Diabetes is a prevalent chronic disease that traditionally requires severe reliance on medication for treatment. Oral medication and exogenous insulin can only temporarily maintain blood glucose levels and do not cure the disease. Most patients need life-long injections of exogenous insulin. In recent years, advances in islet transplantation have significantly advanced the treatment of diabetes, allowing patients to discontinue exogenous insulin and avoid complications.Long-term follow-up results from recent reports on islet transplantation suggest that they provide significant therapeutic benefit although patients still require immunotherapy, suggesting the importance of future transplantation strategies. Although organ shortage remains the primary obstacle for the development of islet transplantation, new sources of islet cells, such as stem cells and porcine islet cells, have been proposed, and are gradually being incorporated into clinical research. Further research on new transplantation sites, such as the subcutaneous space and mesenteric fat, may eventually replace the traditional portal vein intra-islet cell infusion. Additionally, the immunological rejection reaction in islet transplantation will be resolved through the combined application of immunosuppressant agents, islet encapsulation technology, and the most promising mesenchymal stem cells/regulatory T cell and islet cell combined transplantation cell therapy. This review summarizes the progress achieved in islet transplantation, and discusses the research progress and potential solutions to the challenges faced.

Islet transplantation may be the most efficient therapeutic technique for patients with type 1 diabetes mellitus (T1DM). However, the clinical application of this method is faced with numerous limitations, including isolated islet apoptosis, recipient rejection, and graft vascular reconstruction. Mesenchymal stem cells (MSCs) possess anti-apoptotic, immunomodulatory, and angiogenic properties. Here, we review recent studies on co-culture and co-transplantation of islets with MSCs. We have summarized the methods of preparation of co-transplantation, especially the merits of co-culture, and the effects of co-transplantation. Accumulating experimental evidence shows that co-culture of islets with MSCs promotes islet survival, enhances islet secretory function, and prevascularizes islets through various pretransplant preparations. This review is expected to provide a reference for exploring the use of MSCs for clinical islet co-transplantation.

The extracellular matrix (ECM) provides an appropriate microenvironment for many kinds of cells, including pancreatic cells. Collagens are the most abundant components of the ECM. Type I, IV, V and VI collagen has been detected in pancreatic islets, and each type plays important role in the proliferation, survival, function and differentiation of pancreatic cells. In some cases, collagens show behaviours similar to those of growth factors and regulate the biological behaviour of β cells by binding with certain growth factors, including IGFs, EGFs and FGFs. The transcriptional coactivator YAP/TAZ has been widely recognised as a mechanosensor that senses changes in the physical characteristics of the ECM and inhibition of YAP/TAZ enhances insulin production and secretion. Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterised by the destruction of insulin-producing β cells. The crosstalk between collagens and immune cells plays a key role in the development and differentiation of immune cells. Further, Supplementation with collagens during islet transplantation is a promising strategy for improving the quality of the islets. But, excessive collagen deposition results in pancreatic fibrosis and pancreatic carcinoma. Targeting inhibit Piezo, autophagy or IL-6 may reduce excessive collagen deposition-induced pancreatic fibrosis and pancreatic carcinoma. This review provides insights into the treatment of T1DM to prolong life expectancy and provides the potential targets for treating collagen deposition-induced pancreatic fibrosis and pancreatic carcinoma.

Diabetes mellitus (DM) is a systemic metabolic disease with high mortality and morbidity. Extracellular vesicles (EVs) have emerged as a novel class of signaling molecules, biomarkers and therapeutic agents. EVs-mediated intercellular and interorgan crosstalk of pancreatic islets plays a crucial role in the regulation of insulin secretion of β-cells and insulin action in peripheral insulin target tissues, maintaining glucose homeostasis under physiological conditions, and it\'s also involved in pathological changes including autoimmune response, insulin resistance and β-cell failure associated with DM. In addition, EVs may serve as biomarkers and therapeutic agents that respectively reflect the status and improve function and viability of pancreatic islets. In this review, we provide an overview of EVs, discuss EVs-mediated intercellular and interorgan crosstalk of pancreatic islet under physiological and diabetic conditions, and summarize the emerging applications of EVs in the diagnosis and treatment of DM. A better understanding of EVs-mediated intercellular and interorgan communication of pancreatic islets will broaden and enrich our knowledge of physiological homeostasis maintenance as well as the development, diagnosis and treatment of DM.

