Research Summary

IBRI DIABETES CENTER (IDC) - EIZIRIK LAB

Focus: Mechanisms of beta-cell dysfunction and death in type 1 diabetes (T1D) the dialog between beta-cells and the immune system

Type 1 diabetes (T1D) is one of the most common chronic diseases in children, shortening lifespan by >10 years. Its incidence is growing at an alarming rate, making T1D a major health challenge. T1D results from the interaction between predisposing genes and environmental factors, such as viral infections, triggering an autoimmune attack against pancreatic beta-cells that provokes islet inflammation and progressive beta-cell loss due to apoptosis. Islet inflammation takes place in the context of a dialogue between invading immune cells and the targeted beta-cells. This dialog is modulated by T1D candidate genes acting on both immune and pancreatic beta-cells, and by inflammatory mediators (cytokines and chemokines).

Recent studies from the Eizirik team suggest that stress pathways triggered within beta cells early in T1D may initiate and/or accelerate autoimmune beta-cell destruction. These studies also show that T1D candidate genes regulate beta-cell responses to “danger signals”, innate immunity and activation of apoptosis, affecting the beta-cell phenotype. The molecular mechanisms linking genetic variation, environmental factors and the signaling events promoting beta-cell dysfunction and loss remain poorly understood, and this is the main research focus of the Eizirik laboratory.

Specific scientific areas of focus in the lab include:

Understanding the dialogue between the beta cells and the immune system in early T1D.

Dr. Eizirik research interest focuses on the molecular pathways leading to beta-cell dysfunction and death in type 1 diabetes (T1D). His work has led to fundamental concepts such as the dialogue between the immune system and beta-cells that triggers and amplifies insulitis and beta-cell damage. He pioneered studies on global gene expression in pancreatic beta-cells, clarifying the cytokine-, virus- and metabolically-regulated gene networks that define beta-cell dysfunction and death in diabetes. This led to the discovery: a. that key “beta-cell gene modules” define the beta-cell outcomes following injury; b. that >80% of the candidate genes for T1D are expressed in human islets, and expression of at least half of them is modified by cytokines or viral infections. He studied the function of several of these candidate genes, observing that most of them regulate local innate immune responses, particularly type I IFN signaling.

Two other research lines from his group focus on the role of the endoplasmic reticulum (ER) stress and alternative splicing (AS) in beta-cell dysfunction and death and on multi-omics analysis of stress human beta-cells. These multi-omics databases generated are also used to mine for specific-beta cell surface proteins, that can be used for beta-cell imaging and for the targeting of potentially protective agents. Recent findings from his group identified the key role for the type 1 interferon (IFN) IFNa in the induction of three hallmarks of early human beta-cell dysfunction in T1D, namely HLA class I overexpression, ER stress and apoptosis. Interestingly, type 1 IFNs also induce beta-cell “defense” mechanisms against the immune system, such as PDL1 expression. His group is now focusing on characterizing the signal transduction behind these deleterious or beneficial effects of IFNa with the aim to discover novel therapies that may prevent its pro-inflammatory signals while preserving the protective ones.

Use of human iPSC-derived beta cells to characterize the function of candidate genes for T1D acting at the beta cell level.

iPSCs from T1D donors and normoglycemic individuals with relevant risk variants – mostly related to type 1 IFN signal transduction - are differentiated into human pre-beta cells using a well-established 7-step procedure. Isogenic controls for these cells are developed using CRISPR/Cas9. These cells, once differentiated, provide a unique model to understand the role of these candidate genes in beta-cells and in the dialog between beta-cells and the immune system. Furthermore, they provide a unique model to screen for novel drugs that may arrest this dialog and protect beta-cells against cytokine-induced apoptosis.

Lab Team

Olivia Ballew

Olivia Ballew

Postdoctoral Fellow, IBRI Diabetes Center

Olivia Ballew

Olivia Ballew

Postdoctoral Fellow, IBRI Diabetes Center

Olivia Ballew, PhD, joined the IBRI in August 2020 as a postdoctoral fellow. She works on the mechanisms of pancreatic beta-cell dysfunction in type 1 diabetes in the lBRI Diabetes Center under Dr. Decio Eizirik.

Prior to joining the IBRI, Olivia completed her PhD at Indiana University. Under Dr. Soni Lacefield, Olivia studied the mechanisms underlying meiotic commitment in Saccharomyces cerevisiae. She discovered novel roles for two checkpoints in ensuring meiotic commitment.

Olivia received her Bachelor of Science degree in Biology from the University of North Carolina at Chapel Hill in 2012.

Additionally, Olivia competes at the elite level in the marathon. She qualified for and ran in the 2020 U.S. Olympic Trials.

Stephane Demine

Stephane Demine

Postdoctoral Fellow, IBRI Diabetes Center

Stephane Demine

Stephane Demine

Postdoctoral Fellow, IBRI Diabetes Center

Stephane Demine is a postdoctoral fellow working in the Lilly Diabetes Center of Excellence located here in the Diabetes Center. He works with Decio Eizirik, whom he partnered with at the University of Brussels.

