About

Raghu G Mirmira, MD, PhD, is a physician–scientist specializing in diabetes, β-cell biology, and translational endocrinology. He is a tenured Professor of Medicine at the University of Chicago, where he also serves as Director of the NIH-funded Diabetes Research and Training Center and Vice Chair for Research in the Department of Medicine. Dr. Mirmira completed his MD and PhD training at the University of Chicago, followed by residency and fellowship training at the University of California, San Francisco, where he was a Howard Hughes Physician Postdoctoral Fellow. His research focuses on understanding the mechanisms that lead to pancreatic β-cell dysfunction and loss in diabetes, examining transcriptional control of β-cell identity, inflammatory pathways including 12-lipoxygenase, and stress-response mechanisms affecting β-cell survival. His laboratory has contributed to the development of biomarkers reflecting β-cell stress and injury in individuals with or at risk for type 1 diabetes, employing molecular, cellular, human islet studies, and translational approaches to inform new therapeutic strategies. Dr. Mirmira has maintained continuous NIH funding for over two decades and is recognized for his contributions to mentorship and training, receiving the Albert Renold Award from the American Diabetes Association.

Research topics

• Endocrinology
• Biology
• Medicine
• Internal medicine
• Genetics
• Immunology
• Political Science
• Computational biology
• Cancer research
• Virology
• Law
• Intensive care medicine
• Surgery
• Bioinformatics
• Physiology
• Biochemistry
• Cell biology

Selected publications

• Assessing extracellular vesicle proteins as predictive biomarkers for developing type 1 diabetes

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-02-09

  articleOpen access

  Plasma extracellular vesicles (EVs) are considered excellent sources for biomarker discovery since they carry signatures of their cellular origin and disease processes. In this paper, we evaluate the potential of plasma EV proteomics analysis for identifying predictive biomarkers of developing type 1 diabetes (T1D), which results from autoimmune destruction of insulin-producing β cells in the islet. We used strong anion exchange beads (Mag-Net) to capture plasma EVs from 19 donors with islet autoimmunity (diagnosed by circulating autoantibodies against islet proteins - AAB+) vs. 17 control individuals and analyzed their protein cargo by mass spectrometry. The analysis identified and quantified 5,480 proteins, a 3.2-fold increase in proteome coverage compared to our previous T1D biomarker proteomics study that used whole plasma depleted of the 14 most abundant proteins. The Mag-Net approach also detected 1,306 out of the 1,717 proteins (76%) that we previously verified as EV proteins. Statistical tests revealed 448 proteins to be differentially abundant in AAB+ vs control volunteers, including 69 previously verified EV proteins. A functional-enrichment analysis resulted in overrepresentation of 25 pathways among the differentially abundant proteins, including pathways related to autoimmune response and lipid metabolism. The capacity of this data to predict AAB+ was tested with a machine learning analysis using a random forest model, resulting in a receiver operating characteristic-area under the curve of 0.81. Overall, our study indicates that plasma EV proteomics analysis can be an exciting approach for studying biomarkers for developing T1D. Significance of the study: Type 1 diabetes (T1D) is a disease characterized by the body's inability to produce insulin and consequently, to control blood glucose levels. Despite the initial trigger being unclear, the disease development process involves an autoimmune response to the islets of Langerhans, resulting in the death of insulin-producing β cells. There is no cure for the disease, and treatment relies on exogenous administration of insulin. Therefore, preventive therapies that block the autoimmune process are attractive for treating T1D. In fact, anti-CD3 antibody (Teplizumab) delays the onset of T1D by 2 years by targeting T cells. Predictive biomarkers for developing T1D are needed to aid the development and implementation of new therapies and to identify the initial trigger and mechanisms of the islet autoimmune process. In this paper, we assess the potential of plasma extracellular vesicle (EV) proteomics analysis for identifying predictive biomarkers of T1D. Our results show excellent potential of the approach, opening opportunities to perform broader studies to identify biomarkers for developing T1D.

