Open research questions in Pancreatic function and diabetes
534 gap statements mined from Pancreatic function and diabetes papers in our 7.9M-paper local library, which holds 2,240 papers on the topic — drawn mostly from each paper's own stated research gap, future-work, challenge and limitation notes, and its abstract. The ones listed below are a selection still marked open; each names the study that raised it, with a DOI link where the paper has one.
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What the literature leaves open
Existing 3D β-cell culture models are hindered by high costs and technical complexity. Traditional high-throughput screening methods rely on 2D β-cell cultures, which do not mimic the 3D organization of β-cells in pancreatic islets. The lack of a high-throughput assay for measuring Ca2+ oscillations and insulin release from pancreatic β-cells.
A high-throughput assay for the measurement of Ca2+ oscillations and insulin release from uniformly sized mouse β-cell (MIN6) spheroids · 2026 · DOITo address this gap in knowledge, we employed soft X-ray tomography (SXT), which can quantitatively measure the biochemical density of ISGs within whole beta cells.
Classifying biophysical subpopulations of insulin secretory granules using quantitative whole-cell structure analysis · 2026 · DOIOne of the challenges is the limited availability of pancreatic tissue from pregnant donors. Another challenge is the need for sensitive and specific methods to identify and quantify δ cells. The study also had to account for potential outliers in the data using the ROUT method.
While β-cells possess inherent adaptive mechanisms—such as HIF-mediated glycolytic reprogramming, autophagy, mitophagy, and antioxidant defense—these responses are often insufficient under chronic or severe oxygen deprivation, as seen in T2D, islet amyloidosis, OSA, and during islet transplantation.
Metabolic Stress and Adaptation in Pancreatic β-Cells to Hypoxia: Mechanisms, Modulators, and Implications for Transplantation · 2025 · DOIDespite the well-documented positive effects of ASC co-transplantation with islets, such as enhanced islet viability, reduced inflammation, and improved insulin secretion, the exact mechanisms underlying these benefits remain unclear.
Secretome Analysis of Human and Rat Pancreatic Islets Co-Cultured with Adipose-Derived Stromal Cells Reveals a Signature with Enhanced Regenerative Capacities · 2025 · DOIFuture studies could integrate genetic and environmental data with advanced machine-learning techniques to develop comprehensive risk models for T2DM. Adopting multimodal approaches, as highlighted in several studies, by combining diverse data types such as SNPs, gene expression profiles, and environmental factors (e.g., diet and physical activity) can enhance the predictive accuracy of these models.
Distinct Roles of Common Genetic Variants and Their Contributions to Diabetes: MODY and Uncontrolled T2DM · 2025 · DOIIn conclusion, neonatal diabetes (NDM) is a rare and complex genetic disorder that presents unique challenges in both diagnosis and management. Identifying KCNJ11 and ABCC8 mutations has significantly advanced our understanding of NDM and enabled the development of targeted therapies, particularly sulfonylureas, which have greatly improved glycemic control and reduced the need for insulin injections.
Diagnosis and Treatment of Neonatal Diabetes Caused by ATP-Channel Mutations: Genetic Insights, Sulfonylurea Therapy, and Future Directions · 2025 · DOIThe causal role of elevated serum uric acid levels in the pathogenesis of diabetes remains inconclusive and the mechanism of how uric acid takes effect on the pancreatic β cells remains to be investigated.
Uric Acid Causes Pancreatic β Cell Death and Dysfunction via Modulating CHOP-Mediated Endoplasmic Reticulum Stress Pathways · 2025 · DOIFuture research should focus on elucidating the precise molecular mechanisms underlying the insulin–cardiac axis and its cardiovascular manifestations. Investigating novel therapeutic targets, such as specific signaling pathways and molecular mediators involved in insulin-stimulated glucose uptake and cardiac insulin signaling, holds promise for developing more effective treatments.
Further research is needed to elucidate detailed mechanisms of action and identify ways to enhance their efficacy or develop even more effective novel therapies. Additionally, there is a growing need for diabetes mellitus interventional trials focused on restoring functional β-cell mass to improve disease management and prevention.
New-Generation Glucokinase Activators: Potential Game-Changers in Type 2 Diabetes Treatment · 2024 · DOITo address the challenges presented by novel modalities in T1DM effectively, collaboration and concerted action among stakeholders are imperative. Healthcare professionals should prioritize comprehensive education and training to adeptly use emerging treatments and technologies.
Exploring Novel Treatment Modalities for Type 1 Diabetes Mellitus: Potential and Prospects · 2024 · DOIFurthermore, some natural products have been demonstrated to have islet-protective or glucose-lowering effects, but their precise molecular targets and signaling networks have not yet been fully elucidated.
Targeted Regulation of Pancreatic Islet Function by Natural Products Against Type 2 Diabetes Mellitus: Advances and Prospects · 2026 · DOIFuture investigations should focus on comprehensive preclinical safety assessment, optimization of vector dosage, and evaluation of translational feasibility in humans, with particular attention to age-dependent responses and regenerative capacity.
Lentiviral GLP-1 gene therapy elicits developmental stage–dependent β-cell regeneration in diabetic rats · 2026 · DOIThis dynamic view of β-cell heterogeneity has important clinical implications: it suggests that the therapeutic window for preserving β-cell function may extend into the early stages of T2D, rather than being limited to the pre-diabetic phase alone.