While at the University of Brussels, he helped to identify new biomarkers suitable for the in vivo imaging of pancreatic beta cells, in collaboration with other universities (University of Mons, University of Brussels (VIB)) and industrial partners (Eurogentec). The most-advanced probe, a short camelid antibody targeting DPP6, was recently shown to accumulate in human beta cells grafted in mice and to correlate with the number of cells transplanted. The preclinical development of these probes is continuing at the IBRI Diabetes Center.

He also focused on the characterization of beta cells derived from human induced pluripotent stem cells (iPSC). He showed that human iPSC-derived beta cells respond to pro-inflammatory cytokines (IL-1β + IFNγ and IFNα), by activating the same pathogenic processes as adult human primary beta cells. These cells thus represent a valuable tool for future research on the pathogenesis of type 1 diabetes. His future goal is to use this cell model to better understand how some single nucleotide polymorphisms are associated to type 1 diabetes developments.

Stephane obtained his PhD at the University of Namur in Belgium in 2016, where he worked extensively on the elucidation of the molecular mechanisms triggered by a mild mitochondrial uncoupling in white adipocytes, a new anti-obesity therapeutic approach.

Decio Eizirik

Decio Eizirik, MD, PhD

Scientific Director, IBRI Diabetes Center

Decio Eizirik

Decio Eizirik, MD, PhD

Scientific Director, IBRI Diabetes Center

Dr. Eizirik is a Professor at the Université Libre de Bruxelles (ULB) Center for Diabetes Research, Brussels, Belgium, and a member of the ULB medical faculty. He is also an Investigator for the Indiana Biosciences Research Institute (IBRI) and Scientific Director of the IBRI Diabetes Center.

He has published more than 370 full papers and reviews in peer-reviewed international journals and has received several national and international prizes, including the Juvenile Diabetes Research Foundation (JDRF) Diabetes Care Research Award in 1998; the “2012 Albert Renold Prize Lecture for Outstanding Achievements in Research on the Islets of Langerhans” awarded by the European Association for the Study of Diabetes (EASD) in 2012, and the “2013 Rumbough Award for outstanding achievements in type 1 diabetes research” awarded by the JDRF.

Dr. Eizirik is listed by the ISI Essential Science Indicators among the 1 percent most cited scientists in Clinical Medicine and Biology & Biochemistry, with an h-index of 81. He has served as Honorary (Scientific) Secretary of the EASD and as Deputy Editor of Diabetologia, the official journal of the EASD. His research focuses on the molecular mechanisms regulating insulitis and beta cell apoptosis in type 1 diabetes, pancreatic beta cell imaging, generation of beta cells from inducible pluripotent cells and on the search for novel approaches to prevent the progressive loss of beta cell mass in diabetes.

Austin House

Austin House

Research Associate, IBRI Diabetes Center

Austin House

Austin House

Research Associate, IBRI Diabetes Center

Austin House joined the IBRI in July 2020 as a Research Associate in the IBRI Diabetes Center (IDC). He is part of a team focused on the molecular basis of diabetes and its complications, including mechanisms for beta cell regeneration. He and the IDC team are seeking to understand the disease while achieving technological breakthroughs in the way we diagnose, treat and manage diabetes in Indiana and beyond.

Prior to joining the IBRI, he served as a graduate research assistant at Southern Illinois University – Edwardsville, which is where he obtained his bachelor’s degree in chemistry in 2018 and just recently received his master’s degree in pharmacology.

Austin has a background in bioassays including qPCR, ELISA, calcium and nitrite assays. He also is experienced in cell culturing, CRISPR-Cas9 and plasmid cloning techniques. His recent work has been to evaluate an immortalized microglia cell model activated with LPS and treated with a drug toward the determination of whether treatment affects inflammatory pathways.

Daniel Preston

Daniel Preston

Research Associate, IBRI Diabetes Center

Daniel Preston

Daniel Preston

Research Associate, IBRI Diabetes Center

Daniel Preston joined the IBRI in July 2020 as a Research Associate in the lab of Dr. Decio Eizirik in the IBRI Diabetes Center. He is part of a team responsible for maintaining and differentiating inducible pluripotent stem cells (iPSC), deriving pancreatic beta cells and conducting functional studies utilizing iPSCs.

Prior to joining the IBRI, he worked as a molecular biologist for Advanced Testing Laboratories in the Lilly Research Labs, identifying novel biomarkers and studying their roles in several autoimmune diseases. From 2016 until 2019, he studied as a graduate student in the Blazer-Yost lab at Indiana University Purdue University Indianapolis. There he focused on identifying the molecular pathways responsible for the production and secretion of cerebrospinal fluid from the choroid plexus and contributed to studies aimed at ameliorating the pathophysiology associated with hydrocephalus.

Daniel received his Bachelor of Science in Biology and Bachelor of Arts in Chemistry from Indiana University Purdue University Indianapolis in 2015. He obtained his Master of Science in Biology with a focus on Molecular Biology and Cell Physiology from Indiana University Purdue University Indianapolis in 2019.

