Helmholtz Diabetes Center Institut für Pankreatische Inselzellforschung
Die Mission des IPI ist der Schutz und die Wiederherstellung der Insulin-produzierenden Betazellen der Bauchspeicheldrüse zur Prävention und Heilung des Diabetes mellitus.
Die Mission des IPI ist der Schutz und die Wiederherstellung der Insulin-produzierenden Betazellen der Bauchspeicheldrüse zur Prävention und Heilung des Diabetes mellitus.
Die Forschung am IPI konzentriert sich auf die Langerhans´schen Inseln der Bauchspeicheldrüse. In diesen Inseln befinden sich die Insulin-produzierenden Betazellen welche beim Typ-1 und Typ-2 Diabetes geschädigt oder gar zerstört werden. Das Studium der zugrunde liegenden Mechanismen und deren besseres Verständnis helfen den Wissenschaftlern bei der Entwicklung neuer Therapieansätze.
Seit Januar 2016 gehört das IPI als Satelliten-Institut zu Helmholtz Munich und bildet den Kern des bereits zuvor gegründeten Paul-Langerhans-Instituts Dresden (PLID) des Deutschen Zentrums für Diabetesforschung (DZD e.V.).
Derzeit umfasst das IPI 16 Forschungsgruppen, die sich mit verschiedenen Aspekten der Diabeteserkrankung beschäftigen. Die Wissenschaftler arbeiten daran, die Mechanismen zu entschlüsseln, die die Zerstörung und/oder Funktionseinschränkung der Betazellen bedingen und versuchen darüber hinaus, neue Ansätze zu entwickeln um die geschädigten bzw. zerstörten Betazellen zu ersetzen.
Unsere Mission ist daher der Schutz und die Wiederherstellung der Insulin-produzierenden Betazellen der Bauchspeicheldrüse zur Prävention und Heilung des Diabetes mellitus.
Ein internationales Wissenschaftlerteam verschiedenster Fachrichtungen konnte über die letzten Jahre für den Standort Dresden gewonnen werden und macht das IPI zu einem der führende Orte für Diabetesforschung in Deutschland. Die interdisziplinäre Zusammenarbeit und die enge Verknüpfung von Experten verschiedener Fachdisziplinen wie der Genetik, Immunologie, Zell- und Entwicklungsbiologie mit den klinischen Abteilungen der Inneren Medizin und der Viszeral-, Thorax- und Gefäßchirurgie oder den Stammzellexperten garantieren dabei eine translationale Ausrichtung der Forschung. Die exzellente Forschungsinfrastruktur am Dresdner Standort stellt die Basis für zukünftige wissenschaftliche Spitzenleistungen.
Unsere Mitarbeiter am IPI
Prof. Dr. Michele SolimenaInstitute Director Profil anzeigen
Juha Torkko, PhDPostdoc
Dr. Andreas MüllerPostdoc
Carolin EckertTechnische Assistenz
Daniela FriedlandTechnische Assistenz
Katharina GanßTechnische Assistenz
Katja PfriemAdministrative Coordination
Prof. Dr. Ünal CoskunGruppenleiter Profil anzeigen
Michal Grzybek, PhDPostdoc
Beate BrankatschkTechnische Assistenz
Prof. Anthony Gavalas, PhDGruppenleiter Profil anzeigen
Alin JurischTechnische Assistenz
Prof. Stephan Speier, PhDGruppenleiter Profil anzeigen
Dr. Christian CohrsPostdoc
Katharina HüttnerTechnische Assistenz
Dr. Frank MöllerScientific Coordination
Zeina Nicola, PhDPostdoc / Labormanager
Carla MünsterTechnische Assistenz
Eyke SchönigerTechnische Assistenz
Alessandra Palladini, PhDPostdoc
Annika Hutschreuther-AziziAdministration Assistance
Dr. Christine HerrmannPostdoc
Sarah HermannTechnische Assistenz
Ivan Perez RodriguezPredoc
Ana Karen Mojica AvilaPredoc
Characterization of gene expression in pancreatic islets and its alteration in type 2 diabetes (T2D) are vital in understanding islet function and T2D pathogenesis. We leveraged RNA sequencing and genome-wide genotyping in islets from 188 donors to create the Islet Gene View (IGW) platform to make this information easily accessible to the scientific community. Expression data were related to islet phenotypes, diabetes status, other islet-expressed genes, islet hormone-encoding genes and for expression in insulin target tissues. The IGW web application produces output graphs for a particular gene of interest. In IGW, 284 differentially expressed genes (DEGs) were identified in T2D donor islets compared with controls. Forty percent of DEGs showed cell-type enrichment and a large proportion significantly co-expressed with islet hormone-encoding genes; glucagon (GCG, 56%), amylin (IAPP, 52%), insulin (INS, 44%), and somatostatin (SST, 24%). Inhibition of two DEGs, UNC5D and SERPINE2, impaired glucose-stimulated insulin secretion and impacted cell survival in a human β-cell model. The exploratory use of IGW could help designing more comprehensive functional follow-up studies and serve to identify therapeutic targets in T2D.
