Immuno-endocrinology laboratory

Understand the intersections of the immune, metabolic and endocrine systems

Immuno-endocrinology and immuno-metabolism are rapidly developing fields of research that seek to understand the intersections of the immune, metabolic and endocrine systems. The mutual regulation of immune, metabolic and endocrine functions by hormones, nutrients and immune mediators such as cytokines is an exciting evolving field in physiology and pathophysiology.

The immune system is the largest endocrine organ and relays metabolic signals to endocrine cells

Excess nutrients and metabolites are sensed as danger signals that activate the innate immune system that in turn regulate endocrine functions. More and more hormones are found to affect immune function, and cytokines are increasingly recognised to have homeostatic importance and to exert auto-, para- and endocrine actions. This makes the immune system the largest endocrine organ in the body.

Manage non-curable diseases

Autoimmune and inflammatory endocrinopathies are non-curable diseases, and clinical management focuses on either hormonal substitution therapy or disease activity modification. Substitution therapy of most hormonal deficiencies secondary to inflammatory endocrine tissue destruction is gratifying and restores normal life quality and expectancy. Notable exceptions from these are type 1 and type 2 diabetes that are notoriously problematic to manage and still associated with significant over-morbidity and mortality. Therefore, these diseases present pressing needs for better causative treatments based on detailed insights into the molecular and cellular pathogenetic mechanisms.

Our vision

Our vision is to prevent and cure type 1 and type 2 diabetes by targeting the inflammatory and metabolic pathways leading to pancreatic beta-cell failure.

Our mission

Our mission is to define the transcriptional, translational and posttranslational responses of the pancreatic beta-cell to immune, inflammatory, metabolic and oxidative stress, with the aim of identifying novel therapeutic targets to be tested in preclinical models and clinical trials.

Our research strategy 

The Immuno-endocrinology lab employs an interdisciplinary and collaborative research strategy to unravel beta-cell transcriptional, translational and posttranslational responses to stress by two complementary approaches: a hypothesis-driven approach evolving from new discoveries in the lab and an unbiased screening approach employing systems biology and using functional genomics, transcriptomics, proteomics secretomics and post-translatomics.

Our tactics

Our experimental tactics utilise systems biology, bioinformatics, and in silico modelling, cell-free and cell-based in vitro models, ex vivo and in vivo studies in induced and genetic experimental animals, and clinical trials, epidemiological analyses and biomarker studies.

Our history

The immuno-endocrinology lab was launched in January 2014 as a consequence of a Faculty and Department decision to fill a full professorship in immuno-endocrinology.

Research education

The Immuno-endocrinology lab prioritises research-based teaching by taking responsibility for pre- and postgraduate courses as well as practical research training of our Bachelor’s, Master’s and PhD students as well as Postdocs and Visiting Scientists.

Training in our lab

All lab members are encouraged to participate in fundraising, scientific reviews, academic assessments, research administration and intra- and extra-mural committee work and to contribute actively and positively to section, department, faculty and university activities.

The dissemination policy of the Immuno-endocrinology lab

The Immuno-endocrinology lab is careful to secure intellectual property rights via patenting and priority publication in high-rank international periodicals.

Furthermore, we are very particular when it comes to data sharing via public databases and dissemination of research findings to the broader public by press releases, presentations at scientific and public meetings, in patient organisations and in the media.

We are looking for highly motivated Master's students to work with us.

The overall aim of the current research portfolio of the Immuno-endocrinology lab is to identify novel therapeutic targets in the pathways leading to pancreatic beta-cell failure with a focus on pancreatic islet beta-cell responses to immune, inflammatory, metabolic and oxidative stress.

Our translational experimental strategy is to move from insulin-producing cell-lines to primary intact or dispersed islets to human islet experiments, the latter mainly used to confirm critical observations from cell lines and rodent islets. Studies also involve animal, clinical and epidemiological studies.

The projects involve PhD, Master’s, Bachelor’s and ERASMUS students with a close and direct supervision and coaching from postdocs and tenured faculty members. They encourage independence from the start and the opportunity to learn about the diverse aspects of science: literature search, experimental design, experimental planning and execution, data-analysis and -presentation, interaction with our collaborators as well as grant-writing and active participation in administrative and social aspects of faculty, laboratory and group life.

PhD students are involved in undergraduate teaching and offered mentoring of Bachelor’s or Master’s students in their senior years.

