A critical function of the Fraternal Order of Eagles Diabetes Research Center is to train new generations of diabetes researchers. To this end, since 2017, the FOEDRC has received a “T32” grant from the NIH that funds up to six annual positions for postdoctoral fellows to receive advanced training in diabetes research. Postdoctoral fellows are scientists and/or physicians who have recently received their doctorate degree and who are in the final stages of training to become independent scientists.

We want to share the work of one of our recent T32 trainees who has now gone on to further success in the field of diabetes research. Dr. Catherina Pinnaro is a physician, who in 2018 applied to our T32 program in hopes to obtain advanced training in diabetes research. Her goal was to devise research approaches to better understanding why women with Turner syndrome (TS) develop diabetes. Women with TS have a much higher risk of developing diabetes mellitus compared to the general population; however, the reasons for this are unknown.

Dr. Pinnaro was accepted into our T32 program for two years of training. A research mentorship team helped guide her through learning about advanced diabetes research techniques. Dr. Pinnaro finished the T32 program in 2020 and joined the faculty at the University of Iowa as a physician scientist, splitting her time between taking care of patients with endocrine conditions such as diabetes and running her clinical research program studying women with TS. She recently applied for an NIH “K23” grant to support her new research program, and we are pleased to announce that her grant is now funded.

Her research will take three approaches to better understand diabetes risk in women with TS. The first approach will study the genetics of women with TS. She will determine if it is women with TS who are missing genes from their father or mother who are at risk for diabetes.  The second approach will determine whether there are changes in pancreas function among women with TS that might contribute to diabetes risk. The third approach will study the home glucose patterns in women with TS using continuous glucose monitoring.

Dr. Pinnaro was recently bestowed The Corridor Business Journal’s Forty Under 40 award which recognize 40 leaders under the age of 40 who have made a significant impact in their business and community early in their careers. She was recognized for creating a positive experience for her patients at the University of Iowa Stead Family Children’s Hospital, while simultaneously pursuing her passion for research on pediatric diabetes.

Congratulations to Dr. Pinnaro for achieving NIH funding and being recognized as a leader. We look forward to what her studies will teach us about diabetes and its causes.

The Fraternal Order of Eagles Diabetes Research Center is pleased to announce the results of its thirteenth round of Pilot and Feasibility Grants. These grant awards fund innovative pilot projects by early career investigators who are entering the diabetes research field, or established investigators with innovative ideas that focus on a new direction in diabetes research. The goal of the program is to generate data that will enable awardees to compete for peer-reviewed national funding for diabetes related projects that show exceptional promise. 

Over a dozen researchers from across the University of Iowa campus submitted meritorious proposals that underwent a comprehensive and competitive peer-review process. Two applicants were selected to receive a catalyst award grant of $50,000 to support their research proposal, with the possibility for a second year of funding, for a total of $100,000 over a two-year period. Two applicants were selected to receive one-year seed grant awards of $5,000 each to support discreet research proposals to obtain data needed to generate essential preliminary data in a diabetes-related project to increase competitive for subsequent extramural funding.

Catalyst Grant Winners

Brian O’Neill, MD, PhD, Associate Professor of Internal Medicine-Endocrinology and Metabolism 

Project: Role of Lrrc2 in the muscle mitochondrial adaptations to diabetes Uncontrolled diabetes decreases energy production in mitochondria, the cellular powerhouses. This leads to decreased muscle strength and poor recovery from illness or surgery. Dr. O’Neill’s previous work showed that mice with Type 1 diabetes have mitochondrial problems in muscle. Intriguingly, the mitochondria of these diabetic mice had increased levels of protein called Lrrc2, which seemed to be helping increase energy production to compensate for the diabetic state of the animals. The goal of this new project is to see if Lrrc2 is indeed a beneficial factor for mitochondrial function in diabetes. In aim 1, they will test whether increased Lrrc2 expression improves mitochondria and strength in diabetic muscle. Aim 2 will determine which other proteins interact with Lrrc2 in normal and diabetic muscle. These studies on Lrrc2 will help better understand the connections between diabetes, mitochondria, and muscle weakness that contributes to disability.