  PublisherOA PDFDOI

• Beta cell microRNAs function as molecular hubs of type 1 diabetes pathogenesis and as biomarkers of diabetes risk

  Diabetologia · 2026-04-21

  articleOpen access

  Abstract Aims/hypothesis Clinically actionable biomarkers that accurately reflect the health status of the beta cell are needed to improve risk stratification and optimise the timing of interventions in type 1 diabetes. We hypothesised that inflammatory stress elicits a reproducible microRNA (miRNA) program in human islets and islet-derived extracellular vesicles (EVs) that can be detected in plasma EVs to stratify diabetes risk, while also providing insight into molecular pathways linked to beta cell dysfunction. Methods Human islets were exposed to IL-1β+IFN-γ, and small RNA-seq was performed on islets and islet-derived EVs. Differentially expressed miRNAs were validated in islets, using RT-PCR, in plasma-derived EVs from individuals with autoantibody positivity (AAb + ) or recent-onset type 1 diabetes and matched control individuals using ultrasensitive, label-free localised surface plasmon resonance (LSPR) biosensors, and in pancreatic sections from organ donors using in situ hybridisation and spatial feature analysis. Finally, beta cell-targeted in vivo inhibition of miR-155 was tested in the NOD mouse model. Results Inflammatory cytokine exposure altered a restricted subset of miRNAs, identifying 20 differentially expressed miRNAs in islets and 14 in islet-derived EVs. Only two miRNAs, miR-155-5p and miR-146a-5p, were concordantly upregulated in both compartments. Machine learning prioritised an EV miRNA panel for translational validation, and custom LSPR biosensors enabled quantification of these miRNAs in plasma EVs. This plasma EV miRNA signature, consisting of miR-155-5p, miR-146a-5p, miR-30c-1-3p, miR-802 and miR-124-3p, differentiated individuals with AAb + and those with recent-onset type 1 diabetes from control individuals with good sensitivity and specificity. In pancreatic tissue, miR-155 abundance and beta cell spatial/subcellular distribution were altered in donors with AAb + and type 1 diabetes compared with non-diabetic control individuals. Functionally, beta cell-targeted inhibition of miR-155 improved glucose tolerance and reduced insulitis in prediabetic NOD mice. Conclusions/interpretation Using an organ-based model system of inflammatory stress, we validated a signature of EV-associated miRNAs capable of stratifying type 1 diabetes risk. Furthermore, we provided new mechanistic and imaging insights into miRNA expression patterns in pancreatic sections from human organ donors with type 1 diabetes or AAb + , and we used a preclinical model of type 1 diabetes to demonstrate the potential therapeutic efficacy of targeting these miRNAs. Data availability The data from small RNA sequencig of human islets and islet-derived EVs have been deposited in the GEO database (accession no. GSE160391). Graphical Abstract

  PublisherDOI

• Using animal models to decipher the role of polyamines in the pancreas and β Cell

  Amino Acids · 2026-02-12

  articleOpen access

  Pancreatic islet β cells are insulin-secreting cells that are responsible for sensing blood glucose levels and maintaining normoglycemia. Polyamines are vital to supporting the transcriptional and translational demands placed on secretory cells such as the β cell; however, recent evidence suggests the polyamine pathway may also be detrimental to normal β cell function. β cell dysfunction instigated by inflammation is common to both type 1 and type 2 diabetes, and notably, interventions that target the polyamine pathway may offer therapeutic benefits. The objective of this review is to synthesize the roles of polyamine metabolism in the pancreas and to frame this pathway as a link between nutrient status, immune activation, and β cell stress in diabetes. This review summarizes key findings from animal models used to study the polyamine pathway in pancreatic islet growth, development, and function. It also explores the prospects of polyamine inhibition to modify diabetes pathogenesis and improve β cell health.

