Pancreatic Islet Beta Cells Research Articles

Engineering Strategies to Improve Islet Transplantation for Type 1 Diabetes Therapy.

Type 1 diabetes is an autoimmune disease in which the immune system attacks insulin-producing beta cells of pancreatic islets. Type 1 diabetes can be treated with islet transplantation; however, patients must be administered immunosuppressants to prevent immune rejection of the transplanted islets if they are not autologous or not engineered with immune protection/isolation. To overcome biological barriers of islet transplantation, encapsulation strategies have been developed and robustly investigated. While islet encapsulation can prevent the need for immunosuppressants, these approaches have not shown much success in clinical trials due to a lack of long-term insulin production. Multiple engineering strategies have been used to improve encapsulation and post-transplantation islet survival. In addition, more efficient islet cryopreservation methods have been designed to facilitate the scaling-up of islet transplantation. Other islet sources have been identified including porcine islets and stem cell-derived islet-like aggregates. Overall, islet-laden capsule transplantation has greatly improved over the past 30 years and is moving towards becoming a clinically feasible treatment for type 1 diabetes.

IL-6 is present in beta and alpha cells in human pancreatic islets: Expression is reduced in subjects with type 1 diabetes

IL-6 is a pro-inflammatory cytokine upregulated in some autoimmune diseases. The role of IL-6 in the development of type 1 diabetes (T1D) is unclear. Clinical studies are investigating whether tocilizumab (anti-IL-6 receptor) can help preserve beta cell function in patients recently diagnosed with T1D. However, in some rodent models and isolated human islets, IL-6 has been found to have a protective role for beta cells by reducing oxidative stress. Hence, we systematically investigated local tissue expression of IL-6 in human pancreas from non-diabetic, auto-antibody positive donors and donors with T1D and T2D. IL-6 was constitutively expressed by beta and alpha cells regardless of the disease state. However, expression of IL-6 was highly reduced in insulin-deficient islets of donors with T1D, and the expression was then mostly restricted to alpha cells. Our findings suggest that the implication of IL-6 in T1D pathogenesis might be more complex than previously assumed.

Iron status in diabetes mellitus

Diabetes mellitus can be defined as chronic metabolic disease which results from either relative or complete absence of insulin by the pancreatic beta islet cells. This in-turn may lead to hyperglycemia due to disturbances in the metabolism of glucose. In the human body, iron is con- 
 sidered to be an effective pro-oxidant and participates in the generation of reactive oxygen species (ROS) such as hydroxyl radical. Because of the poor antioxidant defense mechanism of beta cells (low production of antioxidant enzymes such as catalase, glutathione peroxidase and dismutase), so they are highly prone to iron-induced oxidative stress and iron deposition in it and this will lead to apoptosis, and subsequently insulin deficiency. This iron deposition in beta cells will also lead to insulin resistance by reducing insulin extracting ability of the liver and inhibiting glucose uptake in muscle tissues and fats, this in turn will result in high production of hepatic glucose. Ferritin which is an acute phase reactant protein, that responds to acute stress like trauma, infections, tissue necrosis and surgery, it can produce diabetes mellitus either through inflammation or by increasing iron stores.

Therapeutic administration of Tregitope-Human Albumin Fusion with Insulin Peptides to promote Antigen-Specific Adaptive Tolerance Induction

Type 1 Diabetes (T1D) is an autoimmune disease that is associated with effector T cell (Teff) destruction of insulin-producing pancreatic beta-islet cells. Among the therapies being evaluated for T1D is the restoration of regulatory T cell (Treg) activity, specifically directed toward down-modulation of beta-islet antigen-specific T effector cells. This is also known as antigen-specific adaptive tolerance induction for T1D (T1D ASATI). Tregitopes (T regulatory cell epitopes) are natural T cell epitopes derived from immunoglobulin G (IgG) that were identified in 2008 and have been evaluated in several autoimmune disease models. In the T1D ASATI studies presented here, Tregitope peptides were administered to non-obese diabetic (NOD) mice at the onset of diabetes within two clinically-relevant delivery systems (liposomes and in human serum albumin [HSA]-fusion products) in combination with preproinsulin (PPI) target antigen peptides. The combination of Tregitope-albumin fusions and PPI peptides reduced the incidence of severe diabetes and reversed mild diabetes, over 49 days of treatment and observation. Combining HSA-Tregitope fusions with PPI peptides is a promising ASATI approach for therapy of T1D.

