Helmholtz Diabetes Center Institute for Pancreatic Islet Research
The mission of the Institute for Pancreatic Islet Research (IPI) is to protect and restore the insulin-producing beta cells of the pancreas to prevent and cure diabetes mellitus.
The mission of the Institute for Pancreatic Islet Research (IPI) is to protect and restore the insulin-producing beta cells of the pancreas to prevent and cure diabetes mellitus.
About our Research
The research at the IPI focuses on the pancreatic islets, in which the insulin-producing beta cells, which are damaged or even destroyed in type-1 and type-2 diabetes, are located. The study of the underlying mechanisms and their better understanding helps scientists to develop new therapeutic approaches.
Since January 2016, the IPI has been part of Helmholtz Munich as a satellite institute and forms the core of the previously founded Paul Langerhans Institute Dresden (PLID) of the German Center for Diabetes Research (DZD e.V.).
Currently, the IPI comprises 16 research groups dealing with various aspects of diabetes. The scientists are working on deciphering the mechanisms that lead to the destruction and/or functional impairment of beta cells and are also trying to develop new approaches to replace damaged or destroyed beta cells.
Therefore, our mission is to protect and restore the insulin-producing beta cells of the pancreas to prevent and cure diabetes mellitus.
Over the past years, an international team of scientists from a wide variety of disciplines has been recruited to perform their research in Dresden, making IPI to one of the leading diabetes research locations in Germany. The interdisciplinary cooperation and the close connection of experts from different disciplines such as genetics, immunology, cell and developmental biology with the clinical departments of internal medicine and visceral, thoracic and vascular surgery or stem cell experts guarantee a translational orientation of the research. The excellent research infrastructure in Dresden provides moreover the basis for future scientific excellence.
Our Staff at IPI
Publications
Read more2025 Scientific Article in EMBO Journal, The
Aldolase-regulated G3BP1/2+ condensates control insulin mRNA storage in beta cells.
Upregulation of insulin mRNA translation upon hyperglycemia in pancreatic islet β-cells involves several RNA-binding proteins. Here, we found that G3BP1, a stress granule marker downregulated in islets of subjects with type 2 diabetes, binds to insulin mRNA in glucose concentration-dependent manner. We show in mouse insulinoma MIN6-K8 cells exposed to fasting glucose levels that G3BP1 and its paralog G3BP2 colocalize to cytosolic condensates with eIF3b, phospho-AMPKαThr172 and Ins1/2 mRNA. Glucose stimulation dissolves G3BP1+/2+ condensates with cytosolic redistribution of their components. The aldolase inhibitor aldometanib prevents the glucose- and pyruvate-induced dissolution of G3BP1+/2+ condensates, increases phospho-AMPKαThr172 levels and reduces those of phospho-mTORSer2448. G3BP1 or G3BP2 depletion precludes condensate assembly. KO of G3BP1 decreases Ins1/2 mRNA abundance and translation as well as proinsulin levels, and impaires glucose-stimulated insulin secretion. Further, other insulin secretagogues such as exendin-4 and palmitate, but not high KCl, prompts the dissolution of G3BP1+/2+ condensates. G3BP1+/2+/Ins mRNA+ condensates are also found in primary mouse and human β-cells. Hence, G3BP1+/2+ condensates represent a conserved glycolysis/aldolase-regulated compartment for the physiological storage and protection of insulin mRNA in resting β-cells.
2025 Scientific Article in Science
Measurements of molecular size and shape on a chip.
Size and shape are critical discriminators between molecular species and states. We describe a microchip-based high-throughput imaging approach offering rapid and precise determination of molecular properties under native solution conditions. Our method detects differences in molecular weight across at least three orders of magnitude and down to two carbon atoms in small molecules. We quantify the strength of molecular interactions across more than six orders of magnitude in affinity constant and track reactions in real time. Highly parallel measurements on individual molecules serve to characterize sample-state heterogeneity at the highest resolution, offering predictive input to model three-dimensional structure. We further leverage the method's structural sensitivity for diagnostics, exploiting ligand-induced conformational changes in the insulin receptor to sense insulin concentration in serum at the subnanoliter and subzeptomole scale.
