Mirmira Lab

The research laboratory of Raghu Mirmira, MD, PhD, focuses on the pathogenesis of diabetes mellitus and the biology of the islet.

The Mirmira Lab is interested in three key areas: the role of mRNA translation in the cellular response of islet β cells to inflammation; the role of lipoxygenases in dysfunction of β cells in Type 1 and Type 2 diabetes; and the identification of biomarkers of β-cell stress and death in diabetes.

Active Research

The role of mRNA translation in the cellular response of islet β cells to inflammation.

The Mirmira Lab identified the unique amino acid hypusine (hydroxyputrescine lysine) in eIF5A as regulating a specific mRNA translational program under conditions of β cell stress and inflammation.  These studies point to inhibitors of the hypusine-forming pathway as a novel approach to limiting the β cell responses to stress in Type 1 and Type 2 diabetes.

Figure 1: Maier B, Tersey SA, Mirmira RG. (2010) Hypusine: a new target for therapeutic intervention in diabetic inflammation. Discovery Medicine 10(50): 18-23. PMID: 20670594.

The role of lipoxygenases in dysfunction of β cells in type 1 and type 2 diabetes.

Recent publications in the Mirmira Lab have shown that 12-LO products promote oxidative and ER stress in β cells.  Inhibition or deletion of 12-LO markedly reduces β cell stress and increases the activity of the Nrf2 transcription factor.  These studies have led to the identification of novel 12-LO inhibitors, in collaboration with Dr. J. Nadler, T. Holman, and D. Maloney.  These inhibitors are currently in pre-clinical testing.

Figure 2: Hernandex-Perez M, Chopra G, Fine J, Anderson RM, Benjamin C, Nalder JL, Maloney DJ, Tersey SA, Mirmira RG. (2017) Inhibition of 12/15-Lipoxygenase Protects Against β-Cell Oxidative Stress and Glycemic Deterioration in Mouse Models of Type 1 Diabetes. Diabetes, 66(11):2875-87. PMID: 28842399

Identification of biomarkers of β cell stress and death in diabetes.

Studies by the Mirmira Lab were the first to suggest that stress pathways—notably ER stress—in β cells sets in motion a process whereby β cells undergo dysfunction and possibly lead to the formation of “neoantigens.”  This work has contributed to the opening of an entirely new field in Type 1 diabetes, wherein the β cell rather than the immune system, may be central to the initiation and propagation of human Type 1 diabetes.  The Mirmira Lab is now focused on developing biomarkers to distinguish healthy β cells from dysfunctional, diabetes-prone β cells.

Figure 3: Tersey SA, Nishiki Y, Templin AT, Cabrera SM, Stull ND, Colvin SC, Evans-Molina C, Rickus JL, Maier B, Mirmira RG. (2012) Islet beta cell endoplasmic reticulum stress precedes the onset of type 1 diabetes in the non-obese diabetic mouse model. Diabetes 61(4): 818-27. PMID: 22442300; PMCID: PMC3314371.

Current Research Funding

Transcriptional Mechanisms Governing β-cell Differentiation

Validation of small molecule inhibitors of 12-lipoxygenase in metabolic disease

Biomarkers of beta cell stress in type 1 diabetes (BetaMarker)

Indiana Diabetes Research Center

Biomarkers of β Cell Stress and Death in T1D

Targeting Polyamines using DFMO in Persons with T1D

Indiana University (IU) Clinical Center for Chronic Pancreatitis Clinical Research Network

Recent Publications

Dr. Mirmira has contributed to more than 100 peer-reviewed publications. For a complete list of these works, find him on PubMed.

Fisher MM, Watkins RA, Blum JS, Evans-Molina C, Chalasani N, DiMeglio LA, Mather KJ, Tersey SA, Mirmira RG (2015). Elevations in Circulating Methylated and Unmethylated Preproinsulin DNA in New-Onset Type 1 Diabetes. Diabetes. 64:3867-72. PMID:  26216854.  PMCID:  PMC 4613977.

Maganti AV, Maier B, Tersey SA, Sampley ML, Mosley AL, Özcan S, Pachaiyappan B, Woster PM, Hunter CS, Stein R, Mirmira RG. (2015) Transcriptional Activity of the Islet β Cell Factor Pdx1 Is Augmented by Lysine Methylation Catalyzed by the Methyltransferase Set7/9. J. Biol. Chem. 290:9812–9822. PMID: 25713082. PMCID: PMC4392279.

Hernandez-Perez M, Chopra G, Fine J, Conteh AM, Anderson RM, Linnemann AK, Benjamin C, Nelson JB, Benninger KS, Nadler JL, Maloney DJ, Tersey SA, Mirmira RG.  (2017).  Inhibition of 12/15-Lipoxygenase Protects Against β Cell Oxidative Stress and Glycemic Deterioration in Mouse Models of Type 1 Diabetes.  Diabetes. 66(11):2875-2887  PMID: 28842399.  PMCID: PMC5652601

Simmons ZB, Morgan RC, Rose L, Nelson JB, Tersey SA, Mirmira RG. (2018) Hypoglycemia in a Patient with a Polyhormonal Pancreatic Neuroendocrine Tumor with Evidence of Endocrine Progenitors. J. Endocr Soc. 16;2(2):172-177 PMID:295568813. PMCID: 5841169

Mastracci TL, Turatsinze JV, Book BK, Restrepo IA, Pugia MJ, Wiebke EA, Pescovitz MD, Eizirik DL, Mirmira RG (2018). Distinct Gene Expression Pathways in Islets from Individuals with Short- and Long-Duration Type 1 Diabetes. Diabetes Obes Metab. 2018 Mar 22. [Epub ahead of print]. PMID: 29569324

Faculty Research Team

Raghu G. Mirmira, MD, PhD

Raghu G. Mirmira, MD, PhD

Director, Diabetes Research Center
Sarah A. Tersey, PhD

Sarah A. Tersey, PhD

Associate Research Professor of Pediatrics
Wenting Wu, PHD

Wenting Wu, PHD

Assistant Research Professor of Medical & Molecular Genetics
Kentaro Yamada, PhD

Kentaro Yamada, PhD

Research Associate in Pediatrics
Farooq Syed, PhD

Farooq Syed, PhD

Postdoctoral Fellow in Pediatrics
Christopher A. Reissaus, PHD

Christopher A. Reissaus, PHD

Postdoctoral Fellow in Pediatrics

Additional Research Team Members

Additional research team members include Marimar Hernandez-Perez, PhD (postdoctoral fellow), Abhishek Kulkarni (graduate student), Kara Orr (research analyst), Jennifer Nelson (research technician) and Karishma Randhave (research technician).