Donalyn Scheuner

Donalyn Scheuner, PhD

Senior Staff Scientist, IBRI Diabetes Center

Donalyn Scheuner

Donalyn Scheuner, PhD

Senior Staff Scientist, IBRI Diabetes Center

Donalyn Scheuner, Ph.D., joined the IBRI in March 2019 as Senior Staff Scientist in the IBRI Diabetes Center. In this role, she is responsible for planning and coordinating the research on the mechanisms of pancreatic beta-cell dysfunction and death in type 1 diabetes, working in close collaboration with Dr. Decio Eizirik.

Prior to the IBRI and since 2017, she worked as a Scientific Consultant for DLS Consulting in Greenfield, IN, on a multisite NIH project grant. From 2009 to 2017, she served as Senior Scientist in Islet Biology at Lilly Research Laboratories in Indianapolis. From 2004 to 2009, Dr. Scheuner was a Research Specialist at Howard Hughes Medical Institute (HHMI) at the University of Michigan, Ann Arbor, MI. From 1995 to 2004, she was a Postdoctoral Fellow at HHMI. And from 1994 to 1995, she was a Postdoctoral Fellow focusing on NIH Developmental Neurobiology and Neuroscience at Case Western Reserve University in Cleveland, OH.

Dr. Scheuner has been responsible for more than three-dozen scientific publications and nearly the same number of presentations, and she has been recognized with numerous honors, awards and fellowships. She earned her Ph.D. in Pharmacology at the University of Michigan in Ann Arbor, MI, and her B.S. in Chemistry, also at Michigan.


Highlights and Publications

  • Eizirik DL, Sammeth M, Bouckenooghe T, Bottu G, Sisino G, Igoillo-Esteve M, Ortis F, Santin I, Colli ML, Barthson J, Bouwens L, Hughes L, Gregory L, Lunter G, Marselli L, Marchetti P, McCarthy MI, Cnop M. The human pancreatic islet transcriptome: expression of candidate genes for type 1 diabetes and the impact of pro-inflammatory cytokines. PLoS Genetics 8: e1002552, 2012 
  • Nogueira TC, Paula FV, Villate O, Colli ML, Moura RF, Cunha DA, Marselli L, Marchetti P, Cnop M, Julier C, Eizirik DL. GLIS3, a susceptibility gene for type 1 and 2 diabetes mellitus, modulates pancreatic beta cell apoptosis via regulation of a splice variant of the BH3-only protein Bim. PLoS Genet 9: e1003532, 2013 
  • Marroqui L, Lopes M, Santos RSD, Roivainen M, Richardson S, Morgan N, Op de Beeck A, Eizirik DL. Differential cell autonomous immune responses determine the outcome of coxsackievirus infections in pancreatic β and α cells. eLIFE 4: e06990, 2015 
  • Gonzalez-Duque S, Azoury ME, Colli ML, Afonso G, Turatsinze J-V, Nigi L, Lalanne AI, Sebastiani G, Carre A, Pinto S, Culina S, Corcos N, Bugliani M, Marchetti P, Armanet M, Diedisheim M, Kyewski B, Steinmetz LM, Buus S, You S, Dubois-Laforgue D, Larger E, Beressi JP, Bruno G, Dotta F, Scharfmann R, Eizirik DL*, Verdier Y*, Vinh J*, Mallone R. Conventional and neo-antigenic peptides presented by ? cells are targeted by circulating naïve CD8+ T cells in type 1 diabetic and healthy donors. Cell Metab, 28: 946-960, 2018 (*equal contribution)
  • Ramos-Rodriguez M, Raurell-Vila H, Colli ML, Alvelos MI, Subirana M, Juan-Mateu J, Norris R, Turatsinze JV, Nakayasu ES, Webb-Robertson BJ, Marchetti P, Piemonti L, Esteller M, Todd JA, Metz TO, Eizirik DL, Pasquali L The impact of pro-inflammatory cytokines on the ?-cell regulatory landscape provides new insights into the genetics of type 1 diabetes. Nature Genet, “in press”, 2019
  • Eizirik DL, Pasquali L, Cnop M Pancreatic β-cells in type 1 and type 2 diabetes: different pathways to failure. Nature Rev Endocrinol, 16:349-362, 2020
  • Colli M, Ramos-Rodriguez M, Nakayasu E, Alvelos MI, Lopes M, Hill JL, Turatsinze J-V, Brachene AC, Russel MA, Raurell-Villa H, Castela A, Juan-Mateu J, Webb-Robertson B-J, Krogvold L, Dahl-Jorgensen K, Marselli L, Marchetti P, Richardson SJ, Morgan NG, Metz TO, Pasquali L, Eizirik DL. An integrated multi-omics approach identifies the landscape of interferon-alpha-mediated responses of human pancreatic beta cells. Nature Commun, 11: 2584-2601, 2020

View all publications