2025 Scientific Article in BMC Surgery
Glucose metabolism after distal pancreatectomy - deterioration of beta cell function becomes noticeable at an early stage: A retrospective cohort study.
BACKGROUND: Distal pancreatectomy (DP) can worsen pancreatic endocrine function. Effects on glucose metabolism and underlying mechanisms after DP remains a topic of significant interest and not yet fully understood. This study aimed to examine the impact of DP on blood glucose homeostasis with a particular focus on metabolic outcomes and development of postoperative diabetes. METHODS: Considered were all patients who underwent DP between 01/2010 and 09/2021 and participated simultaneously in extended blood glucose monitoring with a 12 months follow-up. Blood samples were analyzed for markers of pancreatic endocrine function both fasting and after an oral glucose tolerance test preoperatively and 3 and 12 months after DP. RESULTS: Included patients (n = 69) were preoperatively categorized into three groups according to American Diabetes Association (ADA) criteria: 17 patients (24.6%) were normoglycemic (NG), 22 (31.9%) had prediabetes (impaired fasting glucose / impaired glucose tolerance - IFG/IGT) and 30 (43.5%) had diabetes mellitus (DM). In the NG subgroup, beta-cell function (HOMA2%B - updated homeostasis model assessment) significantly decreased from 117.4% (101.1-135%) to 66.9% (49.7-102.1%) at 12 months postoperatively (p < 0.05). Insulin sensitivity (HOMA2%S) significantly increased from 48.2% (33.4-66.9%) to 63.5% (49.8-86%) at 12 months postoperatively (p < 0.05). In the IFG/IGT subgroup, there was a non-significant trend of decreased HOMA2%B and increased HOMA2%S postoperatively. Postoperatively, 11.8% of NG patients and 60% of prediabetic patients developed DM. CONCLUSION: DP already leads to significant changes in glucose metabolism within a 12 month follow-up period. Patients with preoperative prediabetes are particularly at high risk of developing postoperative DM. Therefore, the indication for DP should be critically evaluated, especially in cases with a relative indication for surgery. If possible parenchymal sparing surgical options should be contemplated. TRIAL REGISTRATION: Not applicable.
2025 Scientific Article in EMBO Journal, The
Somatostatin triggers local cAMP and Ca2+ signaling in primary cilia to modulate pancreatic β-cell function.
Somatostatin, released from δ-cells within pancreatic islets of Langerhans, is one of the most important negative regulators of islet hormone secretion. We find that islet δ-cells are positioned near, and release somatostatin onto, primary cilia of the other islet cell types, including insulin-secreting β-cells. Somatostatin activates ciliary somatostatin receptors, resulting in rapid lowering of the ciliary cAMP concentration which in turn promotes more sustained nuclear translocation of the cilia-dependent transcription factor GLI2 through a mechanism that operates in parallel with the canonical Hedgehog pathway and depends on ciliary Ca2+ signaling. We also find that primary cilia length is reduced in islets from human donors with type-2 diabetes, which is associated with a reduction in interactions between δ-cells and cilia. Our findings show that islet cell primary cilia constitute an important target of somatostatin action, which endows somatostatin with the ability to regulate islet cell function beyond acute suppression of hormone release.
2025 Scientific Article in Diabetes Care
Proteomic and metabolomic signatures in prediabetes progressing to diabetes or reversing to normoglycemia within 1 Year.
