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Open research questions in Pancreatic function and diabetes

27 unresolved questions extracted from the limitations and future-work sections of 291 Pancreatic function and diabetes papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • Conclusions: These findings suggest that CP4, as a food-derived bioactive peptide candidate, warrants further investigation into its potential applications in the field of metabolic health.

    A Donkey Blood-Derived Bioactive Peptide (YPWTQ) Alleviates Insulin Resistance in HepG2 Cells Through Multi-Target Regulation of Glucose and Lipid Metabolism and Oxidative Stress · 2026 · DOI

  • General control nonderepressible 2 (GCN2) is a key sensor of cellular stress and a central mediator of the integrated stress response; however, its role in GDM remains unclear.

    Assessment of the role of general control nonderepressible 2 in gestational diabetes mellitus progression and the underlying mechanisms · 2026 · DOI

  • In the present study, the contribution of the histone‑modifying enzymes to lactylation within TECs during DKD was not investigated. Further studies employing quantitative mass spectrometry and site‑directed mutagenesis are warranted to determine the specific enzymes and residues mediating histone lactylation and to elucidate its biological implications in renal pathology.

    Tubular PFKFB3 drives diabetic kidney fibrosis via lactate‑dependent H4K12 lactylation and HIPK2 transactivation · 2026 · DOI

  • Although oligomeric IAPP intermediates are widely considered the principal cytotoxic species, the relative contributions of the many biological and kinetic processes governing their formation, clearance, and conversion into fibrils remain poorly quantified.

    Accumulated Cytotoxicity Induced by Islet Amyloid Polypeptide Oligomers in Type 2 Diabetes · 2026 · DOI

  • Insulin signaling stabilizes cardiomyocyte mechanical homeostasis by coordinating myofilament protein composi- tion and phosphorylation, titin splicing and phosphorylation, calcium handling and microdomain signaling, mitochondrial dynamics and ATP production, and substrate metabolism. Type 2 diabetes disrupts this integrated network and pro- duces a composite mechanical phenotype characterized by altered force–pCa relationships, impaired contractile kinet- ics, increased passive stiffness, modified viscoelastic behav- ior, energetic insufficiency, and defective mechanotransduc- tion involving costameres, integrins/FAK, and YAP/TAZ signaling. These alterations are not only molecular but quan- tifiable physical changes measurable through AFM, TFM, skinned-cell mechanics, real-time calcium–motion plat- forms, EHT systems, and microphysiological heart-on-chip devices. Future work will benefit from integrating multiscale mechanical measurements with signaling and proteostasis readouts, testing therapies that directly restore mechanical pathways such as NO–cGMP–PKG–titin phosphorylation and AGE reduction and leveraging iPSC/EHT/microflu- idic models to systematically map causal links from insulin resistance to mechanical failure. Author contribution MK,EH, andNH wrote the main manuscript, and prepared the figures, All authors reviewed, designed, edited and cor- rected the manuscript. Funding Open Access funding enabled and organized by Projekt DEAL. This research was also supported by the European Union’s Horizon 2020 research and innovation program under grant agree- ment number 739593 (to N.H.), Deutsche Forschungsgemeinschaft HA 7512/2‐4 and HA 7512/2‐1 (to N.H.) and Innovation Forum program of the Medical Faculty number IF‐023‐22 and IF‐034‐22 (to N.H. and I.E.B.), and the Hector-Stiftung (No. MED1814, M2401) to N.H, I. El-B, and I.A and the German Heart foundation (F/17/23) to I. El-B.; funding from Else-Kröner-Fresenius foundation to I. El-B. Project no. RRF-2.3.1-21-2022-00003 has been implemented with the support provided by the European Union. Data availability No datasets were generated or analyzed during the current study.

    Mechanobiology of the diabetic cardiomyocyte: insulin signaling, titin elasticity, and multiscale mechanical dysfunction · 2026 · DOI

  • The discourse on type 5 diabetes is grounded in the current knowledge with lean individuals experiencing undernutrition and relevant animal models. This diabetic phenotype necessitates comprehensive further investigation to elucidate its etiology, impact, longitudinal studies are and natural progression. Furthermore, crucial for comprehending the lifelong effects of undernutrition on diabetes risk and the potentially complicated pathophysiology of this diabetes type. Creating a global registry could enhance such studies. International research collaborations aimed at assessing the diagnostic criteria for this type of diabetes across many populations would enhance the definition of this phenotype. The implementation of diagnostic tools should, at a minimum, involve a fasting C-peptide level to confirm definitive beta cell insufficiency, and in more resource-rich environments, a postprandial C-peptide level as well. At a minimum, an anti-GAD (glutamic acid decarboxylase) antibody test is necessary to exclude Type 1 diabetes, however many resource-limited settings may find it challenging to do this test, let alone the complete array of tests. An abdominal ultrasound, or preferably a CT scan of the abdomen, is necessary to exclude pancreatic diabetes. Ultimately, interventional studies are essential to develop evidence-based care guidelines for doctors treating patients with type 5 diabetes. The Vellore Declaration urges the global diabetes community to offi- cially acknowledge this overlooked condition, which probably impacts the quality and duration of life for millions globally. We urge international organizations, including the IDF and WHO, to advocate for further study on the phenotype, etiology, and treatment of type 5 diabetes. Additional investigations involving both retrospective databases and clinical interventional trials concerning food, exercise, and medicinal drugs are crucial in this field. In conclusion, Type 5 diabetes represents a unique, non-autoimmune, lean diabetes phenotype with distinct pathophysiology and clinical features compared to Type 1 and Type 2 diabetes, as summarized in (Table 1). Further evidence of changes in a:b cell spatial ratios and remodeling of islet cytoarchitecture under metabolic stress conditions is provided by multiplexed ion beam imaging and imaging mass cytometry investigations. Crucially, integration of single-cell and spatial multi-omics has shown defective insulin granule formation, endoplasmic reticulum stress signaling, and mitochondrial dysfunction pathways that are exclusive to b-cell clusters exposed to inflammatory microenvironments. The use of spatially resolved molecular profiling in Type 5 diabetes may help determine whether developmental nutritional programming causes niche-specific bcell vulnerability rather than uniform endocrine loss, given the documented b-cell depletion, altered a:b ratio, and epigenetic PDX1 silencing seen in malnutrition-associated diabetes.

