Islet dysfunction and destruction are the common cause for both type 1 and type 2 diabetes mellitus (T2DM). The islets of Langerhans are highly vascularized miniorgans, and preserving the structural integrity and full function of the microvascular endothelium is vital for protecting the islets from the infiltration of immune cells and secondary inflammatory attack. Mesenchymal stromal cell (MSC)-based therapies have been proven to promote angiogenesis of the islets; however, the underlying mechanism for the protective role of MSCs in the islet endothelium is still vague. In this study, we used MS-1, a murine islet microvascular endothelium cell line, and an MSC-MS1 transwell culturing system to investigate the protective mechanism of rat bone marrow-derived MSCs under oxidative stress in vitro. Cell apoptosis was detected by TUNEL staining, annexin V/PI flow cytometry analysis, and cleaved caspase 3 western blotting analysis. Endothelial cell activation was determined by expression of intercellular cell adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM), as well as eNOS phosphorylation/activation. The changes of VCAM-1, eNOS, and the β-catenin expression were also tested in the isolated islets of T2DM rats infused with MSCs. We observed that treating MS-1 cells with H2O2 triggered significant apoptosis, induction of VCAM expression, and reduction of eNOS phosphorylation. Importantly, coculturing MS-1 cells with MSCs prevented oxidative stress-induced apoptosis, eNOS inhibition, and VCAM elevation in MS-1 cells. Similar changes in VCAM-1 and eNOS phosphorylation could also be observed in the islets isolated from T2DM rats infused with MSCs. Moreover, MSCs cocultured with MS-1 in vitro or their administration in vivo could both result in an increase of β-catenin, which suggested activation of the β-catenin-dependent Wnt signaling pathway. In MS-1 cells, activation of the β-catenin-dependent Wnt signaling pathway partially mediated the protective effects of MSCs against H2O2-induced apoptosis and eNOS inhibition. Furthermore, MSCs produced a significant amount of Wnt4 and Wnt5a. Although both Wnt4 and Wnt5a participated in the interaction between MSCs and MS-1 cells, Wnt4 exhibited a protective role while Wnt5a seemed to show a destructive role in MS-1 cells. Our observations provide evidence that the orchestration of the MSC-secreted Wnts could promote the survival and improve the endothelial function of the injured islet endothelium via activating the β-catenin-dependent Wnt signaling in target endothelial cells. This finding might inspire further in-vivo studies.

Background. COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has threatened every civilian as a global pandemic. The immune system poses the critical interactive chain between the human body and the virus. Here, we make efforts to examine whether comorbidity with type 2 diabetes (T2D) affects the immunological response in COVID-19 patients. Methods. We conducted a retrospective pilot study investigating immunological characteristics of confirmed cases of COVID-19 with or without comorbid T2D. Two subcohorts of sex- and age-matched participants were eligible for data analysis, of which 33 participants were with T2D and the remaining 37 were nondiabetic (NDM). Cellular immunity was assessed by flow cytometric determination of surface markers including CD3, CD4, CD8, CD19, CD16, and CD56 in peripheral blood. Levels of C reactive protein, immunoglobulin (IgG, IgM, IgA, and IgE), and complements (C3, C4) were detected by rate nephelometry immunoassay. And Th1/Th2 cytokines (IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ) were detected by Cytometric Bead Array. Results. Neutrophil counts were found to be significantly higher in the T2D group than in the NDM group and had a significant relevance with clinical severity. Lymphocyte frequencies showed no significant differences in the two groups. However, the proportions and absolute counts of T, Tc, Th, and NK cells decreased in both groups to different degrees. An abnormal increase in neutrophil count and a decrease in lymphocyte subpopulations may represent risk factors of COVID-19 severity. The level of IgG, IgM, IgA, C3, and C4 showed no significant difference between the two groups, while the IgE levels were higher in the T2D group than in the NDM group ( p < 0.05 ). Th1 cytokines including IFN-γ, TNF-α, and IL-6, as well as CRP, appeared significantly higher in the T2D group. Conclusions. The COVID-19 patients comorbid with T2D demonstrated distinguishable immunological parameters, which represented clinical relevancies with the predisposed disease severity in T2D.

Background. Mutations in human KLF11 may lead to the development of maturity-onset diabetes of the young 7 (MODY7). This occurs due to impaired insulin synthesis in the pancreas. To date, the clinical and functional characteristics of the novel KLF11 mutation c.1061G > T have not yet been reported. Methods. Whole-exon sequencing was used to screen the proband and family members with clinical suspicion of the KLF11 variant. Luciferase reporter assays were used to investigate whether the KLF11 variant binds to the insulin promoter. Real-time PCR, western blotting, and glucose-stimulated insulin secretion (GSIS) analysis were used to analyze the KLF11 variant that regulates insulin expression and insulin secretion activity in beta cell lines. The Freestyle Libre H (Abbott Diabetes Care Ltd) was used to dynamically monitor the proband daily blood glucose levels. Results. Mutation screening for the whole exon genes identified a heterozygous KLF11 (c.1061G > T) variant in the proband, her mother, and her maternal grandfather. Cell-based luciferase reporter assays using wild-type and mutant transgenes revealed that the KLF11 (c.1061G > T) variant had impaired insulin promoter regulation activity. Moreover, this variant was found to impair insulin expression and insulin secretion in pancreatic beta cells. The proband had better blood glucose control without staple food intake ( ). Conclusions. Herein, for the first time, we report a novel KLF11 (c.1061G > T) monogenic mutation associated with MODY7. This variant has impaired insulin promoter regulation activity and impairs insulin expression and secretion in pancreatic beta cells. Therefore, administering oral antidiabetic drugs along with dietary intervention may benefit the proband.

Data science has now significantly penetrated the realm of Type 1 diabetes (T1D) management, offering invaluable assistance to healthcare providers in forecasting, monitoring, and treating the disease. Leveraging computer technology, Data science enables real-time monitoring or even predication of patients’ blood sugar levels as well as complication development. By medical big data analytics involving patients’ blood sugar, dietary habits, exercise patterns, and other relevant information, it contributes to personalized follow-up plans that are tailored to each patient’s unique circumstances. Utilizing artificial intelligence (AI) algorithms, it also provides health management services, including health education and lifestyle guidance, to help patients better manage their diabetes and improve their quality of life. The AI-based individualized insulin-glucose precision regulation and response system (artificial pancreas) also provide precision insulin dosages in real time according to the real-time changes in glycemic levels and other physiological indicators, to maintain stable glycemic control. Moreover, integrated clinical and biological multi-omics data and application of machine learning (ML) grant researchers the capability to explore the genetic foundations, molecular pathways, and prospective therapeutic targets of T1DM with greater depth and precision. With continued technological advancements and deeper applications, Data science is expected to play an even greater role in the future.