Pancreatic sympathetic innervation can directly affect the function of islet. The disorder of sympathetic innervation in islets during the occurrence of type 1 diabetes (T1D) has been reported to be controversial with the inducing factor unclarified. Several studies have uncovered the critical role that sympathetic signals play in controlling the local immune system. The survival and function of endocrine cells can be regulated by immune cell infiltration in islets. In the current review, we focused on the impact of sympathetic signals working on islets cell regulation, and discussed the potential factors that can induce the sympathetic innervation disorder in the islets. We also summarized the effect of interference with the islet sympathetic signals on the T1D occurrence. Overall, a comprehensive understanding of the regulatory effect of sympathetic signals on islet cells and local immune system could facilitate better strategies design to control inflammation and protect β cells in T1D therapy.

Severe burns are often complicated with hyperglycemia caused by mitochondrial oxidative stress-related pancreatic islet dysfunction. Silent information regulator of transcription 3 (Sirt3) can regulate mitochondrial oxidative stress. However, the role and mechanism of Sirt3 on islet function after severe burns remain unclear. Therefore, this study aimed to investigate whether Sirt3 played a role in both mitochondrial oxidative stress in islets and mediating islet function post severe burns.
A mouse model of 30% total body surface area full-thickness burn and an in vitro MIN6 cell hypoxia model were established. Sirt3 KO mice were used to demonstrate further the role of Sirt3 in maintaining redox homeostasis and regulating islet function. Fasting blood glucose and glucose-stimulated insulin secretion (GSIS) were detected to assess the islet function. The levels of mitochondrial ROS and deacetylation, and the activities of Mn-SOD and IDH2 were measured to evaluate oxidative stress. The mitochondrial membrane potential (MMP)was detected and the apoptosis rate measured.
In vitro MIN6 cells, the hypoxia treatment significantly reduced Sirt3 expression, resulting in increased deacetylation of Mn-SOD and IDH2, which further led to a higher level of mitochondrial ROS. In addition, hypoxia reduced MMP and increased apoptosis rate, which impaired GSIS eventually. Knockdown of Sirt3 caused similar alterations. The hypoxia-induced high level of mitochondrial ROS and apoptosis and impaired GSIS could be reversed by overexpression of Sirt3. Similarly, after severe burns, the expression of Sirt3 in islets decreased significantly with a high level of deacetylation of Mn-SOD, IDH2, mitochondrial ROS and apoptosis, and islet dysfunction. Oxidative stress and apoptosis also occurred in islets of Sirt3 KO mice, accompanied by islet dysfunction.
Sirt3 and downstream signalling are critical in modulating the islet function post severe burns by regulating mitochondrial oxidative stress and apoptosis.

The high levels of oxidative stress and apoptosis of pancreatic islet cells after severe burns lead to the dysfunction of islets and glucose metabolism disorders. Silent information regulator of transcription 1 (SIRT1) can decrease oxidative stress and apoptosis of islets in diabetes mellitus. This study aimed to investigate the role of SIRT1 on pancreatic islets and whether nicotinamide mononucleotide (NMN) can impact the function of pancreatic islets after severe burns.
A 30% total body surface area full-thickness burn model was established using male C57BL/6 mice, and mice were randomized into sham group, burn group, burn + NMN group and burn + NMN + EX-527 group. The concentration of nicotinamide adenine dinucleotide (NAD), the expression of SIRT1, apoptosis induction, mitochondrial function and related signalling pathways of pancreatic islets at 24 h after severe burns were tested.
Severe burns led to decreased NAD level and SIRT1 expression of pancreatic islets, increased apoptosis rate, and mitochondrial dysfunction of pancreatic islets. NAD repletion by NMN and upregulation of SIRT1 expression reduced the phosphorylation and acetylation levels of NF-κB p65 and burn-induced apoptosis. Meanwhile, the mitochondrial function of islets was rescued by NMN treatment through the SIRT1/UCP2 axis and SIRT1/PGC1-α axis. In addition, the fasting blood glucose decreased and glucose-stimulated insulin secretion was improved with NMN treatment after severe burns. This protective effect of NMN could be abolished by EX-527, the inhibitor of SIRT1.
NMN can increase the concentration of NAD+ of pancreatic islets and regulate SIRT1 and its downstream targets, thereby reducing apoptosis, maintaining mitochondrial function and improving pancreatic islet function after severe burn injury.