  PublisherDOI

• IL-1β priming triggers an adaptive stress response that enhances pancreatic β-cell resilience to subsequent cytotoxic inflammatory insult

  Cell Death and Disease · 2025-10-21 · 5 citations

  reviewOpen access

  Abstract Pancreatic β-cells fine-tune glucose homeostasis through insulin secretion. The endoplasmic reticulum (ER) is critical for insulin production, relying on the unfolded protein response (UPR) to adapt to the body’s fluctuating demands. Islets from both type 1 (T1D) and type 2 diabetes (T2D) exhibit inflammation, β-cell dysfunction, and loss. ER stress is present in the inflamed islets of autoimmune diabetes-prone mice and individuals with T1D and T2D. Inflammatory cytokines induce ER stress and disrupt UPR regulation, driving β-cell apoptosis and contributing to diabetes development. Inflammatory cytokines, e.g ., IL-1β, impair β-cell function and survival, contributing to diabetes pathogenesis by inducing stress, altering gene expression, driving dedifferentiation, and reducing insulin production. Paradoxically, β-cells exhibit a high density of IL-1R1, and IL-1R1/KO mice display impaired glucose tolerance and reduced insulin secretion. Postprandial IL-1β secreted by macrophages helps maintain blood glucose homeostasis. These observations suggest that circulating low IL-1β concentrations may have physiologically relevant roles; however, their effects on β-cell function and survival remain unclear due to conflicting reports. Preconditioning β-cells with physiological circulating levels of IL-1β (IL-1β low ) induced a resilient state, protecting them from pro-inflammatory cytokine (CYT)-induced cell death while preserving glucose-stimulated insulin secretion through hormesis. IL-1β low -treated INS-1E cells reduced CYT-induced NO secretion by suppressing NF-κB signaling and decreasing iNOS expression, correlating with reduced β-cell death. IL-1β low conditioning reduced ER stress and upregulated p-eIF2α in response to CYT, thereby enhancing the expression of ER chaperones and biomarkers linked to improved β-cell identity/functionality. Transcriptomic analysis revealed that IL-1β low preconditioning mitigated the CYT-induced loss of genes involved in β-cell function/identity, and suppressed the expression of genes linked to NF-κB signaling, cytokine-induced inflammation, and apoptosis. IL-1β low treatment counteracted the upregulation of stress-related genes triggered by pro-inflammatory stimuli. Enhancing IL-1β low -induced stress-response hormesis may provide a novel strategy to sustain β-cell function and survival during harmful diabetic inflammation.

  PublisherOA PDFDOI

• Supplementary Figures S1-S7 from The Polyamine–Hypusine Circuit Controls an Oncogenic Translational Program Essential for Malignant Conversion in MYC-Driven Lymphoma

  2025-11-24

  articleOpen access

  <p>Supplementary Figures S1-S7 includes Supplementary Figure S1-S7 and the figure legend for each figure. Supplementary Fig. S1 shows that the polyamine-hypusine circuit is activated in many human cancers including MYC-driven lymphoma. Supplementary Fig. S1 is related to Fig. 1. Supplementary Fig. S2 shows that inhibition of DHPS enzyme activity, or silencing eIF5A or DHPS, suppresses the growth of mouse MYC-driven lymphoma. Supplementary Fig. S2 is related to Fig. 2. Supplementary Fig. S3 shows that hypusinated eIF5A (eIF5AHyp) contributes to the tumorigenic potential and maintenance of MYC-driven lymphoma. Supplementary Fig. S3 is related to Fig. 3. Supplementary Fig. S4 shows the effects of eIF5A or DHPS depletion on the transcriptional landscape of MYC-driven lymphoma. Supplementary Fig. S4 is related to Fig. 4. Supplementary Fig. S5 shows that depletion of eIF5A or DHPS impairs the translation efficiency of subsets of mRNA in MYC-driven lymphoma. Supplementary Fig. S5 is related to Fig. 5. Supplementary Fig. S6 shows the validation of select eIF5AHyp translation targets identified by the multi-omics analyses, and that the translation of key regulatory cell cycle factors is controlled by hypusinated eIF5A. Supplementary Fig. S6 is related to Fig. 6. Supplementary Fig. S7 shows that hypusinated eIF5A is essential for the development of MYC-driven lymphoma. Supplementary Fig. S7 is related to Fig. 7.</p>

