Human Diabetes Research Articles

Deletion of Carboxypeptidase E in β-Cells Disrupts Proinsulin Processing but Does Not Lead to Spontaneous Development of Diabetes in Mice.

Carboxypeptidase E (Cpe) is an enzyme that removes the carboxy-terminal arginine and lysine residues from peptide precursors. Mutations in CPE lead to obesity and type 2 diabetes in humans, and whole-body Cpe knockout or mutant mice are obese and hyperglycemic and fail to convert proinsulin to insulin. We show that β-cell-specific Cpe deletion in mice (βCpeKO) does not lead to the development of obesity or hyperglycemia, even after prolonged high-fat diet treatment. However, β-cell proliferation rate and β-cell area are increased, and the development of hyperglycemia induced by multiple low-dose streptozotocin injections is accelerated in βCpeKO mice.

87-OR: Engineered Vasculature Induces Functional Maturation of Pluripotent Stem Cell–Derived Islet Organoids

Blood vessels play a critical role in islet health and function. Native islets are richly vascularized and their interaction with blood vessels is important for β-cell function. Therefore, vasculature ought to be an integral component of a model for studying human islet physiology and diabetes pathobiology. Here, we develop a vascularized islet organoid model by integrating hPSC-derived islets (SC-islets) with human endothelial cells (ECs) and fibroblasts (FBs). To analyze β-cell function, we generated an hPSC line carrying GCaMP6f, a Ca2+ reporter, as Ca2+ oscillation can be used as a proxy for insulin secretion. Comparing β-cell Ca2+ responses of non-vascularized and vascularized SC-islets revealed more frequent and stronger Ca2+ influx in response to high glucose and the GLP-1 analogue in vascularized SC-islets. To identify vasculature-derived signals beneficial to β-cell function, we performed cell-cell interaction network analyses based on single-cell transcriptomic data from SC-islets, ECs, and FBs. Among the top candidates were integrin receptors that interact with extracellular matrix proteins. Consistent with these predictions, a higher number of β-cells were in contact with EC-derived basement membrane proteins (e.g., laminin α1, collagen IV) and exhibited activation of integrin β1. The analysis also revealed BMP4-BMPR2 as a potential crosstalk between ECs and β-cells. Indeed, BMP4 addition augmented Ca2+ response and insulin secretion of β-cells under glucose stimulation. Finally, to develop a system mimicking in vivo physiology, we integrated SC-islets into a microfluidic platform where the organoids are supported by a network of perfused microvessels. Our newly-established model of vascularized SC-islet organoids will enable further studies of crosstalk between β-cells and vasculature under conditions mimicking the native islet microenvironment. The model will serve as a platform to study disease mechanisms of diabetes and test therapeutics. Disclosure K.Nguyen-ngoc: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (UG3DK1226390); JDRF (3-PDF-2017-386-A-N, 3-PDF-2020-932-A-N)

1755-P: EndoC-ßH5 Is a Storable and Ready-to-Use Human Pancreatic Beta Cell That Can Model Type 1 and 2 Diabetes

EndoC-βH5 is a newly developed human pancreatic beta cell model and an optimized version among the EndoC-βH (EndoC-βH1/2/3) family. EndoC-βH5 cells are storable and ready-to-use and they robustly and reproducibly secrete insulin in response to glucose and incretins across experiments and laboratories. Specifically, they dose dependently respond to physiological concentrations of glucose. In addition, their response to GLP-1 and GIP receptor agonists is also highly reproducible and dose-dependent. Given the continuously increasing number of diabetes patients worldwide, the need for physiologically relevant human cellular models is greater than ever and EndoC-βH5 cells represent a novel human pancreatic beta cell solution that can help developing human diabetes models and drug screening and validation assays. In this study, we are developing pathological and drug screening models. EndoC-βH5 cells are sensitive to palmitate/high glucose as well as cytokine induced cell loss, recapitulating hallmarks of T2D. In addition, we evaluated impairment of insulin secretion and ER stress in these contexts in order to assess the mechanistic relevance of the models. We then addressed T1D modeling. We generated HLA-A2 expressing EndoC-βH5 cells and evaluated HLA-A2 alloreactive T lymphocyte activation and diabetogenic T lymphocyte induced cytotoxicity. Finally, we determined that EndoC-βH5 cells express functional glucagon (GCG) receptor, which contributes to the modulation of glucose induced insulin secretion, highlighting the potential of EndoC-βH5 as a model to study dual and triple GLP-1/GIP/GCG receptor agonists in a reproducible human cellular model. Overall, EndoC-βH5 cells appear to be a powerful tool to develop Type 1/2 diabetes and drug discovery models. Disclosure H.Olleik: None. B.Blanchi: Employee; Human Cell Design.

