Dr. Jen Ikle completed a combined MD/PhD program at the University of Colorado Denver, Anschutz Medical campus. While earning her PhD, she worked in the lab of Dr. David Clouthier studying genetics and transcriptional regulatory networks, with an emphasis on craniofacial development in the embryo. After completion of her MD, Jen completed both Pediatrics Residency and Fellowship in Pediatric Endocrinology and Diabetes at Washington University in St. Louis and St. Louis Children’s Hospital. During her fellowship, Jen worked in the lab of Dr. Colin Nichols where she developed a passion for regulation of insulin secretion from the beta cells of the pancreas. She has a specific interest in the role of ATP-sensitive potassium (KATP) channels. Genetic disruption of these channels leads to neonatal diabetes (in KATP gain of function mutations) or congenital hyperinsulinism (in KATP loss of function mutations). Jen also has a clinical interest in diabetes and hyperinsulinism.

Clinical Focus

  • Pediatric Endocrinology

Boards, Advisory Committees, Professional Organizations

  • Member, American Diabetes Association (2020 - Present)
  • Member, Pediatric Endocrine Society (2017 - Present)
  • Member, American Academy of Pediatrics (2013 - Present)

Professional Education

  • Board Certification: American Board of Pediatrics, Pediatric Endocrinology
  • Fellowship: St Louis Children's Hospital Washington University (2020) MO
  • Board Certification: American Board of Pediatrics, Pediatrics (2017)
  • Residency: St Louis Children's Hospital Washington University Pediatric Residency (2017) MO
  • Medical Education: University of Colorado School of Medicine (2014) CO
  • Fellowship, Washington University and St. Louis Children's Hospital, Pediatric Endocrinology and Diabetes (2020)
  • Board Certification, American Board of Pediatrics, General Pediatrics (2017)
  • Residency, Washington University and St. Louis Children's Hospital, Pediatrics (2017)
  • Internship, Washington University and St. Louis Children's Hospital, Pediatrics (2015)
  • Ph.D., University of Colorado Denver, Cells, Stem Cells, and Developmental Biology (2012)
  • M.D., University of Colorado Denver (2014)

Current Research and Scholarly Interests

Jen is interested in the genetic factors that lead to abnormal beta-cell function and insulin secretion, causing disorders such as hyperinsulinism and neonatal diabetes. Jen’s current research focus is the use of zebrafish models, combined with genetics and genomics, to understand cellular and molecular mechanisms of glucose metabolism and elucidate previously unknown players involved in the regulation of insulin secretion.

All Publications

  • The use of precision diagnostics for monogenic diabetes: a systematic review and expert opinion. Communications medicine Murphy, R., Colclough, K., Pollin, T. I., Ikle, J. M., Svalastoga, P., Maloney, K. A., Saint-Martin, C., Molnes, J., Misra, S., Aukrust, I., de Franco, E., Flanagan, S. E., Njølstad, P. R., Billings, L. K., Owen, K. R., Gloyn, A. L. 2023; 3 (1): 136


    Monogenic diabetes presents opportunities for precision medicine but is underdiagnosed. This review systematically assessed the evidence for (1) clinical criteria and (2) methods for genetic testing for monogenic diabetes, summarized resources for (3) considering a gene or (4) variant as causal for monogenic diabetes, provided expert recommendations for (5) reporting of results; and reviewed (6) next steps after monogenic diabetes diagnosis and (7) challenges in precision medicine field.Pubmed and Embase databases were searched (1990-2022) using inclusion/exclusion criteria for studies that sequenced one or more monogenic diabetes genes in at least 100 probands (Question 1), evaluated a non-obsolete genetic testing method to diagnose monogenic diabetes (Question 2). The risk of bias was assessed using the revised QUADAS-2 tool. Existing guidelines were summarized for questions 3-5, and review of studies for questions 6-7, supplemented by expert recommendations. Results were summarized in tables and informed recommendations for clinical practice.There are 100, 32, 36, and 14 studies included for questions 1, 2, 6, and 7 respectively. On this basis, four recommendations for who to test and five on how to test for monogenic diabetes are provided. Existing guidelines for variant curation and gene-disease validity curation are summarized. Reporting by gene names is recommended as an alternative to the term MODY. Key steps after making a genetic diagnosis and major gaps in our current knowledge are highlighted.We provide a synthesis of current evidence and expert opinion on how to use precision diagnostics to identify individuals with monogenic diabetes.