Isolated pancreatic islet yield and quality is inversely related to organ donor age in rats.

Pancreatic islets consist of several endocrine cell types that maintain glucose homeostasis. Type 1 diabetes (T1D) results from autoimmune-mediated destruction of insulin producing beta cells in pancreatic islets. Islet transplantation is a treatment for certain individuals with T1D. Islet transplantation in rodents, as an experimental model of the clinical scenario, requires consistency of islet quantity and quality to obtain reproducible results. In this study, we investigated the yield and function of the isolated islets from rats of different ages. Pancreata were harvested from young (10-20 week-old), intermediate (21-40 week-old) and old (>41 week-old) male rats and islets were isolated using a standard protocol. Islet number, morphometry, viability, function, and metabolism were characterized. Islet yield, normalized to body weight, decreased as a function of increasing donor age. Islets from pancreata from young animals were larger and less fragmented compared to islets from organs from intermediate and older animals. Islet viability following overnight culture was the same for islets derived from young and intermediate aged donors but less for islets from old donors. Glucose-stimulated insulin secretion was decreased in islets from older donors. Islet metabolism following glucose challenge, as measured by oxygen consumption, revealed that islets from old donors were metabolically slower and lagged in response to glucose-stimuli. These data demonstrate that increasing donor age has a negative impact on isolated islet yield and quality.

Soluble FAS ligand is not required for pancreatic islet inflammation or beta-cell destruction in non-obese diabetic mice

CD8+ T cells play a central role in beta-cell destruction in type 1 diabetes. CD8+ T cells use two main effector pathways to kill target cells, perforin plus granzymes and FAS ligand (FASL). We and others have established that in non-obese diabetic (NOD) mice, perforin is the dominant effector molecule by which autoreactive CD8+ T cells kill beta cells. However, blocking FASL pharmacologically was shown to protect NOD mice from diabetes, indicating that FASL may have some role. FASL can engage with its receptor FAS on target cells either as membrane bound or soluble FASL. It has been shown that membrane-bound FASL is required to stimulate FAS-induced apoptosis in target cells, whereas excessive soluble FASL can induce NF-κB-dependent gene expression and inflammation. Because islet inflammation is a feature of autoimmune diabetes, we tested whether soluble FASL could be important in disease pathogenesis independent of its cell death function. We generated NOD mice deficient in soluble FASL, while maintaining expression of membrane-bound FASL due to a mutation in the FASL sequence required for cleavage by metalloproteinase. NOD mice lacking soluble FASL had normal numbers of lymphocytes in their spleen and thymus. Soluble FASL deficient NOD mice had similar islet inflammation as wild-type NOD mice and were not protected from diabetes. Our data indicate that soluble FASL is not required in development of autoimmune diabetes.

Random Matrix Analysis of Ca2+ Signals in β-Cell Collectives.