    Decoding type 5 diabetes using spatial omics: microarchitectural and molecular mechanisms of malnutrition-associated diabetes · 2026 · DOI

  • β-cells can be viewed as a function with four independent variables (PID gains and ATP target values) and there- fore optimization methods should be explored for parameter selection.

    PID-controller enhanced artificial β-cells · 2026 · DOI

  • Cells within the arcuate nucleus of the hypothalamus (ARC), which are crucial for regulating metabolism, become insulin resistant during the progression of metabolic disease3–8, but these mechanisms are not fully understood.

    Pathogenic hypothalamic extracellular matrix promotes metabolic disease · 2024 · DOI

  • These mechanisms underlying these associations remain unclear, but they likely include the angiotensin converting enzyme receptor 2, a binding site for SARS-CoV-2, which is expressed in key metabolic organs such as in the pancreas, in particular in β-cells.

    Diabetes mellitus in combination with COVID-19: modern views on therapy · 2021 · DOI

  • The paper discusses cell aggregation optimization for pancreatic progenitor differentiation (Toyoda et al., 2015) but does not establish the precise aggregate size ranges, cell density parameters, or temporal dynamics of aggregation needed to scale from laboratory-optimized conditions to clinically relevant cell volumes for transplantation.

    Applied Developmental Biology · 2016 · DOI

  • The paper references DNA methylation as directing functional maturation of pancreatic beta cells (Dhawan et al., 2015) and epigenetic priming of enhancers (Wang et al., 2015), but does not specify which epigenetic modifications are sufficient or necessary, or how to predictively manipulate epigenetic states during in vitro differentiation to achieve adult-level beta cell function.

    Applied Developmental Biology · 2016 · DOI

  • While the paper discusses islet encapsulation as an approach to prevent immune rejection, it does not address the specific material properties, encapsulation thickness, permeability parameters, or long-term biocompatibility requirements needed to maintain functional glucose-responsive insulin secretion in encapsulated stem cell-derived islet grafts.

    Applied Developmental Biology · 2016 · DOI

  • The paper notes that stem cell-derived beta cells resemble fetal rather than adult beta cells (Hrvatin et al., 2014), but does not establish the specific developmental stage markers, gene expression profiles, or functional maturation protocols needed to convert fetal-like beta cells into fully mature, adult-phenotype beta cells for clinical transplantation.

    Applied Developmental Biology · 2016 · DOI

  • The paper identifies that specific cells responsible for autoimmunity in type 1 diabetes need to be identified, but does not specify which autoimmune cell populations (T cells, B cells, or other subsets) should be targeted or how to distinguish them from non-pathogenic populations during pancreatic beta cell differentiation and transplantation.

    Applied Developmental Biology · 2016 · DOI

  • Mutations in the tRNA-modifying enzyme TRMT10A cause a rare monogenic syndrome characterized by early-onset diabetes and neurodevelopmental defects, yet the molecular mechanisms underlying TRMT10A diabetes remain unclear.

    TRMT10A deficiency and tRNA fragmentation disrupt human pancreatic β-cell identity and insulin maturation · 2026 · DOI

  • Despite growing interest in the pathological consequences of insulin aggregation, prevention efforts are limited by an incomplete understanding of the endogenous mechanisms that counteract it.

    FAIM Inhibits Insulin Amyloidogenesis through a Noncanonical Aggregation Pathway · 2026 · DOI

  • Although ectopic lipid accumulation is established as a driver of impaired insulin secretion, the acute contribution of adipocyte lipolysis to islet function remains poorly documented.

    Fatty acids from adipocyte lipolysis stimulate insulin secretion · 2026 · DOI

  • We find that installation of cysteines at these positions is insufficient to install redox sensitivity into cGCK.

    Conformational Expansion Underlies the Evolutionary Emergence of Redox Sensitivity in Vertebrate Glucokinases · 2026 · DOI

  • Significant human beta-cell turnover is limited to the first three decades of life as determined by in vivo thymidine analog incorporation and radiocarbon dating.

    Epigenetic adaptation of beta cells across lifespan and disease · 2026 · DOI

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27 open questions have been extracted from the limitations and future-work passages of 291 Pancreatic function and diabetes papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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