    View details for DOI 10.1038/s43856-023-00369-8

    View details for PubMedID 37794142

    View details for PubMedCentralID 6058077

  • Loss of RREB1 in pancreatic beta cells reduces cellular insulin content and affects endocrine cell gene expression. Diabetologia Mattis, K. K., Krentz, N. A., Metzendorf, C., Abaitua, F., Spigelman, A. F., Sun, H., Ikle, J. M., Thaman, S., Rottner, A. K., Bautista, A., Mazzaferro, E., Perez-Alcantara, M., Manning Fox, J. E., Torres, J. M., Wesolowska-Andersen, A., Yu, G. Z., Mahajan, A., Larsson, A., MacDonald, P. E., Davies, B., den Hoed, M., Gloyn, A. L. 2023


    Genome-wide studies have uncovered multiple independent signals at the RREB1 locus associated with altered type 2 diabetes risk and related glycaemic traits. However, little is known about the function of the zinc finger transcription factor Ras-responsive element binding protein 1 (RREB1) in glucose homeostasis or how changes in its expression and/or function influence diabetes risk.A zebrafish model lacking rreb1a and rreb1b was used to study the effect of RREB1 loss in vivo. Using transcriptomic and cellular phenotyping of a human beta cell model (EndoC-βH1) and human induced pluripotent stem cell (hiPSC)-derived beta-like cells, we investigated how loss of RREB1 expression and activity affects pancreatic endocrine cell development and function. Ex vivo measurements of human islet function were performed in donor islets from carriers of RREB1 type 2 diabetes risk alleles.CRISPR/Cas9-mediated loss of rreb1a and rreb1b function in zebrafish supports an in vivo role for the transcription factor in beta cell mass, beta cell insulin expression and glucose levels. Loss of RREB1 also reduced insulin gene expression and cellular insulin content in EndoC-βH1 cells and impaired insulin secretion under prolonged stimulation. Transcriptomic analysis of RREB1 knockdown and knockout EndoC-βH1 cells supports RREB1 as a novel regulator of genes involved in insulin secretion. In vitro differentiation of RREB1KO/KO hiPSCs revealed dysregulation of pro-endocrine cell genes, including RFX family members, suggesting that RREB1 also regulates genes involved in endocrine cell development. Human donor islets from carriers of type 2 diabetes risk alleles in RREB1 have altered glucose-stimulated insulin secretion ex vivo, consistent with a role for RREB1 in regulating islet cell function.Together, our results indicate that RREB1 regulates beta cell function by transcriptionally regulating the expression of genes involved in beta cell development and function.

    View details for DOI 10.1007/s00125-022-05856-6

    View details for PubMedID 36633628

  • Genome-edited zebrafish model of ABCC8 loss-of-function disease. Islets Ikle, J. M., Tryon, R. C., Singareddy, S. S., York, N. W., Remedi, M. S., Nichols, C. G. 2022; 14 (1): 200-209


    ATP-sensitive potassium channel (KATP)gain- (GOF) and loss-of-function (LOF) mutations underlie human neonatal diabetes mellitus (NDM) and hyperinsulinism (HI), respectively. While transgenic mice expressing incomplete KATP LOF do reiterate mild hyperinsulinism, KATP knockout animals do not exhibit persistent hyperinsulinism. We have shown that islet excitability and glucose homeostasis are regulated by identical KATP channels in zebrafish. SUR1 truncation mutation (K499X) was introduced into the abcc8 gene to explore the possibility of using zebrafish for modeling human HI. Patch-clamp analysis confirmed the complete absence of channel activity in β-cells from K499X (SUR1-/-) fish. No difference in random blood glucose was detected in heterozygous SUR1+/- fish nor in homozygous SUR1-/- fish, mimicking findings in SUR1 knockout mice. Mutant fish did, however, demonstrate impaired glucose tolerance, similar to partial LOF mouse models. In paralleling features of mammalian diabetes and hyperinsulinism resulting from equivalent LOF mutations, these gene-edited animals provide valid zebrafish models of KATP -dependent pancreatic diseases.

