Nav: Home

A common insulin signaling pathway across cancer and diabetes

December 04, 2019

An oncology researcher has made an unexpected contribution to the understanding of type 2 diabetes. In results published in Science Advances, Patrick Hu, M.D., associate professor of medicine at Vanderbilt University Medical Center, found a protein that modulates a signaling pathway often targeted by cancer therapies is also required for insulin biogenesis.

Hu and colleagues showed a protein controlling the PI3K/Akt pathway, a pathway targeted by more than 40 anti-tumor drugs, is absolutely required for the synthesis, processing and secretion of insulin. Hu initiated the discovery using the nematode worm Caenorhabditis elegans, a model system commonly used in research on genetics and development.

"We approached our work on the PI3K/Akt pathway from a cancer perspective, but this is a primordial pathway." Hu said. "It is equally relevant to diabetes and cancer. Understanding how this pathway is regulated could lead to new strategies to treat both diseases."

Insulin signaling is certainly involved in diabetes, but a related insulin-like growth factor signaling network is also implicated in cancer, Hu explained. In C. elegans, a primordial pathway exists that likely gave rise to both human pathways, providing a convenient research model.

"Both networks involve PI3K/Akt in humans, and we were looking for new components of this pathway," Hu said.

The researchers used a forward genetic approach to screen C. elegans worms for components of the pathway that are altered during abnormal insulin signaling. They landed on TRAP-alpha, a highly conserved protein across worms, flies and mammalian systems, including humans.

TRAP-alpha sits on a structure inside cells called the endoplasmic reticulum (ER), where it helps make proteins that will eventually be secreted. Deleting the worm equivalent of TRAP-alpha activated ER stress responses, the researchers found.

Given some people with type 2 diabetes have common genetic variants in the TRAP-alpha gene, Hu moved the experiments to pancreatic beta cells.

Hu collaborated with Ming Liu, M.D. and Peter Arvan, M.D. of the University of Michigan to delete TRAP-alpha from rat beta cells. The deletion caused a 90 percent reduction in total insulin content inside the cells. Instead of being shuttled through the ER for conversion to insulin and secretion, most parent molecules of insulin were degraded, and those that escaped degradation accumulated inside beta cells. They were never processed to insulin, or secreted. The finding shows how without TRAP-alpha, insulin biogenesis is drastically impaired.

Said Hu, "TRAP-alpha is the first situation where we've identified a mutant in the worm and then were able to move it into mammalian cell culture to show it affects a disease phenotype."

In both models, the researchers found deleting TRAP-alpha triggered the ER unfolded protein response. The cells detected unfolded proteins accumulating inside them, and decreased corresponding gene expression to combat it. The cells also increased expression of chaperone proteins that help fold proteins properly.

"We're moving toward the role of TRAP-alpha in maintaining protein homeostasis," Hu said. "Maintaining proper protein folding in the ER is certainly important for cellular health, and it likely contributes to human health in general."

Beyond diabetes, many other diseases are associated with abnormal protein folding responses and protein imbalances. These include neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer's disease.

"It's likely other secreted molecules besides insulin might be affected by TRAP-alpha deletion," Hu said. "If we can understand the broader role that TRAP-alpha is playing in maintaining protein homeostasis, we might develop new ways to approach other diseases, too."

Vanderbilt University Medical Center

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

Accessing Better Health
Essential health care is a right, not a privilege ... or is it? This hour, TED speakers explore how we can give everyone access to a healthier way of life, despite who you are or where you live. Guests include physician Raj Panjabi, former NYC health commissioner Mary Bassett, researcher Michael Hendryx, and neuroscientist Rachel Wurzman.
Now Playing: Science for the People

#543 Give a Nerd a Gift
Yup, you guessed it... it's Science for the People's annual holiday episode that helps you figure out what sciency books and gifts to get that special nerd on your list. Or maybe you're looking to build up your reading list for the holiday break and a geeky Christmas sweater to wear to an upcoming party. Returning are pop-science power-readers John Dupuis and Joanne Manaster to dish on the best science books they read this past year. And Rachelle Saunders and Bethany Brookshire squee in delight over some truly delightful science-themed non-book objects for those whose bookshelves are already full. Since...
Now Playing: Radiolab

An Announcement from Radiolab