A Gluten-Free Diet during Pregnancy and Early Life Increases Short Chain Fatty Acid-Producing Bacteria and Regulatory T Cells in Prediabetic NOD Mice.

The incidence of the autoimmune disease type 1 diabetes is increasing, likely caused by environmental factors. A gluten-free diet has previously been shown to ameliorate autoimmune diabetes in non-obese diabetic (NOD) mice and humans. Although the exact mechanisms are not understood, interventions influencing the intestinal microbiota early in life affect the risk of type 1 diabetes. Here, we characterize how NOD mice that are fed a gluten-free (GF) diet differ from NOD mice that are fed a gluten-containing standard (STD) diet in terms of their microbiota composition by 16S rRNA gene amplicon sequencing and pancreatic immune environment by real-time quantitative PCR at the prediabetic stage at 6 and 13 weeks of age. Gut microbiota analysis revealed highly distinct microbiota compositions in both the cecum and the colon of GF-fed mice compared with STD-fed mice. The microbiotas of the GF-fed mice were characterized by an increased Firmicutes/Bacteroidetes ratio, an increased abundance of short chain fatty acid (particularly butyrate)-producing bacteria, and a reduced abundance of Lactobacilli compared with STD mice. We found that the insulitis score in the GF mice was significantly reduced compared with the STD mice and that the markers for regulatory T cells and T helper 2 cells were upregulated in the pancreas of the GF mice. In conclusion, a GF diet during pre- and early post-natal life induces shifts in the cecal and colonic microbiota compatible with a less inflammatory environment, providing a likely mechanism for the protective effect of a GF diet in humans.

Productive Germinal Center Responses Depend on the Nature of Stimuli Received by Anti-Insulin B Cells in Type 1 Diabetes-Prone Mice.

Islet autoantibodies, including those directed at insulin, predict type 1 diabetes (T1D) in mice and humans and signal immune tolerance breach by B lymphocytes. High-affinity insulin autoantibodies and T follicular helper cell involvement implicate germinal centers (GCs) in T1D. The VH125SD BCR transgenic model, in which 1-2% of peripheral B lymphocytes recognize insulin, enables direct study of insulin-binding B cells. Our prior studies showed that anti-insulin B cell receptor transgene site-directed to H chain locus mice fail to generate insulin Ab following T-dependent immunization, but it was unclear whether anti-insulin B cells were blocked for GC initiation, survival, or differentiation into Ab-secreting cells. Here, we show that insulin-binding B cells in T1D-prone anti-insulin B cell receptor transgene site-directed to H chain locus mice can spontaneously adopt a GC phenotype and undergo class switching to the IgG1 isotype, with little if any switching to IgG2b. T-dependent immunizations with insulin SRBC or insulin CFA drove anti-insulin B lymphocytes to adopt a GC phenotype, despite blunted insulin Ab production. Dual immunization against self (insulin) and foreign (4-hydroxy-3-nitrophenylacetyl hapten conjugated to keyhole limpet hemocyanin) Ags showed an anti-insulin (but not anti-4-hydroxy-3-nitrophenylacetyl) Ab block that tracked with increased expression of the apoptosis marker, activated caspase 3, in self-reactive GC B cells. Finally, T-independent immunization with insulin conjugated to Brucella abortus ring test Ag released immune tolerance to allow robust expansion of anti-insulin GC B cells and IgG-switched insulin Ab production. Overall, these data pinpoint GC survival and Ab-secreting cell differentiation as immune tolerance blocks that limit T-dependent, but not T-independent, stimulation of anti-insulin B cell responses.