    View details for DOI 10.1080/19382014.2022.2149206

    View details for PubMedID 36458573

  • ATP-sensitive potassium channels in zebrafish cardiac and vascular smooth muscle. The Journal of physiology Singareddy, S. S., Roessler, H. I., McClenaghan, C., Ikle, J., Tryon, R., van Haaften, G., Nichols, C. G. 2021


    KEY POINTS: Zebrafish cardiac myocytes (CM) and vascular smooth muscle (VSM) express functional KATP channels of similar subunit composition, structure, and metabolic sensitivity to their mammalian counterparts. In contrast to mammalian cardiovascular KATP channels, zebrafish channels are insensitive to potassium channel opener drugs (pinacidil, minoxidil) in both chambers of the heart and in VSM. We provide a first characterization of the molecular properties of fish KATP channels and validate the use of such genetically modified fish as models of human Cantu Syndrome and ABCC9-related Intellectual disability and Myopathy Syndrome.ABSTRACT: ATP-sensitive potassium channels (KATP channels) are hetero-octameric nucleotide-gated ion channels that couple cellular metabolism to excitability in various tissues. In the heart, KATP channels are activated during ischemia and potentially during adrenergic stimulation. In the vasculature, they are normally active at a low level, reducing vascular tone, but the ubiquitous nature of these channels leads to complex and poorly understood channelopathies as a result of gain- or loss-of-function mutations. Zebrafish (ZF) models of these channelopathies may provide insights to the link between molecular dysfunction and complex pathophysiology, but this requires understanding the tissue dependence of channel activity and subunit specificity. Thus far, direct analysis of ZF KATP expression and functional properties has only been performed in pancreatic beta-cells. Using a comprehensive combination of genetically modified fish, electrophysiology, and gene expression analysis, we demonstrate that ZF cardiac myocytes (CM) and vascular smooth muscle (VSM) express functional KATP channels of similar subunit composition, structure, and metabolic sensitivity to their mammalian counterparts. However, in contrast to mammalian cardiovascular KATP channels, ZF channels are insensitive to potassium channel opener drugs (pinacidil, minoxidil) in both chambers of the heart and in VSM. The results provide a first characterization of the molecular properties of fish KATP channels and validate the use of such genetically modified fish as models of human Cantu Syndrome and ABCC9-related Intellectual disability and Myopathy Syndrome. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1113/JP282157

    View details for PubMedID 34820842

  • Neonatal Hypoglycemia: Progress and Predicaments JOURNAL OF PEDIATRICS Ikle, J. M., Prince, L. S., Maahs, D. M. 2021; 235: 82
  • A brief history of diabetes genetics: insights for pancreatic beta-cell development and function. The Journal of endocrinology Ikle, J. M., Gloyn, A. L. 2021


    Since the discovery of insulin 100 years ago, our knowledge and understanding of diabetes has grown exponentially. Specifically, with regards to the genetics underlying diabetes risk, our discoveries have paralleled developments in our understanding of the human genome and our ability to study genomics at scale; these advancements in genetics have both accompanied and led to those in diabetes treatment. This review will explore the timeline and history of gene discovery and how this has coincided with progress in the fields of genomics. Examples of genetic causes of monogenic diabetes are presented and the continuing expansion of allelic series in these genes and the challenges these now cause for diagnostic interpretation along with opportunities for patient stratification are discussed.