Thorsten Maretzky, PhD, Assistant Professor of Internal Medicine-Infectious Diseases

Project: Novel functions of the inactive rhomboid protein 2 in diet-induced obesity In obesity, fat undergoes significant changes, impacting metabolic health. These changes include increase in size and number of fat cells. Dr. Maretzky’s research focuses on understanding this balance and the role of iRhom2, a protein known for regulating cell surface molecules related to inflammation and cell growth. His preliminary findings show that iRhom2 dramatically alters how adipose tissue responds during excess dietary intake. The goal of his new project is to uncover the intricate processes that iRhom2 uses to alter fat structure and function in obesity, offering insights into potential metabolic disorder therapies.

Seed Grant Winners

Sukirth Ganesan, BDS, PhD, Assistant Professor, Department of Periodontics, College of Dentistry 

Project: Determining the Role of Perfluoroalkyl Substances (PFAS) in the Oral Environment of Children with Obesity and Metabolic Syndrome Evidence is rapidly accumulating for the worldwide environmental contamination of air and water by Perfluroalkyl substances (PFAS), a class of synthetic chemicals, also known as ‘Forever Chemicals’ leading to widespread human exposure such that, in many developed countries, nearly all individuals have detectable PFAS in their blood. Emerging evidence link PFAS exposure to a wide range of adverse health effects including insulin resistance and diabetes, altered glucose homeostasis, and obesity in adolescents and children. While blood markers for PFAS exposure are being actively investigated, such investigations in saliva are yet to be performed. Dr. Ganesan’s studies will search for potential associations between PFAS levels in saliva and childhood diabetes and Obesity.

Gourav Bhardwaj, MSc, PhD, Research Assistant Professor, Internal Medicine-Endocrinology/Metabolism 

Project: Generation of a cardiomyocyte-restricted inducible striated muscle-enriched protein kinase (Speg) overexpression mouse model to determine the role FoxO3-Speg axis in Diabetic Cardiomyopathy Patients with diabetes are at a high risk of developing heart failure with preserved ejection fraction, an emerging epidemic without effective treatment strategies. Heart abnormalities and calcium mishandling are the characteristics of diabetic cardiomyopathy, but the underlying processes are incompletely understood. Dr. Bhardwaj recently discovered that a calcium regulating protein called striated muscle-enriched protein kinase (abbreviated as Speg) was decreased in hearts of diabetic animals. Support from this seed grant will be used to generate an animal model that enable increasing levels of Speg specifically in heart cells. This work will help determine the role of Speg in diabetic cardiomyopathy and improve our understanding of heart failure progression in patients with diabetes.

Women who develop gestational diabetes during pregnancy are two times more likely to develop cardiovascular disease and 7 times more likely to develop type 2 diabetes in the decade after pregnancy, but the reason why this occurs is unclear and there are currently no specific treatment strategies to prevent this disease progression.

This project addresses this public health issue. The grant will help fund her research for the next five years. “I was very surprised and really excited,” Stanhewicz says on earning the grant. “Career-wise, it’s a big step; getting this grant will help me continue to establish my work at the university, as an independent investigator capable of conducting meaningful research on campus.” 

Stanhewicz reflects that, although she had long researched high blood pressure during pregnancy, it was the FOEDRC that inspired her to craft a research plan to study gestational diabetes. During her first summer at the university, when the pandemic was at its peak and human volunteers were low, the FOEDRC sent out a call for proposals, which Stanhewicz was happy to respond to. 

The FOEDRC reviewed her proposal favorably, recognizing the potential impact of her project. The pilot grant funding from the FOEDRC helped her research project grow into what eventually received the major federal NIH grant. “If it weren’t for the diabetes research center, I probably wouldn’t have pursued this research question at all,” Stanhewicz explains. 

Stanhewicz says she is grateful to the diabetes research center, but also to the people who volunteer their time for the sake of research. “All the research that we do in my lab and in a lot of groups on campus is really dependent on human volunteer subjects, so we’re really indebted and appreciative of them for the effort that they put into the work,” says Stanhewicz. “As scientists, we get a lot of credit, but the participants really are an equal part of the team. We appreciate them.”