Inflammation versus regulation: how interferon-gamma contributes to type 1 diabetes pathogenesis.

Type 1 diabetes is an autoimmune disease with onset from early childhood. The insulin-producing pancreatic beta cells are destroyed by CD8+ cytotoxic T cells. The disease is challenging to study mechanistically in humans because it is not possible to biopsy the pancreatic islets and the disease is most active prior to the time of clinical diagnosis. The NOD mouse model, with many similarities to, but also some significant differences from human diabetes, provides an opportunity, in a single in-bred genotype, to explore pathogenic mechanisms in molecular detail. The pleiotropic cytokine IFN-γ is believed to contribute to pathogenesis of type 1 diabetes. Evidence of IFN-γ signaling in the islets, including activation of the JAK-STAT pathway and upregulation of MHC class I, are hallmarks of the disease. IFN-γ has a proinflammatory role that is important for homing of autoreactive T cells into islets and direct recognition of beta cells by CD8+ T cells. We recently showed that IFN-γ also controls proliferation of autoreactive T cells. Therefore, inhibition of IFN-γ does not prevent type 1 diabetes and is unlikely to be a good therapeutic target. In this manuscript we review the contrasting roles of IFN-γ in driving inflammation and regulating the number of antigen specific CD8+ T cells in type 1 diabetes. We also discuss the potential to use JAK inhibitors as therapy for type 1 diabetes, to inhibit both cytokine-mediated inflammation and proliferation of T cells.

A Combined Method for Diabetes Mellitus Diagnosis Using Deep Learning, Singular Value Decomposition, and Self-Organizing Map Approaches.

Diabetes in humans is a rapidly expanding chronic disease and a major crisis in modern societies. The classification of diabetics is a challenging and important procedure that allows the interpretation of diabetic data and diagnosis. Missing values in datasets can impact the prediction accuracy of the methods for the diagnosis. Due to this, a variety of machine learning techniques has been studied in the past. This research has developed a new method using machine learning techniques for diabetes risk prediction. The method was developed through the use of clustering and prediction learning techniques. The method uses Singular Value Decomposition for missing value predictions, a Self-Organizing Map for clustering the data, STEPDISC for feature selection, and an ensemble of Deep Belief Network classifiers for diabetes mellitus prediction. The performance of the proposed method is compared with the previous prediction methods developed by machine learning techniques. The results reveal that the deployed method can accurately predict diabetes mellitus for a set of real-world datasets.

Brief Review: Pancreatic Islet Transplantation for Type 1 Diabetes in Humans

Pancreatic islet transplantation (ITx) has moved from the experimental phase of development to a position of an accepted and appropriate procedure to apply in clinical medicine. The primary indication for use of ITx is for management of dangerous and recurrent hypoglycemia secondary to use of exogenous insulin for management of hyperglycemia in people with type 1 diabetes. ITx involves procurement of a pancreas donated by a person who has died. The organ is taken to a specialized laboratory for isolation of islets that will be infused into the liver via a cannula put into the hepatic portal vein of an awake recipient by a radiologist. Success rates of maintaining normal blood glucose after the ITx are very high and almost as effective as transplanting an entire pancreas via surgery. Often more than one procedure is required to achieve success. One major attraction to the procedure is that it avoids the more dangerous and complicated procedure of surgical transplantation of the entire pancreas. However, in both instances recipients must undergo and maintain immunosuppressive drugs to avoid rejection of the islets. ITx is also used for management of patients with chronic, painful pancreatitis who undergo pancreatectomy. In this instance the patient’s own islets are returned by infusion into the liver as is done with type 1 diabetes patients. No immunosuppression is required. Success rates of autoislet transplantations are also quite high if a sufficiently mass of islets can be recovered from the resected pancreas.

Developmental origins of diabetes mellitus: Environmental epigenomics and emerging patterns.