OBJECTIVE: Progression of prediabetes to type 2 diabetes has been associated with β-cell dysfunction, whereas its remission to normoglycemia has been related to improvement of insulin sensitivity. To understand the mechanisms and identify potential biomarkers related to prediabetes trajectories, we compared the proteomics and metabolomics profile of people with prediabetes progressing to diabetes or reversing to normoglycemia within 1 year. RESEARCH DESIGN AND METHODS: The fasting plasma concentrations of 1,389 proteins and the fasting, 30-min, and 120-min post-oral glucose tolerance test (OGTT) plasma concentrations of 152 metabolites were measured in up to 134 individuals with new-onset diabetes, prediabetes, or normal glucose tolerance. For 108 participants, the analysis was repeated with samples from 1 year before, when all had prediabetes. RESULTS: The plasma concentrations of 14 proteins were higher in diabetes compared with normoglycemia in a population with prediabetes 1 year before, and they correlated with indices of insulin sensitivity. Higher levels of dicarbonyl/L-xylulose reductase and glutathione S-transferase A3 in the prediabetic state were associated with an increased risk of diabetes 1 year later. Pathway analysis pointed toward differences in immune response between diabetes and normoglycemia that were already recognizable in the prediabetic state 1 year prior at baseline. The area under the curve during OGTT of the concentrations of IDL particles, IDL apolipoprotein B, and IDL cholesterol was higher in new-onset diabetes compared with normoglycemia. The concentration of glutamate increased in prediabetes progressing to diabetes. CONCLUSIONS: We identify new candidates associated with the progression of prediabetes to diabetes or its remission to normoglycemia. Pathways regulating the immune response are related to prediabetes trajectories.
2024 Review in International Journal of Molecular Sciences
Immune and metabolic mechanisms of endothelial dysfunction.
Endothelial dysfunction is a strong prognostic factor in predicting the development of cardiovascular diseases. Dysfunctional endothelium loses its homeostatic ability to regulate vascular tone and prevent overactivation of inflammation, leading to vascular dysfunction. These functions are critical for vascular homeostasis and arterial pressure control, the disruption of which may lead to hypertension. Hypertension itself can also cause endothelial dysfunction, as endothelial cells are susceptible to haemodynamic changes. Although it is unclear which of those factors appear first, they create a vicious circle further damaging multiple organs, including the heart and vessels. There are also sex-specific differences in homeostatic functions of the endothelium regarding vessel tone regulation, which may contribute to differences in arterial blood pressure between men and women. Even more importantly, there are sex-differences in the development of endothelial dysfunction and vessel remodelling. Hence, an understanding of the mechanisms of endothelial dysfunction and its contribution to pathological vascular remodelling during hypertension is of critical importance. This review addresses immunological and metabolic aspects in mechanisms of endothelial dysfunction and the resulting mechanisms in vascular remodelling with respect to arterial hypertension, including the potential role of sex-specific differences.
2024 Scientific Article in Nature metabolism
Inceptor binds to and directs insulin towards lysosomal degradation in β cells.
Blunted first-phase insulin secretion and insulin deficiency are indicators of β cell dysfunction and diabetes manifestation. Therefore, insights into molecular mechanisms that regulate insulin homeostasis might provide entry sites to replenish insulin content and restore β cell function. Here, we identify the insulin inhibitory receptor (inceptor; encoded by the gene IIR/ELAPOR1) as an insulin-binding receptor that regulates insulin stores by lysosomal degradation. Using human induced pluripotent stem cell (SC)-derived islets, we show that IIR knockout (KO) results in enhanced SC β cell differentiation and survival. Strikingly, extended in vitro culture of IIR KO SC β cells leads to greatly increased insulin content and glucose-stimulated insulin secretion (GSIS). We find that inceptor localizes to clathrin-coated vesicles close to the plasma membrane and in the trans-Golgi network as well as in secretory granules, where it acts as a sorting receptor to direct proinsulin and insulin towards lysosomal degradation. Targeting inceptor using a monoclonal antibody increases proinsulin and insulin content and improves SC β cell GSIS. Altogether, our findings reveal the basic mechanisms of β cell insulin turnover and identify inceptor as an insulin degradation receptor.
2024 Scientific Article in Nature Communications
Structure, interaction and nervous connectivity of beta cell primary cilia.