  PublisherDOI

• Reshaping lipid metabolism with long-term alternate day feeding in type 2 diabetes mice

  npj Metabolic Health and Disease · 2025-02-03 · 2 citations

  articleOpen access

  Strategies to improve metabolic health include calorie restriction, time restricted eating and fasting several days per week or month. These approaches have demonstrated benefits for individuals experiencing obesity, metabolic syndrome, and prediabetes. However, their impact on established diabetes remains incompletely studied. The chronicity of type 2 diabetes (T2D) requires that interventions must be undertaken for extended periods of time, typically the entire lifetime of the individual. In this study, we examined the impact of intermittent fasting (IF), with an every-other-day protocol for a duration of 6 months in a murine model of T2D, the db/db (D) mouse on metabolism and liver steatosis. We compared D-IF mice with diabetic ad-libitum (AL; D-AL), control-IF (C-IF) and control-AL (C-AL) cohorts. We demonstrated using lipidomic, microbiome, metabolomic and liver transcriptomic studies that chronic IF improved carbohydrate utilization and glucose homeostasis without weight loss and reduced white adipose tissue inflammation and significantly impacted lipid metabolism in the liver. Microbiome studies and predicted functional analysis of gut microbiota showed that IF increased beneficial bacteria involved in sphingolipid (SL) metabolism. The metabolomic studies showed that oxidation of lipid species and ceramide levels were reduced in D-IF compared to D-AL. The liver lipidomic analysis and liver microarray confirmed a reduction in overall lipid content in D-IF mice compared to D-AL mice, especially in the feeding state as well as an overall reduction in oxidized lipids and ceramides. These studies support that long-term IF can improve glucose homeostasis and dramatically altered lipid metabolism in the absence of weight loss.

  PublisherOA PDFDOI

• The G Protein-Coupled Receptor GPR31 Promotes Pro-inflammatory Responses in Pancreatic Islets and Macrophages

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-04

  preprintOpen access

  ABSTRACT In type 1 diabetes (T1D), the innate and adaptive immune systems attack and eventually destroy the insulin-secreting pancreatic β cells. During this process, β cells activate inflammatory signaling pathways that augment the dysfunction and destruction imposed by cellular autoimmunity. The 12-lipoxygenase (12-LOX) pathway produces the pro-inflammatory eicosanoid 12-HETE, which induces oxidative and endoplasmic reticulum stress and results in diminished insulin secretion and apoptosis. The G protein-coupled receptor GPR31 has been identified as a putative receptor for 12-HETE. In this study, we generated conventional GPR31 knockout (KO) mice on the C57BL/6J background. To interrogate the role of GPR31 in β cells, we treated islets from wildtype and Gpr31b KO mice with pro-inflammatory cytokines and subjected the islets to RNA sequencing. Differentially expressed pathways in Gpr31b KO islets included those pertaining to inflammation and oxidative stress, consistent with functional studies that demonstrated reduced cytokine-induced oxidative stress in Gpr31b KO islets compared to wildtype controls. Bone marrow-derived macrophages from Gpr31b KO mice showed reduced macrophage migration and decreased inflammatory IFN-α and IFN-γ signaling by RNA sequencing. To mimic islet and macrophage inflammation as seen in T1D, wildtype and Gpr31b KO mice were treated with the diabetogenic toxin streptozotocin. Compared to wildtype, Gpr31b KO mice had improved glucose tolerance and preserved β-cell mass. siRNA knockdown of Gpr31b in non-obese diabetic (NOD) mice reduced insulitis, macrophage infiltration, and oxidative stress. Collectively, these findings are consistent with previously published data using 12/15-LOX KO mice and suggest that GPR31 mediates the pro-inflammatory responses of 12-HETE in both β cells and macrophages.

  PublisherOA PDFDOI

• Proinflammatory stress activates neutral sphingomyelinase 2 based generation of a ceramide-enriched β-cell EV subpopulation