Mounting epidemiological evidence indicates that environmental exposures in early life have roles in diabetes susceptibility in later life. Additionally, environmentally induced diabetic susceptibility could be transmitted to subsequent generations. Epigenetic modifications provide a potential association with the environmental factors and altered gene expression that might cause disease phenotypes. Here, we bring the increasing evidence that environmental exposures early in development are linked to diabetes through epigenetic modifications. This review first summarizes the epigenetic targets, including metastable epialleles and imprinting genes, by which the environmental factors can modify the epigenome. Then we review the epigenetics changes in response to environmental challenge during critical developmental windows, gametogenesis, embryogenesis, and fetal and postnatal period, with the specific example of diabetic susceptibility. Although the mechanisms are still largely unknown, especially in humans, the new research methods are now gradually available, and the animal models can provide more in-depth study of mechanisms. These have implications for investigating the link of the phenomena to human diabetes, providing a new perspective on environmentally triggered diabetes risk.

Sudachitin and Nobiletin Stimulate Lipolysis via Activation of the cAMP/PKA/HSL Pathway in 3T3-L1 Adipocytes.

Polymethoxyflavones are flavonoids that are abundant in citrus fruit peels and have beneficial effects on human health. Previous studies have demonstrated that the polymethoxyflavones, namely sudachitin and nobiletin, ameliorate obesity and diabetes in humans and rodents. Although nobiletin induces lipolysis in adipocytes, lipolytic pathway activation by sudachitin has not been clarified in adipocytes. In this study, the effect of sudachitin on lipolysis was elucidated in murine 3T3-L1 adipocytes. Glycerol release into the medium and activation of the cyclic AMP (cAMP)/protein kinase A (PKA)/hormone-sensitive lipase (HSL) pathway was evaluated in 3T3-L1-differentiated adipocytes. Treatment with sudachitin and nobiletin for 24 and 48 h did not induce cytotoxicity at concentrations of up to 50 μM. Sudachitin and nobiletin at concentrations of 30 and 50 μM increased intracellular cAMP and medium glycerol levels in 3T3-L1 adipocytes. Western blotting revealed that sudachitin and nobiletin dose-dependently increased protein levels of phosphorylated PKA substrates and phosphorylated HSL. Sudachitin- and nobiletin-induced glycerol release, phosphorylation of PKA substrates, and HSL phosphorylation were suppressed by pharmacological inhibition of adenylate cyclase and PKA. These findings indicated that sudachitin, similar to nobiletin, exerts anti-obesogenic effects, at least in part through the induction of lipolysis in adipocytes.

Role of Delta/Notch-like EGF-related receptor in blood glucose homeostasis.

Cell-cell interactions are necessary for optimal endocrine functions in the pancreas. β-cells, characterized by the expression and secretion of the hormone insulin, are a major constituent of functional micro-organs in the pancreas known as islets of Langerhans. Cell-cell contacts between β-cells are required to regulate insulin production and glucose-stimulated insulin secretion, which are key determinants of blood glucose homeostasis. Contact-dependent interactions between β-cells are mediated by gap junctions and cell adhesion molecules such as E-cadherin and N-CAM. Recent genome-wide studies have implicated Delta/Notch-like EGF-related receptor (Dner) as a potential susceptibility locus for Type 2 Diabetes in humans. DNER is a transmembrane protein and a proposed Notch ligand. DNER has been implicated in neuron-glia development and cell-cell interactions. Studies herein demonstrate that DNER is expressed in β-cells with an onset during early postnatal life and sustained throughout adulthood in mice. DNER loss in adult β-cells in mice (β-Dner cKO mice) disrupted islet architecture and decreased the expression of N-CAM and E-cadherin. β-Dner cKO mice also exhibited impaired glucose tolerance, defects in glucose- and KCl-induced insulin secretion, and decreased insulin sensitivity. Together, these studies suggest that DNER plays a crucial role in mediating islet cell-cell interactions and glucose homeostasis.

Interspecies Variation Affects Islet Amyloid Polypeptide Membrane Binding.