Even within small organs like pancreatic islets, different endocrine cell types and subtypes form a heterogeneous collective to sense the chemical composition of the extracellular solution and compute an adequate hormonal output. Erroneous cellular processing and hormonal output due to challenged heterogeneity result in various disorders with diabetes mellitus as a flagship metabolic disease. Here we attempt to address the aforementioned functional heterogeneity with comparing pairwise cell-cell cross-correlations obtained from simultaneous measurements of cytosolic calcium responses in hundreds of islet cells in an optical plane to statistical properties of correlations predicted by the random matrix theory (RMT). We find that the bulk of the empirical eigenvalue spectrum is almost completely described by RMT prediction, however, the deviating eigenvalues that exist below and above RMT spectral edges suggest that there are local and extended modes driving the correlations. We also show that empirical nearest neighbor spacing of eigenvalues follows universal RMT properties regardless of glucose stimulation, but that number variance displays clear separation from RMT prediction and can differentiate between empirical spectra obtained under non-stimulated and stimulated conditions. We suggest that RMT approach provides a sensitive tool to assess the functional cell heterogeneity and its effects on the spatio-temporal dynamics of a collective of beta cells in pancreatic islets in physiological resting and stimulatory conditions, beyond the current limitations of molecular and cellular biology.

Diabetes-induced Proteome Changes Throughout Development.

Diabetes Mellitus (DM) is a multisystemic disease involving the homeostasis of insulin secretion by the pancreatic islet beta cells (β-cells). It is associated with hypertension, renal disease, and arterial and arteriolar vascular diseases. The classification of diabetes is identified as type 1 (gene linked β-cell destruction in childhood) and type 2 (late onset associated with β-cell overload and insulin resistance in peripheral tissues. Type 1 diabetes is characterized by insulin deficiency, type 2 diabetes by both insulin deficiency and insulin resistance. The former is a genetically programmed loss of insulin secretion whereas the latter constitutes a disruption of the homeostatic relationship between the opposing activity of β- cell insulin and alpha cell (α-cell) glucagon of the Islets of Langerhans. The condition could also occur in pregnancy, as a prenatal occurring event, possibly triggered by the hormonal changes of pregnancy combined with β-cell overload. This review discusses the molecular basis of the biomolecular changes that occur with respect to glucose homeostasis and related diseases in DM. The underlying link between pancreatic, renal, and microvascular diseases in DM is based on oxidative stress and the Unfolded Protein Response (UPR). Studying proteome changes in diabetes can deepen our understanding of the biomolecular basis of disease and help us acquire more efficient therapies.

Oral delivery of single-chain insulin (SCI-59) analog by bacterium-like particles (BLPs) induces oral tolerance and prevents autoimmune diabetes in NOD mice

Oral tolerance, induced by oral administration of autoantigens, is a promising therapeutic approach to treat type 1 diabetes mellitus (T1DM). However, the degradation of antigens passing through the gastrointestinal tract (GIT) leads to low induction efficiency. Based on our previous study, a single-chain insulin (SCI-59) analog, bound to the surface of lactic acid bacteria (LAB) bacterium-like particles (BLPs), was more stable in the simulated gastric fluid, compared to free SCI-59 and insulin. Based on the analysis of diabetes progression, a significant decrease in the incidence of diabetes was observed in mice fed BLPs-SCI-59. Oral administration of BLPs-SCI-59 can enhance glucose tolerance in NOD mice and this effect may result from the protection of pancreatic islet beta cells, as compared to the free SCI-59 group and BLPs group. Oral administration of BLPs-SCI-59 can significantly reduce insulitis and preserve the ability of insulin secretion in treated mice. Oral vaccination with BLPs-SCI-59 induced SCI-59 specific T cell tolerance in treated mice, which may due to the repair of Th1/Th2 imbalance and increased CD4+CD25+FoxP3+ regulatory T cells (Tregs). These results show that oral vaccination with BLPs-SCI-59 is a promising way to prevent T1DM in NOD mice.