  2025-09-02

  articleOpen access

  <p dir="ltr">β-cell extracellular vesicles (EVs) play a role as paracrine effectors in islet health, yet mechanisms connecting β-cell stress to changes in EV cargo and potential impacts on diabetes remain poorly defined. We hypothesized that β-cell inflammatory stress engages neutral sphingomyelinase 2 (nSMase2)-dependent EV formation pathways, generating ceramide-enriched small EVs that could impact surrounding β cells. Consistent with this, proinflammatory cytokine treatment of INS-1 β cells and human islets concurrently increased β-cell nSMase2 and ceramide abundance, as well as small EV ceramide species. Direct chemical activation or genetic knockdown of nSMase2, chemical treatment to inhibit cell death pathways, or treatment with a GLP-1 receptor agonist also modulated β-cell EV ceramide. RNA sequencing of ceramide-enriched EVs identified a distinct set of miRNAs linked to β-cell function and identity. EV treatment from cytokine-exposed parent cells inhibited peak GSIS in wild-type recipient cells; this effect was abrogated when using EVs from nSMase2 knockdown parent cells. Finally, plasma EVs in children with recent-onset T1D showed increases in multiple ceramide species. These findings highlight nSMase2 as a regulator of β-cell EV cargo and identify ceramide-enriched EV populations as a contributor to EV-related paracrine signaling under conditions of β-cell inflammatory stress and death.</p>

  PublisherDOI

• The Heterogeneity of Type 1 Diabetes: Implications for Pathogenesis, Prevention, and Treatment—2024 <i>Diabetes</i>, <i>Diabetes Care</i>, and <i>Diabetologia</i> Expert Forum

  Diabetes · 2025-07-30 · 5 citations

  reviewOpen access

  This article summarizes the current understanding of the heterogeneity of type 1 diabetes from a June 2024 international Expert Forum organized by the editors of Diabetes, Diabetes Care, and Diabetologia. The Forum reviewed key factors contributing to the development and progression of type 1 diabetes and outlined specific, high-priority research questions. Knowledge gaps were identified, and, notably, opportunities to harness disease heterogeneity to develop personalized therapies were outlined. Herein, we summarize our discussions and review the heterogeneity of genetic risk and immunologic and metabolic phenotypes that influence and characterize type 1 diabetes progression (presented as a palette of risk factors). We discuss how these age-related factors determine disease aggressiveness (along gradients) and describe how variable immunogenetic pathways aggregate (into networks) to affect β-cell and other pancreatic pathologies to cause clinical disease at different ages and with variable severity (described as disease-related thresholds). Heterogeneity of pathogenesis and clinical severity opens avenues to prevention and intervention, including the potential of disease-modifying immunotherapy and islet cell replacement. We conclude with a call for 1) continued research to identify more factors contributing to the disease, both overall and in specific subgroups; 2) investigations focusing on both individuals who surpass metabolic and immune thresholds and develop diabetes and those who remain disease free with the same level of immunogenetic risk; and 3) efforts to identify where the current type 1 diabetes staging system may fall short and determine how it can be improved to capture and leverage heterogeneity in prevention and intervention strategies.

  PublisherOA PDFDOI

• A consensus guide to preclinical indirect calorimetry experiments

  Nature Metabolism · 2025-09-24 · 14 citations

  reviewOpen access
  PublisherOA PDFDOI

Recent grants

• Genetics and Genomics Core

  NIH · $38.6M · 1996–2028

• NIH Grant K08DK002683

  NIH · $611k · 2004

• Novel therapeutic for treatment of type 1 diabetes

  NIH · $300k · 2020–2022

• Role of 12-lipoxygenase and 12-HETE signaling in beta-cell dysfunction

  NIH · $5.5M · 2015–2026

• Polyamines and Hypusine in Type 1 Diabetes Pathogenesis

  NIH · $3.4M · 2020–2030

Frequent coauthors

• Sarah A. Tersey

  University of Chicago

  313 shared

• Carmella Evans‐Molina

  260 shared

• Bernhard Maier

  Indiana University

  127 shared

• Emily K. Sims

  Indiana University – Purdue University Indianapolis

  122 shared

• Teresa L. Mastracci

  Indiana University School of Medicine

  107 shared

• Farooq Syed

  Diabetes Australia

  94 shared

• Ryan M. Anderson

  University of Chicago

  72 shared

• Linda A. DiMeglio

  Indiana University – Purdue University Indianapolis

  65 shared

Labs

• Raghu G Mirmira LabPI

Education

• M.D.

  University of Chicago

• Ph.D.

  University of Chicago

Awards & honors

• Albert Renold Award from the American Diabetes Association