Fixing the Jam: Dr. Anoop Arunagiri’s Quest to Reverse the Damage of Diabetes at ETSU

Dr. Arunagiri’s research is defined by a fascination for the misfits of the protein world. While many scientists focus on the toxic protein clumps that cause brain diseases, he turned his attention to a hormone called Somatostatin. In the grand design of the human body, Somatostatin acts as a biological brake pedal. While growth hormones help our bodies expand, Somatostatin ensures we do not experience overgrowth.

“Somato means body, statin means stop, so it stops the excessive body growth,” Dr. Arunagiri said. For years, this protein was a ghost to researchers because it is intrinsically disordered.

Contributed/ETSU

To solve this, Dr. Arunagiri used a clever bit of timing. He realized that even a disordered protein has to assume an initial structure before it starts to make a larger aggregate. By finding the “sweet spot” in time just before the protein clumped together, he captured the first-ever structural map of this hormone.

“We captured it right away and we saw that structure,” he says of the breakthrough. “How do we solve the structure of a protein which does not have a structure? That was a challenge.”

Moving from the brakes of the body to the fuel, Dr. Arunagiri later shifted his focus to insulin. We have known that insulin is vital for blood sugar for over a century, but the precursor to that hormone, proinsulin, held a deep secret. Proinsulin is like a raw material that must be packaged correctly to become active insulin. According to textbooks, due to a mutation, the protein misfolds like a jammed printer, yet no one had actually seen this happen in a living system. Dr. Arunagiri realized that although the tools existed for years, “nobody ever tried to put them together to actually demonstrate misfolding.”

He developed a simple yet revolutionary method, discovering something that changed our understanding of type 2 Diabetes: the printer starts jamming much earlier than anyone realized. He found that in models of the disease, “even before pre-diabetes, the mouse already shows misfolding.”

He saw that the protein is still the “wild type” without any mutations. “It is a problem with the metabolism and their system,” he explains. This means his work is not just about looking at proteins under a microscope; it is about creating a molecular smoke detector. This discovery gained even more momentum when it intersected with one of the biggest scientific milestones of the decade: the Nobel Prize-winning AlphaFold project.

Recently, the scientific community sought real-world examples of why predicting protein structures is important for human health; they looked to Dr. Arunagiri’s findings. Alongside the news of the Nobel Prize, his paper suddenly “came into the light” due to its proof that when proteins don’t fold into a particular structure, they lead to diseases like diabetes, leading to his research becoming a key piece of the puzzle in explaining the global importance of protein folding.

Today, the research moves to its most hopeful chapter. For a long time, the scientific community believed that once a protein misfolded, it was a dead end. The accepted theory was that these crumpled products were like trash that the cell could never recover. Dr. Arunagiri’s recent work has challenged this “dead-end.” He has discovered that this process is actually reversible.

“We found a way to reverse the misfolding, which was very new, in fact, the first time in our field,” he said.

It is the molecular equivalent of taking a discarded, balled-up piece of paper and perfectly smoothing it back out until it is brand new. This concept of “reversibility” suggests that we could eventually help the body repair itself rather than just managing the symptoms of a disease. As he continues this work at the university, Dr. Arunagiri is proving that in the world of biology, a mistake does not have to be the end of the story. With the right nudge, even the most tangled proteins can find their way back home.