Interpretable single-cell machine learning identifies PINK1-centred mitophagy as a determinant of metabolic fitness in type 2 diabetes · 2026 · DOIAlthough the precise molecular mechanisms remain to be fully elucidated, the present results provide a foundation for future studies investigating the role of paroxetine and related SSRIs in metabolic regulation.
The regulation of this maturation remains poorly understood, especially how secretory stimuli affect ISG maturity and subcellular localization.
Secretory stimuli distinctly regulate insulin secretory granule maturation through structural remodeling · 2025 · DOIFuture research should focus on standardizing protocols, improving delivery systems, addressing safety concerns, and ensuring equitable access to these advanced therapies.
Exploring Novel Treatment Modalities for Type 1 Diabetes Mellitus: Potential and Prospects · 2024 · DOIThe feasibility of transplanting fewer islets should be explored. Furthermore, we could not adequately assess the viability of islet transplantation at a less immunologically challenging site; thus, the optimal conditions should be further explored.
Impact of Prevascularization on Immunological Environment and Early Engraftment in Subcutaneous Islet Transplantation · 2024 · DOIAvailable human studies have primarily focused on safety and feasibility; robust data concerning long-term efficacy remain insufficient.
Current Status of Cellular and Gene-Based Therapies for Congenital Metabolic Disorders: A Review · 2026 · DOIWe propose two possible, non-mutually exclusive explanations, both of which remain to be tested experimentally.
Combined B2M Knockout and Alginate Encapsulation Reduces Immune Rejection of iPSC-Derived Pancreatic Progenitors · 2026 · DOIHowever, their effect on islet engraftment after intraportal co-transplantation remains unclear.
Amniotic epithelial cells enhance islet engraftment by suppressing early inflammation in intraportal transplantation · 2026 · DOISurgical pancreatectomy specimens may represent an accessible alternative source, but factors influencing successful isolation and functional preservation remain poorly defined.
Isolation of functional human islets from pancreatectomy remnants: Determinants of yield and functionality · 2026 · DOIInduced pluripotent stem cells (iPSCs) provide an alternative source for generating insulin-producing cells; however, whether the somatic cell origin of human iPSCs influences pancreatic endocrine differentiation remains incompletely defined.
Human pancreatic duct cell-derived iPSCs show enhanced differentiation into insulin-producing cells · 2026 · DOIPharmacological modulation of mechanosensitive signaling further supported a potential contribution of Piezo1-associated signaling to the stiffness-dependent response, although Piezo1- specific causality could not be established using the current pharmacological approach.
The stiffness of three-dimensional biomimetic matrices regulates insulin secretion via the Piezo1 mechanosensitive ion channel · 2026 · DOIMAM-targeted therapies, ER stress modulators PPAR agonists, peroxisome-targeted…
Metabolic memory in diabetes: decoding the molecular basis of persistent cellular programming for next-generation therapeutic strategies · 2026 · DOI
Most-cited papers in Pancreatic function and diabetes
- Biochemistry and molecular cell biology of diabetic complications · Nature · 2001 · 7,216 citations
- Islet Transplantation in Seven Patients with Type 1 Diabetes Mellitus Using a Glucocorticoid-Free Immunosuppressive Regimen · New England Journal of Medicine · 2000 · 4,463 citations
- Mechanisms linking obesity to insulin resistance and type 2 diabetes · Nature · 2006 · 4,403 citations
- Insulin signalling and the regulation of glucose and lipid metabolism · Nature · 2001 · 4,259 citations
- Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B · Nature · 1995 · 4,219 citations
- Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1 · Nature · 2005 · 2,746 citations
- Cloning of adiponectin receptors that mediate antidiabetic metabolic effects · Nature · 2003 · 2,552 citations
- IRS-1-Mediated Inhibition of Insulin Receptor Tyrosine Kinase Activity in TNF-α- and Obesity-Induced Insulin Resistance · Science · 1996 · 2,108 citations
- Type 2 diabetes: principles of pathogenesis and therapy · The Lancet · 2005 · 1,971 citations
- Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future · The Lancet · 2013 · 1,437 citations
Most recent work
- PDX1 phosphorylation at S61 by mTORC1 links nutrient signaling to β cell function and metabolic disease · Cell Reports · 2026
- Diabetes and its complications: molecular mechanisms, prevention and treatment · Signal Transduction and Targeted Therapy · 2026
- Autologous and allogeneic stem cell-derived islet therapy in three recipients with type 1 diabetes and complete loss of endogenous pancreatic β-cell function pretransplant · The Lancet Diabetes & Endocrinology · 2026
- GLP-1, Pancreatic β-Cells, and Insulin Secretion: What We Know and Where We Need to Go · Diabetes · 2026
- B cell deficiency limits exercise capacity by remodeling liver glutamate metabolism · Cell · 2026
- Antecedent hypoglycaemia impairs glucagon secretion by enhancing somatostatin-mediated negative feedback control · Nature Metabolism · 2026
- Deep single-cell decoding of human pancreatic islets reveals T2D β-cell gene expression defects · The EMBO Journal · 2026
- Primary cilia regulate GLP-1 signaling in pancreatic β cells · Molecular Metabolism · 2026
- Pharmacological or genetic inhibition of Scn9a protects human and mouse beta cells while dampening insulin secretion in type 1 diabetes · bioRxiv · 2026
- Paracrine Hormonal Signals From Islet α-Cells Regulate Microtubule Dynamics in β-Cells to Promote Insulin Secretion in Mouse and Human Islets · Diabetes · 2026
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