The aggregation of islet amyloid polypeptide (IAPP) is associated with β-cell dysfunction in type 2 diabetes (T2D) in humans. One possible mechanism of toxicity is the interaction of IAPP oligomers with lipid membranes to disrupt the bilayer integrity and/or homeostasis of the cell. Amino acid sequence variations of IAPPs between species can greatly decrease their propensity for aggregation. For example, human IAPP is toxic to β-cells, but rat and pig IAPP are not. However, it is not clear how these differences affect membrane association. Using native mass spectrometry with lipid nanodiscs, we explored the differences in the association of human, rat, and pig IAPP with lipid bilayers. We discovered that human and rat IAPP bound nanodiscs with anionic dipalmitoyl-phosphatidylglycerol (DPPG) lipids, but pig IAPP did not. Furthermore, human and rat IAPP interacted differently with the membrane. Human IAPP show potential tetramer complexes, but rat IAPP associated with the membrane sequentially. Thus, overall IAPP-bilayer interactions are not necessarily related to disease, but small differences in oligomeric behavior at the membrane may instead play a role.

Research Progress on Animal Models of Diabetes Mellitus

Diabetes Mellitus (DM) is a complicated metabolic illness defined by hyperglycemia due to faulty insulin production or activity, and it is one of the world’s fastest-growing public health concerns. The construction of a good diabetes mellitus model is crucial for diabetes mellitus pathophysiology research, diabetic mellitus prevention, and the development of effective therapeutic therapy. Diabetes mellitus models are now chemically induced, spontaneous, and genetically created. The models were created using the chemical induction of streptozotocin and alloxan, and the spontaneous type of diabetes mellitus animal models are appropriate for T1DM, T2DM, and related phenotypes, including obesity and insulin resistance. Genetically engineered animal models are much more closely related to human diabetes mellitus, including gene knockout animal models. They can be used to explain the cause of diabetes mellitus in terms of molecular mechanisms and to study the effects of individual genes on insulin secretion and insulin resistance faultlessly. This research provides a detailed description of T1DM and T2DM animal models, illustrating the importance of diabetes mellitus.

Abnormal intraepidermal nerve fiber density in disease: A scoping review.

Intraepidermal nerve fiber density (IENFD) has become an important biomarker for neuropathy diagnosis and research. The consequences of reduced IENFD can include sensory dysfunction, pain, and a significant decrease in quality of life. We examined the extent to which IENFD is being used as a tool in human and mouse models and compared the degree of fiber loss between diseases to gain a broader understanding of the existing data collected using this common technique. We conducted a scoping review of publications that used IENFD as a biomarker in human and non-human research. PubMed was used to identify 1,004 initial articles that were then screened to select articles that met the criteria for inclusion. Criteria were chosen to standardize publications so they could be compared rigorously and included having a control group, measuring IENFD in a distal limb, and using protein gene product 9.5 (PGP9.5). We analyzed 397 articles and collected information related to publication year, the condition studied, and the percent IENFD loss. The analysis revealed that the use of IENFD as a tool has been increasing in both human and non-human research. We found that IENFD loss is prevalent in many diseases, and metabolic or diabetes-related diseases were the most studied conditions in humans and rodents. Our analysis identified 73 human diseases in which IENFD was affected, with 71 reporting IENFD loss and an overall average IENFD change of -47%. We identified 28 mouse and 21 rat conditions, with average IENFD changes of -31.6% and -34.7%, respectively. Additionally, we present data describing sub-analyses of IENFD loss according to disease characteristics in diabetes and chemotherapy treatments in humans and rodents. Reduced IENFD occurs in a surprising number of human disease conditions. Abnormal IENFD contributes to important complications, including poor cutaneous vascularization, sensory dysfunction, and pain. Our analysis informs future rodent studies so they may better mirror human diseases impacted by reduced IENFD, highlights the breadth of diseases impacted by IENFD loss, and urges exploration of common mechanisms that lead to substantial IENFD loss as a complication in disease.

Transplantation of insulin-producing cells derived from human MSCs to treat diabetes in a non-human primate model.