    View details for DOI 10.1530/JOE-21-0067

    View details for PubMedID 34196608

  • Progress in Pediatric Diabetes Prediction, Management, and Outcomes JOURNAL OF PEDIATRICS Ikle, J. M., Maahs, D. M. 2021; 233: 131
  • Beta-cell excitability and excitability-driven diabetes in adult Zebrafish islets. Physiological reports Emfinger, C. H., Lőrincz, R. n., Wang, Y. n., York, N. W., Singareddy, S. S., Ikle, J. M., Tryon, R. C., McClenaghan, C. n., Shyr, Z. A., Huang, Y. n., Reissaus, C. A., Meyer, D. n., Piston, D. W., Hyrc, K. n., Remedi, M. S., Nichols, C. G. 2019; 7 (11): e14101


    Islet β-cell membrane excitability is a well-established regulator of mammalian insulin secretion, and defects in β-cell excitability are linked to multiple forms of diabetes. Evolutionary conservation of islet excitability in lower organisms is largely unexplored. Here we show that adult zebrafish islet calcium levels rise in response to elevated extracellular [glucose], with similar concentration-response relationship to mammalian β-cells. However, zebrafish islet calcium transients are nor well coupled, with a shallower glucose-dependence of cytoplasmic calcium concentration. We have also generated transgenic zebrafish that conditionally express gain-of-function mutations in ATP-sensitive K+ channels (KATP -GOF) in β-cells. Following induction, these fish become profoundly diabetic, paralleling features of mammalian diabetes resulting from equivalent mutations. KATP -GOF fish become severely hyperglycemic, with slowed growth, and their islets lose glucose-induced calcium responses. These results indicate that, although lacking tight cell-cell coupling of intracellular Ca2+ , adult zebrafish islets recapitulate similar excitability-driven β-cell glucose responsiveness to those in mammals, and exhibit profound susceptibility to diabetes as a result of inexcitability. While illustrating evolutionary conservation of islet excitability in lower vertebrates, these results also provide important validation of zebrafish as a suitable animal model in which to identify modulators of islet excitability and diabetes.

    View details for DOI 10.14814/phy2.14101

    View details for PubMedID 31161721

    View details for PubMedCentralID PMC6546968

  • Nkx2.5 regulates endothelin converting enzyme-1 during pharyngeal arch patterning. Genesis (New York, N.Y. : 2000) Iklé, J. M., Tavares, A. L., King, M. n., Ding, H. n., Colombo, S. n., Firulli, B. A., Firulli, A. B., Targoff, K. L., Yelon, D. n., Clouthier, D. E. 2017; 55 (3)


    In gnathostomes, dorsoventral (D-V) patterning of neural crest cells (NCC) within the pharyngeal arches is crucial for the development of hinged jaws. One of the key signals that mediate this process is Endothelin-1 (EDN1). Loss of EDN1 binding to the Endothelin-A receptor (EDNRA) results in loss of EDNRA signaling and subsequent facial birth defects in humans, mice and zebrafish. A rate-limiting step in this crucial signaling pathway is the conversion of immature EDN1 into a mature active form by Endothelin converting enzyme-1 (ECE1). However, surprisingly little is known about how Ece1 transcription is induced or regulated. We show here that Nkx2.5 is required for proper craniofacial development in zebrafish and acts in part by upregulating ece1 expression. Disruption of nkx2.5 in zebrafish embryos results in defects in both ventral and dorsal pharyngeal arch-derived elements, with changes in ventral arch gene expression consistent with a disruption in Ednra signaling. ece1 mRNA rescues the nkx2.5 morphant phenotype, indicating that Nkx2.5 functions through modulating Ece1 expression or function. These studies illustrate a new function for Nkx2.5 in embryonic development and provide new avenues with which to pursue potential mechanisms underlying human facial disorders.

    View details for DOI 10.1002/dvg.23021

    View details for PubMedID 28109039

    View details for PubMedCentralID PMC5364067

  • Identification and characterization of the zebrafish pharyngeal arch-specific enhancer for the basic helix-loop-helix transcription factor Hand2. Developmental biology Iklé, J. M., Artinger, K. B., Clouthier, D. E. 2012; 368 (1): 118–26


    The development of the vertebrate jaw relies on a network of transcription factors that patterns the dorsal-ventral axis of the pharyngeal arches. Recent findings in both mouse and zebrafish illustrate that the basic-helix-loop-helix transcription factor, Hand2, is crucial in this patterning process. While Hand2 has functionally similar roles in these two species, little is known about the regulatory sequences controlling hand2 expression in zebrafish. Using bioinformatics and Tol2-mediated transgenesis, we have generated zebrafish transgenic reporter lines in which either the mouse or zebrafish arch-specific hand2 enhancer direct expression of a fluorescent reporter. We find that both the mouse and zebrafish enhancers drive early reporter expression in a hand2-specific pattern in the ventral pharyngeal arches of zebrafish embryos. These lines provide useful tools to follow ventral arch cells during vertebrate jaw development while also allowing dissection of hand2 transcriptional regulation during this process.

