Developing a Diabetes Research Nexus

IBRI Diabetes Center

Researchers in the IBRI Diabetes Center (IDC), which includes the Lilly Diabetes Center of Excellence (LCDE) at the IBRI, focus on the molecular basis of diabetes and its complications, including mechanisms for beta cell regeneration.

Lilly Diabetes Center of Excellence

With the establishment last fall of the Lilly Diabetes Center of Excellence (LDCE), a collaboration between Eli Lilly and Company, Indiana University (IU) School of Medicine and the IBRI, the LDCE became the research core of the IBRI Diabetes Center (IDC).

The LDCE aims to become a nexus of strategically aligned basic diabetes research in central Indiana by recruiting promising and established principal investigators (PIs) who will pursue cutting-edge research in diabetes, diabetic complications and related metabolic disorders.

The PIs will have five-year sponsored appointments at the IBRI, subsidized by Lilly, as well as faculty appointments at the IU School of Medicine. Each PI will pursue their area of research with full academic freedom. Lilly is providing opportunities for close collaboration, including access to drug discovery tools and expertise, allowing faculty to rapidly explore the translational potential of their research. The LDCE will also serve as a bridge between academia and industry by providing opportunities for interaction, training and mentoring across the IBRI, Lilly and IU School of Medicine. 

Collaborations result in publications

Collaborations with investigators at the IU School of Medicine, Purdue University and University of Illinois-Chicago resulted in four publications in 2018 on a number of diabetes-related topics.

  • The first study examined the effects of GLP-1 on myocardial fuel selection. GLP-1 is a well-known hormone, produced in the small intestine, which stimulates insulin secretion and inhibits glucagon secretion. 
  • The second study examined the ability of oligomeric collagen encapsulation to increase the longevity of transplanted islets and thus to lower blood glucose in diabetic animals. 
  • The third study examined the contribution of inflammation to insulin resistance in polycystic ovarian syndrome. 
  • The fourth study found that non-nutritive sweeteners do not affect body weight and glycemia.

How does the brain respond to sweet taste?

Robert Considine

Robert Considine, Ph.D.
Professor of Medicine
Director, IBRI Diabetes Center

In 2018, IDC Director Dr. Robert Considine, who joined the IBRI last fall, and his team continued to conduct their research into diabetes and its complications and they made progress on a number of fronts.

With funding from the American Diabetes Association, Dr. Considine’s team continues to investigate how the brain responds to sweet taste, and how this response changes following gastric bypass surgery. A reduction in subject preference for sweet taste following surgery has been reported, but the brain areas responsible for this effect are unknown.

Using magnetic resonance imaging and the administration of sucrose to the tongue, the investigative team is measuring the activation of brain areas, including the primary gustatory cortex and reward areas. These studies may lead to a non-surgical solution to reduce the consumption of sweetened high-calorie foods and beverages.

The health benefit of nut consumption

Collaborator: Purdue University  

In collaboration with Dr. Richard Mattes, a leading nutrition scientist at Purdue University’s College of Health and Human Sciences, Dr. Considine’s team is also studying the ingestion of almonds as a means to reduce blood sugar, which will determine if the health benefits of the nuts are driven by the presence of greater body fat in the abdominal or gluteal region.

A manuscript describing the findings of this two-year clinical trial will be published in 2019. This study continues a long-standing collaboration between Drs. Considine and Mattes, which has already yielded three publications on the health benefits of nut consumption.

The quest to regenerate beta cells

Partner: Juvenile Diabetes Research Foundation (JDRF)

In addition to the LDCE and Dr. Considine’s group, the IDC includes the IBRI’s Regenerative Medicine and Metabolic Biology (RMMB) group led by Dr. Teresa Mastracci. This team uses mouse and zebrafish models to determine how cells in the pancreas develop, differentiate and regenerate.

The RMMB group continued to advance several discovery-based projects aiming to slow the progression of diabetes, including the role of developmental pathways in stimulating beta cell regeneration, novel progenitor cell populations as innovative cell sources for the differentiation of beta cells in vitro, and small molecule and drug repurposing to stimulate beta cell regeneration.

The generous Career Development Award granted to Dr. Mastracci in 2016 from the Juvenile Diabetes Research Foundation (JDRF) was renewed in 2018 for a third year and will continue to fund many aspects of this work.

New genetic disease discovered

Partner: Columbia University

In a major breakthrough, a collaboration between Dr. Mastracci’s group and Dr. Wendy Chung’s laboratory at Columbia University Irving Medical Center in New York City resulted in the discovery of a new monogenic disease: DHPS Deficiency.

This project identified the first mutations in the human deoxyhypusine synthase gene encoding the enzyme DHPS. The enzyme is required for the production of the unique amino acid hypusine, which works in every cell of the body to help make proteins. The significance is that these mutations reduce DHPS enzyme activity, which leads to clinical symptoms in humans, including neurodevelopmental delay and seizures.

As a result of this work, the DHPS Foundation provided financial support to Dr. Mastracci to create and study animal models that mimic the human DHPS mutations. This work is necessary to identify therapeutic targets and strategies to reduce the burden of disease for patients suffering from DHPS Deficiency.

Gene differences in short- and long-duration type 1 diabetes

Partners: IU School of Medicine and Université Libre de Bruxelles

Dr. Mastracci’s group published another significant article in 2018 reporting that pancreatic islets from donors with long-duration type 1 diabetes express different genes compared to islets from donors with the disease for only three years. This research, published in the journal, Diabetes, Obesity and Metabolism, was the result of a long-term collaboration with investigators from the Center for Diabetes and Metabolic Diseases at IU School of Medicine and the Center for Diabetes Research at Université Libre de Bruxelles in Belgium. The publication was recognized as the “Top Story of 2018” by Pancreatic Cell News

Drs. Mastracci and Considine also contributed to a recent publication showing that proinsulin can be detected in the blood of individuals with long-duration type 1 diabetes. These observations suggest that therapies addressing beta cell health could improve insulin secretion in patients with type 1 diabetes.

Additional diabetes research collaborations established by Dr. Mastracci are continuing with Drs. Raghu Mirmira, Linda DiMeglio and Emily Sims at IU School of Medicine, Dr. Gaurav Chopra at Purdue University, and Drs. Michael Pugia and Dan Robertson of the IBRI.

Leah Padgett, Ph.D.

Leah Padgett, Ph.D.

Leah Padgett, Ph.D., postdoctoral fellow, and a member of the IBRI’s Regenerative Medicine and Metabolic Biology (RMMB) group, which is part of the IBRI Diabetes Center, sets up a western blot analysis, a molecular biology technique used to assess protein expression.

The IBRI’s diabetes researchers have identified a molecular pathway that is important for pancreas development and cellular regeneration. Their goal is to determine how this pathway can be manipulated to preserve beta cells in the presence of diabetes.

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