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."
-end-


Vanderbilt University Medical Center

Related Diabetes Articles from Brightsurf:

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.

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.

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.