Islet cell transplantation is an emerging therapy in the treatment of diabetes mellitus. Differentiation of islet cells from mesenchymal stem cells (MSCs) is a potential solution to the challenge of insufficient donor sources. This study investigated whether human umbilical cord-derived MSCs could effectively differentiate into insulin-producing cells (IPCs) and evaluated the therapeutic efficacy of IPCs in treating diabetes. IPCs were induced from MSCs by a two-step protocol. IPC expression products were evaluated by western blot and real-time PCR. IPC insulin secretion was evaluated by ELISA. The viability of IPCs was measured by FDA/PI and dithizone staining. The non-human primate tree shrew was used as a diabetes model. After a single STZ induction into a diabetes model, a single intraportal transplantation of IPCs, MSCs, or normal saline was performed (n = 6 per group). Blood glucose was monitored for 3 weeks, then the animals were euthanized and the distribution of IPCs in the liver was examined pathologically. After about 3 weeks of in vitro induction, IPCs formed microspheres of 100-200 μm, with >95% viable cells that were dithizone stain positive. IPCs expressed islet-related genes and proteins and secreted high levels of insulin whether stimulated by low or high levels of glucose. After transplantation of IPCs into diabetic tree shrews, blood glucose levels decreased rapidly to near normal and were significantly lower than the MSC or saline groups for 3 weeks thereafter. We present the novel discovery that IPCs derived from human umbilical cord MSCs exert a therapeutic effect in a non-human primate model of diabetes. This study provides a preliminary experimental basis for the use of autologous MSC-derived IPCs in the treatment of human diabetes.

CuMoO4 nanorods-based acetone chemiresistor-enabled non-invasive breathomic-diagnosis of human diabetes and environmental monitoring

A nano-enabled low-trace monitoring system for acetone has the potential to revolutionize breath omics-based non-invasive diagnosis of human diabetes and environmental monitoring technologies. This unprecedented study presents the state-of-the-art facile and economic template-assisted hydrothermal route to fabricate novel CuMoO4 nanorods for room temperature breath and airborne acetone detection. Physicochemical attribute analysis reveals the formation of crystalline CuMoO4 nanorods with diameters ranging from 90 to 150 nm, and an optical band gap of approximately 3.87 eV. CuMoO4 nanorods-based chemiresistor demonstrates excellent acetone monitoring performance, with a sensitivity of approximately 33.85 at a concentration of 125 ppm. Acetone detection is rapid, with a response time of 23 s and fast recovery within 31 s. Furthermore, the chemiresistor exhibits long-term stability and selectivity towards acetone, compared to other interfering volatile organic compounds (VOCs) commonly found in human breath such as ethanol, propanol, formaldehyde, humidity, and ammonia. The linear detection range of acetone from 25 to 125 ppm achieved by the fabricated sensor is well-suited for human breath-based diagnosis of diabetes. This work represents a significant advancement in the field, as it offers a promising alternative to time-consuming and costly invasive biomedical diagnostics, with the potential for application in cleanroom facilities for indoor contamination monitoring. The utilization of CuMoO4 nanorods as sensing nanoplatform opens new possibilities for the development of nano-enabled, low-trace acetone monitoring technologies for non-invasive diabetes diagnosis and environmental sensing applications.

Epigenetic Mechanisms of Aging and Aging-Associated Diseases.

Aging is an inevitable outcome of life, characterized by a progressive decline in tissue and organ function. At a molecular level, it is marked by the gradual alterations of biomolecules. Indeed, important changes are observed on the DNA, as well as at a protein level, that are influenced by both genetic and environmental parameters. These molecular changes directly contribute to the development or progression of several human pathologies, including cancer, diabetes, osteoporosis, neurodegenerative disorders and others aging-related diseases. Additionally, they increase the risk of mortality. Therefore, deciphering the hallmarks of aging represents a possibility for identifying potential druggable targets to attenuate the aging process, and then the age-related comorbidities. Given the link between aging, genetic, and epigenetic alterations, and given the reversible nature of epigenetic mechanisms, the precisely understanding of these factors may provide a potential therapeutic approach for age-related decline and disease. In this review, we center on epigenetic regulatory mechanisms and their aging-associated changes, highlighting their inferences in age-associated diseases.

