Friday, March 1, 2024
Kristen Rohli conducts research in her lab.

Kristen Rohli always wanted to go to a graduate school that felt like her hometown of Baton Rouge, La. On her recruiting visit to the University of Iowa, Rohli needed only one day to choose Iowa City as her home-away-from-home.

During the 2019 polar vortex, Rohli’s flight was delayed in Baton Rouge, causing her to miss her connecting flight. She arrived in Cedar Rapids, but her bags did not. When Rohli finally landed in Iowa, her graduate college interview outfit included a casual pair of leggings, a t-shirt, and flip-flops. 

“I just showed up and it was a disaster,” Rohli recalls. “No one asked any questions. It was like I wasn’t out of place. Every graduate student I met offered to take me to the store to get clothes, so I wouldn’t freeze. Nothing could feel more at home than strangers volunteering to take me to the mall during a polar vortex. Right then, I knew I was coming here.”

This turned out to be a match made in research heaven.

Helping beta cells to not fail

As Rohli prepares to defend her dissertation this spring, this PhD student in the Genetics Interdisciplinary Program has had a first author publication in Function, a co-first author review in Biomolecules, and co-authored papers in the American Journal of Physiology, Endocrinology and Metabolism, Diabetes, and Journal of Cell Biology, with an additional co-authorship currently in preparation. 

Rohli’s thesis work identifies why beta cells fail to make enough insulin in cases of Type 2 diabetes. Rohli made a novel finding that the redox balance between the oxidative and reductive states in the endoplasmic reticulum of beta cells is altered, causing the proinsulin molecule to not be made correctly. Properly created proinsulin eventually matures into insulin, which is used to counteract high blood glucose levels in the human body.

Kristen Rohli

Rohli used the roGFP sensor – created by Neil Bulleid, a recently deceased professor at the University of Glasgow – to conduct her research. Rohli and her colleagues collaborated with Bulleid to make his sensor more beta cell specific. Using the sensor, she showed that the balance between the oxidative and reductive states in the endoplasmic reticulum is altered.

“Specifically for proinsulin, there’s a very specific structure that has to be achieved or the molecule is not functional and will not become insulin, so it’s not helping someone combat high blood sugar and is contributing toward their diabetes,” Rohli says.

In Type 2 diabetic mice, the redox balance proved to be higher on the oxidative side and the endoplasmic reticulum is hyperoxidized. By adding reducing agents, Rohli and her fellow researchers restored the redox balance and made proinsulin useful again for creating insulin in diabetic mice.

“Her studies have addressed some long-standing questions in the field, particularly how insulin production is compromised in later stages of diabetes,” says Samuel Stephens, Rohli’s adviser, an associate professor of Internal Medicine, and a faculty member in the Genetics Program.  “She showed that metabolic functions are critical to supporting the endoplasmic reticulum’s role in proinsulin folding and export. As metabolic functions deteriorate with diabetes onset, this support of the endoplasmic reticulum becomes sufficiently strained such that insulin production is compromised. Overall, this leads to a cycle of beta-cell dysfunction. The silver lining, however, is that restoration of metabolic functions can reset the defect in insulin production.”

New diabetes understanding

About 15 years ago, it was commonly understood that Type 2 diabetics don’t make enough proinsulin, consequently without enough proinsulin a person would never made enough insulin.

“That is what was thought to be causing insulin deficiency in Type 2 diabetics. They thought the beta cells were no longer healthy and thus not making proinsulin,” Rohli says. “It turned out that was very wrong. Type 2 diabetics make more proinsulin than non-diabetics. There is a problem in the conversion of proinsulin to insulin. People with Type 2 diabetes do make less insulin, but not simply because the cells aren’t trying to produce more insulin.”

People also made an association between Type 2 diabetes and obesity. However, data indicates that most obese people are not diabetic, and most diabetics aren’t obese. It’s hard to say that one causes the other.

“Some people have a pre-disposition to diabetes and for some unknown reason their beta cells fail,” Rohli says. “There are genetic risks and environment risks. Overall, in the scientific field, it’s unknown what causes beta cells to fail.”

Rohil is addressing what causes beta cells to fail in her dissertation.