Attenuated Tregs increase susceptibility to type 1 diabetes in prenatal nicotine exposed female offspring mice

The recession of regulatory T cells (Tregs) is pivotal for type 1 diabetes (T1D) progressing. Our previous study observed the decreased Tregs in prenatal nicotine exposure (PNE) offspring, but whether this led to the onset of T1D remains uncertain. Thus, this study aimed to investigate the effects of PNE on T1D susceptibility and the role of PNE-suppressed Tregs in T1D of female offspring. The decreased body weights and elevated blood glucose levels from postnatal day (PND) 21 to PND 42 indicated that PNE caused persistent impaired glucose homeostasis in offspring. The elevated serum glutamic acid decarboxylase autoantibody, the “Gold Standard” for the detection of T1D, was observed on PND 42, suggesting the early stage of T1D in PNE offspring during adolescence. The reduced pancreatic islet areas and beta cells number in PNE offspring were observed at neonatal period and became more severe during adolescence. In addition, PNE caused immune dysfunction in offspring, manifested as suppressed thymic Tregs percentage from PND 4 to PND 42 and splenic Tregs/Th17 ratio on PND 42. In conclusion, PNE resulted in metabolic changes of offspring that were consistent with T1D characteristics, which could be the consequence of Tregs recession from early life to adolescence.

Iron status in diabetes mellitus

Diabetes mellitus can be defined as chronic metabolic disease which results from either relative or complete absence of insulin by the pancreatic beta islet cells. This in-turn may lead to hyperglycemia due to disturbances in the metabolism of glucose. In the human body, iron is con- sidered to be an effective pro-oxidant and participates in the generation of reactive oxygen species (ROS) such as hydroxyl radical. Because of the poor antioxidant defense mechanism of beta cells (low production of antioxidant enzymes such as catalase, glutathione peroxidase and dismutase), so they are highly prone to iron-induced oxidative stress and iron deposition in it and this will lead to apoptosis, and subsequently insulin deficiency. This iron deposition in beta cells will also lead to insulin resistance by reducing insulin extracting ability of the liver and inhibiting glucose uptake in muscle tissues and fats, this in turn will result in high production of hepatic glucose. Ferritin which is an acute phase reactant protein, that responds to acute stress like trauma, infections, tissue necrosis and surgery, it can produce diabetes mellitus either through inflammation or by increasing iron stores.

A study of 51 subtypes of peripheral blood immune cells in newly diagnosed young type 1 diabetes patients.

Type 1 diabetes (T1D) results from autoimmune destruction of insulin-producing beta cells in pancreatic islets. Various immune cell populations are involved in disease development and natural course. However, to our knowledge, so far there are no comprehensive comparative investigations of all main immune cell populations and their most important subsets at the onset of disease. Therefore, in the current study, we analyzed 51 peripheral blood immune cell populations in 22 young T1D patients and in 25 age-matched controls using a comprehensive polychromatic flow cytometry panel developed for whole blood by theCOST Action no. BM0907 ENTIRE (European Network for Translational Immunology Research and Education: From Immunomonitoring to Personalized Immunotherapy) consortium. We found that in T1D patients, frequencies and absolute counts of natural killer (NK) cells, dendritic cells (DC) and T cells, as well as their respective subsets, were significantly altered compared to controls. Further, we observed that changes in several cell populations (e.g. CD14+ CD16+ non-classical monocytes, plasmablasts) were dependent on the age of the patient. In addition to age-related changes, we also found that alterations in immune cell patterns were associated with parameters such as the presence of ketoacidosis and C-peptide serum levels. Our study provides a foundation for future studies investigating different cell lineages and their role in T1D and illustrates the value of polychromatic flow cytometry for evaluating all main peripheral immune cells and their subsets in whole blood samples.

2143-P: GLP-1 Conjugation Enhances the Activity of Antisense Oligonucleotides Targeting Islet Amyloid Polypeptide (IAPP) or Kelch-Like ECH Associated Protein 1 (Keap1) in Isolated Pancreatic Islets

