How worms revealed a key protein in insulin synthesis and diabetes

By studying the nematode Caenorhabditis elegans, scientists from Vanderbilt University and the University of Michigan have identified a protein that's key for insulin synthesis, the understanding of which they say could lead to new approaches to prevent and treat Type 2 diabetes.

The protein, called TRAP-alpha, is widely shared across worms, flies and mammals, including humans. In a study published in the journal Science Advances, the team showed that TRAP-alpha is required for insulin production, corroborating previous knowledge that alterations in the TRAP-alpha gene are linked to the development of diabetes.

The researchers made the discovery while screening for genetic clues to the PI3K/Akt signaling pathway that may contribute to reduced insulin signaling. Irregularities in the PI3K/Akt pathway have been linked to many human diseases, including cancer, cardiovascular disease and diabetes.

The screens turned up TRAP-alpha. The protein is part of a complex known as translocon that helps move—or “translocate”—newly synthesized proteins into the endoplasmic reticulum (ER) of cells for further processing before they’re eventually secreted.

The researchers discovered that deleting the C. elegans equivalent of TRAP-alpha affects the worms' insulin signaling pathway.

They went on to delete TRAP-alpha in insulin-making pancreatic beta cells of rats. Doing so led to a sharp decline in total insulin, the team found. Preproinsulin, the precursor molecule to insulin, was not properly transferred into the ER for final processing, so most of it was degraded. 

“TRAP-alpha was not on anyone's radar in terms of being required for insulin biogenesis,” Patrick Hu, the study’s senior author, said in a statement. “Our work highlights the value of using a model organism like C. elegans to do an unbiased genetic screen. It led us to a molecule that seems to be important in making insulin and that could very well shed light on the pathogenesis of diabetes, a common disease that affects about 10% of the U.S. population.”

RELATED: Subtle chemical shift reverses prediabetes in Merck-partnered mouse trial

Given the prevalence of diabetes, several research groups are also working on new ways to tackle it. Scientists from the University of Utah, in collaboration with Merck Research Laboratories, recently prevented or reversed prediabetes in mice. They did it by shutting down an enzyme called DES1 to reduce the amount of fatty lipid ceramides, which is key in metabolic health.

A team at the University of Geneva treated Type 1 diabetes in mice by converting non-insulin-producing alpha and gamma endocrine cells into beta cells with the help of two transcription factors, PDX1 and MafA.

Understanding TRAP-alpha could inspire new ideas to prevent or treat Type 2 diabetes—and maybe even more diseases, Hu and colleagues argued.

In the current study, the researchers noticed TRAP-alpha plays a role in promoting ER homeostasis, or the balance between incoming proteins and ER the proteins that help fold them. Loss of TRAP-alpha may cause ER stress, which can lead to cell death, the team reported.

Preproinsulin is the first “client” protein for TRAP-alpha to deliver into the ER for processing, and the scientists hope to find more like it.

“It's likely other secreted molecules besides insulin might be affected by TRAP-alpha deletion,” Hu said in a statement. “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.”