Detailed characterization of human pancreatic islets is key to elucidating the pathophysiology of all forms of diabetes, especially type 2 diabetes. However, access to human pancreatic islets is limited. Pancreatic tissue for islet retrieval can be obtained from brain-dead organ donors or from individuals undergoing pancreatectomy, often referred to as ‘living donors’. Different protocols for human islet procurement can substantially impact islet function. This variability, coupled with heterogeneity between individuals and islets, results in analytical challenges to separate genuine disease pathology or differences between human donors from experimental noise. There are currently no international guidelines for human donor phenotyping, islet procurement and functional characterization. This lack of standardization means that substantial investments from multiple international efforts towards improved understanding of diabetes pathology cannot be fully leveraged. In this Perspective, we overview the status of the field of human islet research, highlight the challenges and propose actions that could accelerate research progress and increase understanding of type 2 diabetes to slow its pandemic spreading.
Wnt4 is heterogeneously activated in maturing β-cells to control calcium signaling, metabolism and function.
Diabetes is a multifactorial disorder characterized by loss or dysfunction of pancreatic β-cells. β-cells are heterogeneous, exhibiting different glucose sensing, insulin secretion and gene expression. They communicate with other endocrine cell types via paracrine signals and between β-cells via gap junctions. Here, we identify the importance of signaling between β-cells via the extracellular signal WNT4. We show heterogeneity in Wnt4 expression, most strikingly in the postnatal maturation period, Wnt4-positive cells, being more mature while Wnt4-negative cells are more proliferative. Knock-out in adult β-cells shows that WNT4 controls the activation of calcium signaling in response to a glucose challenge, as well as metabolic pathways converging to lower ATP/ADP ratios, thereby reducing insulin secretion. These results reveal that paracrine signaling between β-cells is important in addition to gap junctions in controling insulin secretion. Together with previous reports of WNT4 up-regulation in obesity our observations suggest an adaptive insulin response coordinating β-cells.
During pancreas development endocrine cells leave the ductal epithelium to form the islets of Langerhans, but the morphogenetic mechanisms are incompletely understood. Here, we identify the Ca2+-independent atypical Synaptotagmin-13 (Syt13) as a key regulator of endocrine cell egression and islet formation. We detect specific upregulation of the Syt13 gene and encoded protein in endocrine precursors and the respective lineage during islet formation. The Syt13 protein is localized to the apical membrane of endocrine precursors and to the front domain of egressing endocrine cells, marking a previously unidentified apical-basal to front-rear repolarization during endocrine precursor cell egression. Knockout of Syt13 impairs endocrine cell egression and skews the α-to-β-cell ratio. Mechanistically, Syt13 is a vesicle trafficking protein, transported via the microtubule cytoskeleton, and interacts with phosphatidylinositol phospholipids for polarized localization. By internalizing a subset of plasma membrane proteins at the front domain, including α6β4 integrins, Syt13 modulates cell-matrix adhesion and allows efficient endocrine cell egression. Altogether, these findings uncover an unexpected role for Syt13 as a morphogenetic driver of endocrinogenesis and islet formation.