Islets have a high demand for oxygen and most of them will die of hypoxia injury before and after transplantation. Hypoxic damage is one of the key factors associated with islet graft dysfunction. Mesenchymal stem cells (MSCs) have multiple functions and can enhance the therapeutic effect of islet transplantation. In this study, islets were cultured together with or without MSCs derived from umbilical cord (hUC-MSCs) under normal and hypoxic conditions. The effect of hUC-MSCs on the survival and function of isolated islets was detected by immunofluorescence and ELISA. Hypoxia-inducible factor 1 alpha (HIF-1α) and PFKFB3 mRNA and protein expression in different conditions were tested by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western Blot. The islets co-cultured with hUC-MSCs have improved viability and function compared with islets cultured alone. The mRNA transcription of HIF-1α in the co-cultured group increased. The protein expression of PFKFB3 increased with the increase of HIF-1α. This study found that hUC-MSCs could protect islets from dysfunction caused by hypoxia, and HIF-1α/PFKFB3 played an important role in hypoxic resistance, suggesting a potential strategy to improve the outcome of islet transplantation.

Type 2 diabetes mellitus (T2DM) is a systematic multi-organ metabolic disease, which is characterized by the dynamic interplay among different organs. The increasing incidence of T2DM reflects an urgent need for the development of in vitro human-relevant models for disease study and drug therapy. Here, a new microfluidic multi-organoid system is developed that recapitulates the human liver-pancreatic islet axis in normal and disease states. The system contains two compartmentalized regions connected by a microchannel network, enabling 3D co-culture of human induced pluripotent stem cells (hiPSC)-derived liver and islet organoids for up to 30 days under circulatory perfusion conditions. The co-cultured liver and islet organoids exhibit favorable growth and improved tissue-specific functions. Transcriptional analyses reveal the activation of metabolically relevant signaling pathways in the co-cultured organoids. Notably, the co-culture system facilitates sensitive glucose-stimulated insulin secretion from islet organoids and increased glucose utilization in liver organoids by glucose tolerance tests. Both liver and islet organoids display mitochondrial dysfunction and decreased glucose transport capacity under high glucose conditions, which can be alleviated by metformin treatment. This novel multi-organoid system can recapitulate human-relevant liver-islet axis under both physiological and pathological conditions, providing a unique platform for future T2DM research and drug development.

Objective This study aimed to assess the protective value of adiponectin (APN) in pancreatic islet injury induced by chronic intermittent hypoxia (CIH). Methods Sixty rats were randomly divided into three groups: normal control (NC) group, CIH group, and CIH with APN supplement (CIH+APN) group. After 5 weeks of CIH exposure, we conducted oral glucose tolerance tests (OGTT) and insulin released test (IRT), examined and compared the adenosine triphosphate (ATP) levels, mitochondrial membrane potential (MMP) levels, reactive oxygen species (ROS) levels, enzymes gene expression levels of Ant1, Cs, Hmox1, and Cox4i1 which represented mitochondrial tricarboxylic acid cycle function, the protein and gene expression levels of DRP1, FIS1, MFN1, and OPA1 which represented mitochondrial fusion and division, and the protein expression levels of BAX, BCL-2, cleaved Caspase-3, and cleaved PARP which represented mitochondrial associated apoptosis pathway of pancreatic islet. Results OGTT and IRT showed blood glucose and insulin levels had no differences among the NC, CIH and CIH+APN groups (both P>0.05) at 0 min, 20 min, 30 min, 60 min, 120 min. However, we found that compared to NC group, CIH increased the ROS level, reduced ATP level and MMP level. The islets of CIH exposed rats showed reduced gene expression levels of Ant1, Cs, Hmox1, and Cox4i1, decreased protein and gene expression levels of MFN1 and OPA1, increased protein and gene expression levels of DRP1 and FIS1, increased protein expression levels of cleaved Caspase-3 and cleaved PARP, with lower ratio of BCL-2/BAX at protein expression level. All the differences among three groups were statistically significant. APN treated CIH rats showed mitigated changes in the above measurements associated with islet injuries. Conclusion APN may ameliorate the pancreatic islet injury induced by CIH via inhibiting the imbalance in mitochondrial fusion and division.