Students will have the opportunity to learn following techniques:

• islet isolation,
• cell- and islet-culture,
• viability and functional assays,
• gene expression (RT-qPCR),
• protein analysis (reducing and non-reducing SDS-PAGE, Western blotting, immunoprecipitation, protein expression systems, mass spectrometry, size-exclusion chromatography),
• gene knock –down or- out (siRNA, shRNA, CRISPR-Cas9),
• plasmid design,
• cloning, transfection,
• pancreatic islet handling and usage
• advanced imaging
• and many more, depending on the needs of the project

Our projects

The project outlines for the ongoing three current research lines are described briefly in the following.

1) The role of circadian clock perturbation in inflammatory β-cell damage

Funded by the University of Copenhagen, the Novo Nordisk Foundation and the Independent Research Fund Denmark

Staff: Phillip Keller Andersen, PhD student; Sarah Spliid Madsen, Bachelor’s student; Kristian Klindt, lab technician

Collaborators: Charna Dibner, University of Geneva, Switzerland; Zach Gerhart-Hines, University of Copenhagen.

Prolonged perturbation of the circadian clock is associated with detrimental metabolic outcomes and risk factors for obesity and diabetes. There is increasing interest in understanding the mutual interplay between the circadian clock and inflammatory responses. Since the pathogenesis of β-cell failure and death in both Type 1 (T1D) and Type 2 diabetes (T2D) involves inflammatory mechanisms, the hypothesis of this project is that inflammatory conditions perturb the islet circadian clock, and that clock perturbation sensitizes islets to inflammatory damage. We have recently discovered that inflammatory cytokines lead to aberrant regulation of key clock components in INS-1 cells, and we now wish to confirm and extend these observations in human islets, as well as disentangle the molecular mechanisms.

2) Targeting mitophagy to prevent beta cell failure in Type 1 Diabetes

Funded by the Juvenile Diabetes Research Foundation USA, with the University of Michigan Medical School,  the Sehested-Hansen Foundation and the Independent Research Fund Denmark

Staff: Jette Bach Agergaard, MSc, PhD student; Anastasia Adella and Alba Mena, ERASMUS Exchange students; Kristian Klindt, lab technician.

Collaborators/Co-supervisors: Scott Soleimanpour, University of Michigan, USA; Clara Pratts, Core Facility for Integrated Microscopy, University of Copenhagen

Type 1 Diabetes (T1D) results from autoimmune-mediated β-cell damage leading to insufficient functional β-cell mass to meet peripheral insulin demands. β-cells rely upon mitochondrial respiration to generate the energy necessary for insulin synthesis, processing, and secretion. Immune-mediated cytokine release also leads to generation of intracellular reactive oxygen species and mitochondrial damage, which ultimately result in β-cell apoptosis. Indeed, defects in mitochondrial structure and function have been reported in the β-cells of patients with both T1D and T2D. Defects in mitochondrial structure and function are characteristic of impairments in mitophagy, a selective form of mitophagy necessary for elimination of dysfunctional mitochondria; however, the role of mitophagy in T1D pathogenesis is not well understood. Our collaborators at the University of Michigan (PI Scott Soleimanpour) previously discovered a key role for the T1D susceptibility gene Clec16a in control of glucose homeostasis in humans and mice through its regulation of β-cell mitophagy. Therefore, our goal is to dissect the mechanistic and physiologic regulation of Clec16a-mediated mitophagy in β-cells to elucidate its contribution to T1D pathogenesis.

3) Genetic conditions of insulin hypersecretion as models of endoplasmic reticulum stress, beta-cell ageing and Type 2 Diabetes.

Funded by the Novo Nordisk Foundation.

Staff: Anniek Lubberding, MSc, PhD, postdoc; Master’s students; Kristian Klindt, lab technician.

Collaborators/Co-supervisors: Thomas Jespersen, Signe Torekov, Jørgen Kanters, Jonas Treebak, University of Copenhagen.

Type 2 Diabetes (T2D) arises when beta-cell insulin secretion fails to meet insulin demands, typically due to insulin resistance as a consequence of obesity. A polygenetic disposition sets the threshold for at what level of secretory demand decompensations occurs. Since the risk of decompensation increases with age it is important to understand how the gene-age interaction affects insulin biosynthesis, handling and secretion. As secretory demand increases the handling of proinsulin in the endoplasmic reticulum (ER) becomes a limiting factor for insulin biosynthesis and secretion. This handling mismatch may eventually trigger the unfolded protein response and ER stress, known to activate proinflammatory and proapoptotic pathways in turn impairing beta-cell function and viability. The Akita mouse model carrying a mutation in the proinsulin-2 gene is proof of principle for this hypothesis. We study other genetic models with human relevance that affect insulin secretion to clarify the molecular mechanisms underlying beta-cell failure in ageing.

For further information, please contact: Professor Thomas Mandrup-Poulsen, Panum building 12.6.22, tmpo@sund.ku.dk