Hoxb1 regulates distinct signaling pathways in neuromesodermal and hindbrain progenitors to promote cell survival and specification.
Hox genes play key roles in the anterior-posterior (AP) specification of all 3 germ layers during different developmental stages. It is only partially understood how they function in widely different developmental contexts, particularly with regards to extracellular signaling, and to what extent their function can be harnessed to guide cell specification in vitro. Here, we addressed the role of Hoxb1 in 2 distinct developmental contexts; in mouse embryonic stem cells (mES)-derived neuromesodermal progenitors (NMPs) and hindbrain neural progenitors. We found that Hoxb1 promotes NMP survival through the upregulation of Fgf8, Fgf17, and other components of Fgf signaling as well as the repression of components of the apoptotic pathway. Additionally, it upregulates other anterior Hox genes suggesting that it plays an active role in the early steps of AP specification. In neural progenitors, Hoxb1 synergizes with shh to repress anterior and dorsal neural markers, promote the expression of ventral neural markers and direct the specification of facial branchiomotorneuron (FBM)-like progenitors. Hoxb1 and shh synergize in regulating the expression of diverse signals and signaling molecules, including the Ret tyrosine kinase receptor. Finally, Hoxb1 synergizes with exogenous Glial cell line-derived neurotrophic factor (GDNF) to strengthen Ret expression and further promote the generation of FBM-like progenitors. Facial branchiomotorneuron-like progenitors survived for at least 6 months and differentiated into postmitotic neurons after orthotopic transplantation near the facial nucleus of adult mice. These results suggested that the patterning activity of Hox genes in combination with downstream signaling molecules can be harnessed for the generation of defined neural populations and transplantations with implications for neurodegenerative diseases.
Obesity and impaired metabolic health increase risk of COVID-19-related mortality in young and middle-aged adults to the level observed in older people: The LEOSS Registry.
Advanced age, followed by male sex, by far poses the greatest risk for severe COVID-19. An unresolved question is the extent to which modifiable comorbidities increase the risk of COVID-19-related mortality among younger patients, in whom COVID-19-related hospitalization strongly increased in 2021. A total of 3,163 patients with SARS-COV-2 diagnosis in the Lean European Open Survey on SARS-CoV-2-Infected Patients (LEOSS) cohort were studied. LEOSS is a European non-interventional multi-center cohort study established in March 2020 to investigate the epidemiology and clinical course of SARS-CoV-2 infection. Data from hospitalized patients and those who received ambulatory care, with a positive SARS-CoV-2 test, were included in the study. An additive effect of obesity, diabetes and hypertension on the risk of mortality was observed, which was particularly strong in young and middle-aged patients. Compared to young and middle-aged (18-55 years) patients without obesity, diabetes and hypertension (non-obese and metabolically healthy; n = 593), young and middle-aged adult patients with all three risk parameters (obese and metabolically unhealthy; n = 31) had a similar adjusted increased risk of mortality [OR 7.42 (95% CI 1.55-27.3)] as older (56-75 years) non-obese and metabolically healthy patients [n = 339; OR 8.21 (95% CI 4.10-18.3)]. Furthermore, increased CRP levels explained part of the elevated risk of COVID-19-related mortality with age, specifically in the absence of obesity and impaired metabolic health. In conclusion, the modifiable risk factors obesity, diabetes and hypertension increase the risk of COVID-19-related mortality in young and middle-aged patients to the level of risk observed in advanced age.
The impact of pancreatic head resection on blood glucose homeostasis in patients with chronic pancreatitis.