The incidence of type 2 diabetes (T2D) is increasing rapidly and is currently one of the 21st century’s major challenges to human health. While T2D has a complex etiology, beta cell dysfunction is widely regarded as a key contributor to T2D disease progression. Antisense oligonucleotides (ASOs) have been shown to provide substantial therapeutic benefit for numerous unmet medical needs. However, unconjugated ASOs have shown minimal activity in pancreatic beta cells, limiting their use as therapeutics in these cells. It has recently been shown that conjugation of glucagon like peptide 1 receptor (GLP-1R) ligands (GLP-1R-L) to ASOs led to significant, substantial increases of ASO activity in the pancreatic islet beta cell, making them a viable therapeutic option for treatment of beta cell dysfunction.1 Two factors that contribute to beta cell dysfunction are IAPP and oxidative stress. A key inhibitor of the intracellular anti-oxidative response is Keap1. We treated isolated islets with parent or GLP-1R-L conjugated ASOs targeting either Keap1 or IAPP. At the highest dose, the parent ASOs reduced their respective islet target mRNAs by up to 20%, while the GLP-1 conjugated ASOs reduced target mRNA by 85%-95%. Furthermore, the GLP-1R-L conjugated Keap1 ASO treatment increased mRNA expression of the anti-oxidative response gene NAD(P)H quinone dehydrogenase 1 (Nqo1) by 390% when compared to PBS controls. Systemic treatment of C57BL/6 mice with the GLP-1R-L conjugated IAPP ASO reduced islet IAPP mRNA by 79% ± 3.7% when compared to saline treated animals. These data suggest that GLP-1R-L conjugated ASOs show exciting potential as a therapeutic platform for the treatment of beta cell dysfunction. Disclosure W. Fu: None. R. Lee: Employee; Self; Ionis Pharmaceuticals, Inc. E.C. Pirie: Employee; Self; Ionis Pharmaceuticals, Inc. T. Prakash: Employee; Self; Ionis Pharmaceuticals, Inc. S. Murray: Employee; Self; Ionis Pharmaceuticals, Inc. A.F. Powers: Employee; Self; Ionis Pharmaceuticals, Inc. Stock/Shareholder; Self; Ionis Pharmaceuticals, Inc. R.M. Crooke: Employee; Self; Ionis Pharmaceuticals, Inc. Employee; Spouse/Partner; Ionis Pharmaceuticals, Inc.

Visualization of Endogenous Mitophagy Complexes In Situ in Human Pancreatic Beta Cells Utilizing Proximity Ligation Assay.

Mitophagy is an essential mitochondrial quality control pathway, which is crucial for pancreatic islet beta cell bioenergetics to fuel glucose-stimulated insulin release. Assessment of mitophagy is challenging and often requires genetic reporters or multiple complementary techniques not easily utilized in tissue samples, such as primary human pancreatic islets. Here we demonstrate a robust approach to visualize and quantify formation of key endogenous mitophagy complexes in primary human pancreatic islets. Utilizing the sensitive proximity ligation assay technique to detect interaction of the mitophagy regulators NRDP1 and USP8, we are able to specifically quantify formation of essential mitophagy complexes in situ. By coupling this approach to counterstaining for the transcription factor PDX1, we can quantify mitophagy complexes, and the factors that can impair mitophagy, specifically within beta cells. The methodology we describe overcomes the need for large quantities of cellular extracts required for other protein-protein interaction studies, such as immunoprecipitation (IP) or mass spectrometry, and is ideal for precious human isletsamples generally not available in sufficient quantities for these approaches. Further, this methodology obviates the need for flow sorting techniques to purify beta cells from a heterogeneous islet population for downstream protein applications. Thus, we describe a valuable protocol for visualization of mitophagy highly compatible for use in heterogeneous and limited cell populations.