Type 2 diabetes is a disease of metabolism. The body’s metabolism produces hundreds to thousands of small molecules by controlling chemical reactions throughout the body. These processes go awry in type 2 diabetes in a manner that results in elevated blood sugar levels. The FOEDRC Metabolomics Core aids researchers to better understand how changes in the body’s metabolism contribute to type 2 diabetes. 

Because the body’s metabolism includes thousands of chemical reactions that can differ across cells and tissue types, it can be extraordinarily complex and challenging to investigate. The FOEDRC Metabolomics Core Facility helps solve that problem. Studying diabetes metabolism is very complex and requires great expertise. We are fortunate that the FOEDRC Metabolomics Core is directed by a leading expert in diabetes metabolism, Dr. Eric Taylor, who has published his work on diabetes metabolism in leading journals and his research program is funded by grants from the NIH. Using state-of-the-art mass spectrometry, the FOEDRC Metabolomics Core measures the levels of over 300 metabolites from the metabolome in very small amounts of biological samples. 

An especially unique capability of the FOEDRC Metabolomics Core relate to a technique called isotope tracing. This technique allows scientists to follow a metabolic compound as it undergoes biochemical reactions in the body, thereby providing unparalleled insights into the metabolic pathways. This tracing technique reveals properties of metabolism that cannot be clearly observed by simply measuring metabolite levels and is especially important for understanding mechanisms of disease. 

The high-resolution mass spectrometers in the FOEDRC Metabolomics Core make isotope tracing and therefore a deeper investigation of diabetes metabolism possible. Currently, the FOEDRC Metabolomics Core analyzes about 500 samples per month, with the majority coming from the FOEDRC and other University of Iowa researchers. 

Nonetheless, as the capabilities of the FOEDRC Metabolomics Core have become more broadly recognized, we have begun to receive samples from external research scientists, including Iowa State University and 9 other Universities outside of Iowa. A major goal of the Core for the coming year is to develop cutting-edge assays with their new isotope ratio mass spectrometer. 

This instrument enables measurement of the total amount of different tracers in extremely small amount of sample. This is especially useful for measuring properties of metabolism like metabolic rate or how fast glucose is being used by the body. This could lead to the identification of novel targets to improve or develop new treatments for diabetes.

This publication is notable because in it Dr. Sebag and his colleagues report for the first time a new approach to treat diabetes. The new approach uses a molecule they designed that activates a protein called GLUT4 that removes glucose from the blood stream in response to insulin. 

Under normal conditions, GLUT4 transport glucose from the blood to tissues such as skeletal muscle and adipose tissue where it is utilized or stored. The GLUT4 activation process is impaired in type 2 diabetes leading to high levels of glucose in the blood. 

Dr. Sebag reasoned that restoring the activation of GLUT4 should lower blood glucose and protect from type 2 diabetes. To achieve this, he developed a novel high throughput assay that allowed him to screen 50,000 molecules to identify those that can restore GLUT4 activation. In addition, he generated a new mouse model that enables measurement of GLUT4 activation in live animals. 

Using these brand new tools, Dr. Sebag identified an example molecule that improved the activation of GLUT4 by insulin and promoted glucose removal from the blood. He then synthesized several new molecules based on the example molecule, finding ones that are even more potent at restoring GLUT4 activation. 

When given to a mouse model of type 2 diabetes, these new molecules significantly improved the ability of those animals to maintain normal blood glucose. Importantly, he identified the target of the new molecules as the protein called Unc119b. This protein has not previously been implicated in the control of glucose homeostasis and this represent a new potential target for the development of anti-diabetic drugs. 

Ultimately, Dr. Sebag’s study represents a significant advance in the diabetes field since it identifies a new mechanism and new molecules to improve glucose abnormalities in type 2 diabetes. Ongoing work in Dr. Sebag’s lab is aimed at moving these results to humans by testing the safety and efficacy of these new molecules to treat diabetes in people.