Primary cilia are sensory organelles present in many cell types, partaking in various signaling processes. Primary cilia of pancreatic beta cells play pivotal roles in paracrine signaling and their dysfunction is linked to diabetes. Yet, the structural basis for their functions is unclear. We present three-dimensional reconstructions of beta cell primary cilia by electron and expansion microscopy. These cilia are spatially confined within deep ciliary pockets or narrow spaces between cells, lack motility components and display an unstructured axoneme organization. Furthermore, we observe a plethora of beta cell cilia-cilia and cilia-cell interactions with other islet and non-islet cells. Most remarkably, we have identified and characterized axo-ciliary synapses between beta cell cilia and the cholinergic islet innervation. These findings highlight the beta cell cilia's role in islet connectivity, pointing at their function in integrating islet intrinsic and extrinsic signals and contribute to understanding their significance in health and diabetes.
2024 Scientific Article in Scientific Reports
Generation and application of novel hES cell reporter lines for the differentiation and maturation of hPS cell-derived islet-like clusters.
The significant advances in the differentiation of human pluripotent stem (hPS) cells into pancreatic endocrine cells, including functional β-cells, have been based on a detailed understanding of the underlying developmental mechanisms. However, the final differentiation steps, leading from endocrine progenitors to mono-hormonal and mature pancreatic endocrine cells, remain to be fully understood and this is reflected in the remaining shortcomings of the hPS cell-derived islet cells (SC-islet cells), which include a lack of β-cell maturation and variability among different cell lines. Additional signals and modifications of the final differentiation steps will have to be assessed in a combinatorial manner to address the remaining issues and appropriate reporter lines would be useful in this undertaking. Here we report the generation and functional validation of hPS cell reporter lines that can monitor the generation of INS+ and GCG+ cells and their resolution into mono-hormonal cells (INSeGFP, INSeGFP/GCGmCHERRY) as well as β-cell maturation (INSeGFP/MAFAmCHERRY) and function (INSGCaMP6). The reporter hPS cell lines maintained strong and widespread expression of pluripotency markers and differentiated efficiently into definitive endoderm and pancreatic progenitor (PP) cells. PP cells from all lines differentiated efficiently into islet cell clusters that robustly expressed the corresponding reporters and contained glucose-responsive, insulin-producing cells. To demonstrate the applicability of these hPS cell reporter lines in a high-content live imaging approach for the identification of optimal differentiation conditions, we adapted our differentiation procedure to generate SC-islet clusters in microwells. This allowed the live confocal imaging of multiple SC-islets for a single condition and, using this approach, we found that the use of the N21 supplement in the last stage of the differentiation increased the number of monohormonal β-cells without affecting the number of α-cells in the SC-islets. The hPS cell reporter lines and the high-content live imaging approach described here will enable the efficient assessment of multiple conditions for the optimal differentiation and maturation of SC-islets.
2024 Scientific Article in Nature metabolism
Regulated and adaptive in vivo insulin secretion from islets only containing β-cells.
Insulin-producing β-cells in pancreatic islets are regulated by systemic cues and, locally, by adjacent islet hormone-producing 'non-β-cells' (namely α-cells, δ-cells and γ-cells). Yet whether the non-β-cells are required for accurate insulin secretion is unclear. Here, we studied mice in which adult islets are exclusively composed of β-cells and human pseudoislets containing only primary β-cells. Mice lacking non-β-cells had optimal blood glucose regulation, enhanced glucose tolerance, insulin sensitivity and restricted body weight gain under a high-fat diet. The insulin secretion dynamics in islets composed of only β-cells was comparable to that in intact islets. Similarly, human β-cell pseudoislets retained the glucose-regulated mitochondrial respiration, insulin secretion and exendin-4 responses of entire islets. The findings indicate that non-β-cells are dispensable for blood glucose homeostasis and β-cell function. These results support efforts aimed at developing diabetes treatments by generating β-like clusters devoid of non-β-cells, such as from pluripotent stem cells differentiated in vitro or by reprograming non-β-cells into insulin producers in situ.