Carbenoxolone Could Deteriorate Streptozotocin-induced Diabetes through Induction of Heat Shock Protein 70 and IFN-γ in C57BL/6 Mice

Type 1 diabetes (T1D), a spontaneous autoimmune disease, is associated with destruction of insulin-producing β-cells in the pancreas. Since some heat shock proteins (HSP), such as HSP70 exert a protective effect in both tissues and cells, the present study was conducted to elucidate the effects of carbenoxolone (CBX) as an HSP70 inducer on T1D. The disease was induced in male C57BL/6 mice using streptozotocin (STZ) and subjects were allocated to therapeutic 1 and therapeutic 2 groups, as well as negative and positive control groups. The treated mice (therapeutic 1 and therapeutic 2 groups) received 50 mg/kg CBX intraperitoneally every 24 hours, in the therapeutic 1 group the drug was injected before and after disease induction whereas in the therapeutic 2 group the drug was injected only after disease induction. Serum fasting blood sugar (FBS) level, cytokines production (Interferon-gamma (IFN-γ), Interleukin 10 (IL-10), and IL-17), serum HSP70 level and CD4+CD25+Foxp3+ regulatory T cell (Treg) frequency measurements were outperformed 14 days after the last STZ injection. Our results showed that in the treated groups, serum HSP70, IFN-γ, and IL-17 levels were increased in contrast to the untreated groups. The IL-10 level was markedly decreased in comparison to untreated diabetic mice (p<0.05). Moreover, it was found that the frequency of Tregs in treated mice was lower in comparison to the untreated mice but the difference was not significant (p>0.05). Our results confirm that CBX might through HSP70 induction, followed by increasing IFN-γ level leads to suppression of IL-10 production in diabetic mice resulted in toxic effects on pancreatic islet beta cells and deteriorating of disease.

The effect of apelin-13 on pancreatic islet beta cell mass and myocardial fatty acid and glucose metabolism of experimental type 2 diabetic rats

Apelin, a new identified adipokine, and its G protein–coupled receptor named APJ are widely expressed in various tissues. Apelin has been found to play important roles in the physiopathology of multiple diseases. Our aim is to assess the effect of long-term apelin treatment on serum insulin level and pancreatic islet beta-cell mass in the late stage of type 2 diabetes without hyperinsulinemia and to investigate the role of apelin in myocardial fatty acid and glucose metabolism. In the present study, the high-fat diet fed-streptozotocin-induced experimental type 2 diabetic rats were given once daily intraperitoneal injection of apelin-13 (0.1 μmol/kg) for 10 weeks. We observed that apelin significantly improved serum insulin reduction and reduced hyperglycemia. Histologic analysis showed that long-term apelin treatment significantly increased pancreatic islet beta cell mass. Exogenous apelin failed to change dyslipidaemia of type 2 diabetic rats. Apelin treatment markedly decreased elevated myocardial FFA and glycogen content. Treatment of type 2 diabetic rats with apelin markedly reduced increased gene expressions of the cardiac fatty acid transporter CD36, CPT-1, and Peroxisome proliferator-activated receptor (PPAR)-α. Whereas the gene levels of citrate synthase and peroxisome proliferator–activated receptor γ coactivator 1-α (PGC1-α), a transcriptional coactivator, mediating mitochondrial biogenesis in heart were unaltered in response to exogenous apelin. Taken together, longer-term apelin treatment prevented pancreatic beta-cell loss or failure in experimental type 2 diabetic rats. Apelin can regulate myocardial metabolism. Apelin reduced myocadial fatty acid uptake and oxidation through inhibiting PPAR-α but did not affect myocardial mitochondrial biogenesis in type 2 diabetic rats.

Rapid generation of functional mature pancreatic islet-beta cells from human pluripotent stem cells

Rapid generation of functional mature pancreatic islet-beta cells from human pluripotent stem cells

Type 1 Diabetes Mellitus-Associated Genetic Variants Contribute to Overlapping Immune Regulatory Networks.