    View details for DOI 10.1016/j.ydbio.2012.05.003

    View details for PubMedID 22595513

    View details for PubMedCentralID PMC3676283

  • Nkx2.5 regulates hand2 expression in the zebrafish pharyngeal arches via a conserved enhancer Ikle, J., Artinger, K., Clouthier, D. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2011: 233
  • Transcriptional regulation of hand2 in zebrafish neural crest cells and cardiomyocytes Ikle, J., Clouthier, D. E. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2010: 460
  • Pathogen entrapment by transglutaminase--a conserved early innate immune mechanism. PLoS pathogens Wang, Z. n., Wilhelmsson, C. n., Hyrsl, P. n., Loof, T. G., Dobes, P. n., Klupp, M. n., Loseva, O. n., Mörgelin, M. n., Iklé, J. n., Cripps, R. M., Herwald, H. n., Theopold, U. n. 2010; 6 (2): e1000763


    Clotting systems are required in almost all animals to prevent loss of body fluids after injury. Here, we show that despite the risks associated with its systemic activation, clotting is a hitherto little appreciated branch of the immune system. We compared clotting of human blood and insect hemolymph to study the best-conserved component of clotting systems, namely the Drosophila enzyme transglutaminase and its vertebrate homologue Factor XIIIa. Using labelled artificial substrates we observe that transglutaminase activity from both Drosophila hemolymph and human blood accumulates on microbial surfaces, leading to their sequestration into the clot. Using both a human and a natural insect pathogen we provide functional proof for an immune function for transglutaminase (TG). Drosophila larvae with reduced TG levels show increased mortality after septic injury. The same larvae are also more susceptible to a natural infection involving entomopathogenic nematodes and their symbiotic bacteria while neither phagocytosis, phenoloxidase or-as previously shown-the Toll or imd pathway contribute to immunity. These results firmly establish the hemolymph/blood clot as an important effector of early innate immunity, which helps to prevent septic infections. These findings will help to guide further strategies to reduce the damaging effects of clotting and enhance its beneficial contribution to immune reactions.

    View details for DOI 10.1371/journal.ppat.1000763

    View details for PubMedID 20169185

    View details for PubMedCentralID PMC2820530

  • Cardiac expression of the Drosophila Transglutaminase (CG7356) gene is directly controlled by myocyte enhancer factor-2. Developmental dynamics : an official publication of the American Association of Anatomists Iklé, J. n., Elwell, J. A., Bryantsev, A. L., Cripps, R. M. 2008; 237 (8): 2090–99


    The myocyte enhancer factor-2 (MEF2) family of transcription factors plays key roles in the activation of muscle structural genes. In Drosophila, MEF2 accumulates at high levels in the embryonic muscles, where it activates target genes throughout the mesoderm. Here, we identify the Transglutaminase gene (Tg; CG7356) as a direct transcriptional target of MEF2 in the cardiac musculature. Tg is expressed in cells forming the inflow tracts of the dorsal vessel, and we identify the enhancer responsible for this expression. The enhancer contains three binding sites for MEF2, and can be activated by MEF2 in tissue culture and in vivo. Moreover, loss of MEF2 function, or removal of the MEF2 binding sites from the enhancer, results in loss of Tg expression. These studies identify a new MEF2 target in the cardiac musculature. These studies provide a possible mechanism for the activation of transglutaminase genes.

    View details for DOI 10.1002/dvdy.21624

    View details for PubMedID 18627097

    View details for PubMedCentralID PMC2542504