Background: Chronic pancreatitis (CP) often leads to recurrent pain as well as exocrine and/or endocrine pancreatic insufficiency. This study aimed to investigate the effect of pancreatic head resections on glucose metabolism in patients with CP. Methods: Patients who underwent pylorus‐preserving pancreaticoduodenectomy (PPPD), Whipple procedure (cPD), or duodenum-preserving pancreatic head resection (DPPHR) for CP between January 2011 and December 2020 were retrospectively analyzed with regard to markers of pancreatic endocrine function including steady‐state beta cell function (%B), insulin resistance (IR), and insulin sensitivity (%S) according to the updated Homeostasis Model Assessment (HOMA2). Results: Out of 141 pancreatic resections for CP, 43 cases including 31 PPPD, 2 cPD and 10 DPPHR, met the inclusion criteria. Preoperatively, six patients (14%) were normoglycemic (NG), 10 patients (23.2%) had impaired glucose tolerance (IGT) and 27 patients (62.8%) had diabetes mellitus (DM). In each subgroup, no significant changes were observed for HOMA2‐%B (NG: p = 0.57; IGT: p = 0.38; DM: p = 0.1), HOMA2‐IR (NG: p = 0.41; IGT: p = 0.61; DM: p = 0.18) or HOMA2‐%S (NG: p = 0.44; IGT: p = 0.52; DM: p = 0.51) 3 and 12 months after surgery, respectively. Conclusion: Pancreatic head resections for CP, including DPPHR and pancreatoduodenectomies, do not significantly affect glucose metabolism within a follow‐up period of 12 months.
The German Gestational Diabetes Study (PREG), a prospective multicentre cohort study: Rationale, methodology and design.
INTRODUCTION: Even well-treated gestational diabetes mellitus (GDM) might still have impact on long-term health of the mother and her offspring, although this relationship has not yet been conclusively studied. Using in-depth phenotyping of the mother and her offspring, we aim to elucidate the relationship of maternal hyperglycaemia during pregnancy and adequate treatment, and its impact on the long-term health of both mother and child. METHODS: The multicentre PREG study, a prospective cohort study, is designed to metabolically and phenotypically characterise women with a 75-g five-point oral glucose tolerance test (OGTT) during, and repeatedly after pregnancy. Outcome measures are maternal glycaemia during OGTTs, birth outcome and the health and growth development of the offspring. The children of the study participants are followed up until adulthood with developmental tests and metabolic and epigenetic phenotyping in the PREG Offspring study. A total of 800 women (600 with GDM, 200 controls) will be recruited. ETHICS AND DISSEMINATION: The study protocol has been approved by all local ethics committees. Results will be disseminated via conference presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: The PREG study and the PREG Offspring study are registered with Clinical Trials (ClinicalTrials.gov identifiers: NCT04270578, NCT04722900).
PTBP1 promotes hematopoietic stem cell maintenance and red blood cell development by ensuring sufficient availability of ribosomal constituents.
Ribosomopathies constitute a range of disorders associated with defective protein synthesis mainly affecting hematopoietic stem cells (HSCs) and erythroid development. Here, we demonstrate that deletion of poly-pyrimidine-tract-binding protein 1 (PTBP1) in the hematopoietic compartment leads to the development of a ribosomopathy-like condition. Specifically, loss of PTBP1 is associated with decreases in HSC self-renewal, erythroid differentiation, and protein synthesis. Consistent with its function as a splicing regulator, PTBP1 deficiency results in splicing defects in hundreds of genes, and we demonstrate that the up-regulation of a specific isoform of CDC42 partly mimics the protein-synthesis defect associated with loss of PTBP1. Furthermore, PTBP1 deficiency is associated with a marked defect in ribosome biogenesis and a selective reduction in the translation of mRNAs encoding ribosomal proteins. Collectively, this work identifies PTBP1 as a key integrator of ribosomal functions and highlights the broad functional repertoire of RNA-binding proteins.
Cone snail venoms contain a wide variety of bioactive peptides, including insulin-like molecules with distinct structural features, binding modes and biochemical properties. Here, we report an active humanized cone snail venom insulin with an elongated A chain and a truncated B chain, and use cryo-electron microscopy (cryo-EM) and protein engineering to elucidate its interactions with the human insulin receptor (IR) ectodomain. We reveal how an extended A chain can compensate for deletion of B-chain residues, which are essential for activity of human insulin but also compromise therapeutic utility by delaying dissolution from the site of subcutaneous injection. This finding suggests approaches to developing improved therapeutic insulins. Curiously, the receptor displays a continuum of conformations from the symmetric state to a highly asymmetric low-abundance structure that displays coordination of a single humanized venom insulin using elements from both of the previously characterized site 1 and site 2 interactions. [Figure not available: see fulltext.]