Type 1 diabetes (T1D) is a chronic metabolic disorder characterized by the autoimmune destruction of insulin-producing pancreatic islet beta cells in genetically predisposed individuals. Genome-wide association studies (GWAS) have identified over 60 risk regions across the human genome, marked by single nucleotide polymorphisms (SNPs), which confer genetic predisposition to T1D. There is increasing evidence that disease-associated SNPs can alter gene expression through spatial interactions that involve distal loci, in a tissue- and development-specific manner. Here, we used three-dimensional (3D) genome organization data to identify genes that physically co-localized with DNA regions that contained T1D-associated SNPs in the nucleus. Analysis of these SNP-gene pairs using the Genotype-Tissue Expression database identified a subset of SNPs that significantly affected gene expression. We identified 246 spatially regulated genes including HLA-DRB1, LAT, MICA, BTN3A2, CTLA4, CD226, NOTCH1, TRIM26, PTEN, TYK2, CTSH, and FLRT3, which exhibit tissue-specific effects in multiple tissues. We observed that the T1D-associated variants interconnect through networks that form part of the immune regulatory pathways, including immune-cell activation, cytokine signaling, and programmed cell death protein-1 (PD-1). Our results implicate T1D-associated variants in tissue and cell-type specific regulatory networks that contribute to pancreatic beta cell inflammation and destruction, adaptive immune signaling, and immune-cell proliferation and activation. A number of other regulatory changes we identified are not typically considered to be central to the pathology of T1D. Collectively, our data represent a novel resource for the hypothesis-driven development of diagnostic, prognostic, and therapeutic interventions in T1D.

Pancreatic Insulinoma. About a Personal Experience of 3 Cases

Pancreatic insulinomas (IP), are uncommon tumors that come from the beta cells of pancreatic islets, which are characterized by producing insulin excessively, therefore causing hypoglycemia; which is manifested by neuroglycopenic and autonomic symptoms. IP diagnosis is proposed by Whipple's triad, characterized by hypoglycemia, neuroglycopenic symptoms and the reversal of the symptoms following the administration of glucose. Surgery remains the treatment of choice for IP, either by laparotomy or laparoscopy, performing enucleation or segmental pancreatectomies. These procedures are not free of complications, most notably are pancreatic fistula, and pseudocyst formation, and the development of diabetes mellitus. The aim of this paper is to report the personal experience in treating consecutive patients with PI and discuss the related literature.

The human gut microbiome in early-onset type 1 diabetes from the TEDDY study

Type 1 diabetes (T1D) is an autoimmune disease that targets pancreatic islet beta cells and incorporates genetic and environmental factors1, including complex genetic elements2, patient exposures3 and the gut microbiome4. Viral infections5 and broader gut dysbioses6 have been identified as potential causes or contributing factors; however, human studies have not yet identified microbial compositional or functional triggers that are predictive of islet autoimmunity or T1D. Here we analyse 10,913 metagenomes in stool samples from 783 mostly white, non-Hispanic children. The samples were collected monthly from three months of age until the clinical end point (islet autoimmunity or T1D) in the The Environmental Determinants of Diabetes in the Young (TEDDY) study, to characterize the natural history of the early gut microbiome in connection to islet autoimmunity, T1D diagnosis, and other common early life events such as antibiotic treatments and probiotics. The microbiomes of control children contained more genes that were related to fermentation and the biosynthesis of short-chain fatty acids, but these were not consistently associated with particular taxa across geographically diverse clinical centres, suggesting that microbial factors associated with T1D are taxonomically diffuse but functionally more coherent. When we investigated the broader establishment and development of the infant microbiome, both taxonomic and functional profiles were dynamic and highly individualized, and dominated in the first year of life by one of three largely exclusive Bifidobacterium species (B. bifidum, B. breve or B. longum) or by the phylum Proteobacteria. In particular, the strain-specific carriage of genes for the utilization of human milk oligosaccharide within a subset of B. longum was present specifically in breast-fed infants. These analyses of TEDDY gut metagenomes provide, to our knowledge, the largest and most detailed longitudinal functional profile of the developing gut microbiome in relation to islet autoimmunity, T1D and other early childhood events. Together with existing evidence from human cohorts7,8 and a T1D mouse model9, these data support the protective effects of short-chain fatty acids in early-onset human T1D.