in the human disease as well."

Eliminating Senescent Cells Prevents T1 Diabetes in Mice

To test whether eliminating senescent beta cells could help prevent T1 diabetes, Bhushan's group tested a drug called ABT-199 (Venetoclax), recently approved by the FDA as a second-line chemotherapy agent for a type of leukemia that also acts as a so-called senolytic -- a drug that selectively eradicates senescent cells.

Remarkably, the researchers found that while 75 percent of control mice developed diabetes by 28 weeks of age, only 30 percent of mice who were given ABT-199 for two weeks prior to the onset of symptoms went on to develop the disease. The researchers showed that the drug had rapidly eliminated senescent beta cells in these mice, after which their immune systems (which were not directly affected by the treatment) left the remaining, healthy beta cells alone, avoiding the loss of insulin production that causes diabetes.

"These findings support the idea that senescent beta cells are like the bad apples that spoil the whole basket," Shah said. "Here we show that eliminating the bad apples can save the rest, which brings a new therapeutic avenue for treating patients with T1 diabetes."

Bhushan's group hopes these findings will lead to a therapy that could forestall the onset of T1 diabetes in young people at risk of developing the disease -- which can currently be assessed via blood tests -- and preserve remaining beta cell function in people with a recent T1 diabetes diagnoses. The animal experiments suggest that patients might be able to take such a drug periodically to clear out any senescent beta cells, and then perhaps be healthy for years.

"There is great excitement about the potential of senolytic drugs to treat all kinds of diseases of aging," Bhushan said. "Our work is among the first to suggest that clearing senescent cells can also be beneficial in pathological conditions not related to aging, such as type 1 diabetes."
-end-
MEDIA AVAILABLE: Left: In mice bred to develop type 1 diabetes, insulin-producing pancreatic beta cells (green) become senescent (red) before being attacked by the immune system (raw image). Right: A drug that eliminated senescent cells dramatically reduced T1 diabetes risk in mice (raw image). Credit: Bhushan lab / UCSF.

Authors: Additional authors on the study were Frederic Van Gool, of UCSF; Vasilis Ntranos, of UC Berkeley; and Mark Atkinson of the University of Florida.

Funding: This study was funded by startup funds from the UCSF Diabetes Center and a postdoctoral fellowship from the Hillblom Foundation. Flow cytometry experiments were supported by the Diabetes Research Center, established within the UCSF Diabetes Center by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (P30 DK063720).

Disclosures: UCSF has filed a patent application (PCT/US18/31161) for the therapeutic approach described in this study.

About UCSF: UC San Francisco (UCSF) is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with nationally renowned programs in basic, biomedical, translational and population sciences; and a preeminent biomedical research enterprise. It also includes UCSF Health, which comprises three top-ranked hospitals - UCSF Medical Center and UCSF Benioff Children's Hospitals in San Francisco and Oakland - as well as Langley Porter Psychiatric Hospital and Clinics, UCSF Benioff Children's Physicians and the UCSF Faculty Practice. UCSF Health has affiliations with hospitals and health organizations throughout the Bay Area. UCSF faculty also provide all physician care at the public Zuckerberg San Francisco General Hospital and Trauma Center, and the SF VA Medical Center. The UCSF Fresno Medical Education Program is a major branch of the University of California, San Francisco's School of Medicine. Please visit http://www.ucsf.edu/news.

Follow UCSF

ucsf.edu | Facebook.com/ucsf | YouTube.com/ucsf

University of California - San Francisco

Related Diabetes Articles:

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.
Diabetes, but not diabetes drug, linked to poor pregnancy outcomes
New research indicates that pregnant women with pre-gestational diabetes who take metformin are at a higher risk for adverse pregnancy outcomes -- such as major birth defects and pregnancy loss -- than the general population, but their increased risk is not due to metformin but diabetes.
New oral diabetes drug shows promise in phase 3 trial for patients with type 1 diabetes
A University of Colorado Anschutz Medical Campus study finds sotagliflozin helps control glucose and reduces the need for insulin in patients with type 1 diabetes.
Can continuous glucose monitoring improve diabetes control in patients with type 1 diabetes who inject insulin
Two studies in the Jan. 24/31 issue of JAMA find that use of a sensor implanted under the skin that continuously monitors glucose levels resulted in improved levels in patients with type 1 diabetes who inject insulin multiple times a day, compared to conventional treatment.
Complications of type 2 diabetes affect quality of life, care can lead to diabetes burnout
T2D Lifestyle, a national survey by Health Union of more than 400 individuals experiencing type 2 diabetes (T2D), reveals that patients not only struggle with commonly understood complications, but also numerous lesser known ones that people do not associate with diabetes.
A better way to predict diabetes
An international team of researchers has discovered a simple, accurate new way to predict which women with gestational diabetes will develop type 2 diabetes after delivery.
The Lancet Diabetes & Endocrinology: Older Americans with diabetes living longer without disability, US study shows
Older Americans with diabetes born in the 1940s are living longer and with less disability performing day to day tasks than those born 10 years earlier, according to new research published in The Lancet Diabetes & Endocrinology journal.
Reverse your diabetes -- and you can stay diabetes-free long-term
A new study from Newcastle University, UK, has shown that people who reverse their diabetes and then keep their weight down remain free of diabetes.
More Diabetes News and Diabetes Current Events

Top Science Podcasts

We have hand picked the top science podcasts of 2019.
Now Playing: TED Radio Hour

Risk
Why do we revere risk-takers, even when their actions terrify us? Why are some better at taking risks than others? This hour, TED speakers explore the alluring, dangerous, and calculated sides of risk. Guests include professional rock climber Alex Honnold, economist Mariana Mazzucato, psychology researcher Kashfia Rahman, structural engineer and bridge designer Ian Firth, and risk intelligence expert Dylan Evans.
Now Playing: Science for the People

#541 Wayfinding
These days when we want to know where we are or how to get where we want to go, most of us will pull out a smart phone with a built-in GPS and map app. Some of us old timers might still use an old school paper map from time to time. But we didn't always used to lean so heavily on maps and technology, and in some remote places of the world some people still navigate and wayfind their way without the aid of these tools... and in some cases do better without them. This week, host Rachelle Saunders...
Now Playing: Radiolab

Dolly Parton's America: Neon Moss
Today on Radiolab, we're bringing you the fourth episode of Jad's special series, Dolly Parton's America. In this episode, Jad goes back up the mountain to visit Dolly's actual Tennessee mountain home, where she tells stories about her first trips out of the holler. Back on the mountaintop, standing under the rain by the Little Pigeon River, the trip triggers memories of Jad's first visit to his father's childhood home, and opens the gateway to dizzying stories of music and migration. Support Radiolab today at Radiolab.org/donate.