Rapidly-Progressing Pyomyositis After Chest Contusion in a Patient With Well-Controlled Diabetes Mellitus

Pyomyositis is an uncommon acute bacterial infection of the skeletal muscle. It is sometimes referred to as "tropical pyomyositis" because it has been primarily reported as an endemic disease in tropical regions. In temperate climates, it is mainly diagnosed in immunocompromised persons, such as those with human immunodeficiency virus infection, malignancy, diabetes, and various other medical conditions. Early diagnosis and appropriate antimicrobial therapy for pyomyositis are important, however, it is often missed in its early stage. Herein, we report the case of a patient with obesity and well-controlled diabetes in whom rapid onset pyomyositis developed in only 2 days after chest contusion and induced bacteremia in its early stage. He was successfully treated by antimicrobials without any drainage or surgical intervention. Even in patients with well-controlled diabetes or in healthy persons, pyomyositis should be considered for patients who present with fever and muscle swelling and pain, especially when they have obesity and a history of blunt trauma. It should also be noted that pyomyositis, mimicking muscle contusion or hematoma can appear very early after blunt muscle trauma. Prompt diagnosis and antimicrobial treatment for pyomyositis can lead to a favorable outcome, without surgical drainage.

Pathobionts from chemically disrupted gut microbiota induce insulin-dependent diabetes in mice

BackgroundDysbiotic gut microbiome, genetically predisposed or chemically disrupted, has been linked with insulin-dependent diabetes (IDD) including autoimmune type 1 diabetes (T1D) in both humans and animal models. However, specific IDD-inducing gut bacteria remain to be identified and their casual role in disease development demonstrated via experiments that can fulfill Koch’s postulates.ResultsHere, we show that novel gut pathobionts in the Muribaculaceae family, enriched by a low-dose dextran sulfate sodium (DSS) treatment, translocated to the pancreas and caused local inflammation, beta cell destruction and IDD in C57BL/6 mice. Antibiotic removal and transplantation of gut microbiota showed that this low DSS disrupted gut microbiota was both necessary and sufficient to induce IDD. Reduced butyrate content in the gut and decreased gene expression levels of an antimicrobial peptide in the pancreas allowed for the enrichment of selective members in the Muribaculaceae family in the gut and their translocation to the pancreas. Pure isolate of one such members induced IDD in wildtype germ-free mice on normal diet either alone or in combination with normal gut microbiome after gavaged into stomach and translocated to pancreas. Potential human relevance of this finding was shown by the induction of pancreatic inflammation, beta cell destruction and IDD development in antibiotic-treated wildtype mice via transplantation of gut microbiome from patients with IDD including autoimmune T1D.ConclusionThe pathobionts that are chemically enriched in dysbiotic gut microbiota are sufficient to induce insulin-dependent diabetes after translocation to the pancreas. This indicates that IDD can be mainly a microbiome-dependent disease, inspiring the need to search for novel pathobionts for IDD development in humans.BraSzCKLkea6-Duo39HsMTVideo

Alleviating effects and mechanisms of action of large-leaf yellow tea drinking on diabetes and diabetic nephropathy in mice

Our previous study found that large-leaf yellow tea (LYT) had interesting hypoglycemic activity in high-fat diet-induced obese mice and highly safety in healthy mice. To study the anti-diabetic potential of LYT, the present study further investigated the preventive effects and mechanisms of action of LYT administration on diabetes and diabetic nephropathy in high-fat diet plus streptozotocin-induced diabetic mice. Results showed that LYT infusions (1/100 and 1/50, m/V) as drinking fluid for 4 weeks reduced diabetic polydipsia and polyuria, enhanced glucose tolerance and insulin sensitivity, and lowered fasting blood glucose level. The underlying mechanisms involve downregulation of gluconeogenesis (lower protein levels of TXNIP and FBP and enzyme activity of FBP), upregulation of lipid catabolism (higher protein levels of CPT-1α and PPARα), downregulation of lipogenesis (lower protein level of SREBP-1), and modification of the structure and abundance of gut microbiota to modulate metabolic homeostasis. Moreover, LYT administration prevented diabetic nephropathy, possibly due to reduced glucose-caused osmotic diuresis and lowered levels of renal PKC-β2, NLRP3 as well as membrane PKC-α, AQP2 and glycosylated AQP2 proteins. Taken together, LYT exhibits the activities in alleviating diabetic symptoms, ameliorating glucose and lipid dysmetabolism and fatty liver, and preventing diabetic nephropathy in diabetic mice. These activities may be explored for the prevention and treatment of diabetes in humans.