Type 1 Diabetes Progression Research Articles

Protein Glycation by Glyoxal Promotes Amyloid Formation by Islet Amyloid Polypeptide

Protein glycation, also known as nonenzymatic glycosylation, is a spontaneous post-translational modification that would change the structure and stability of proteins or hormone peptides. Recent studies have indicated that glycation plays a role in type 2 diabetes (T2D) and neurodegenerative diseases. Over the last two decades, many types of advanced glycation end products (AGEs), formed through the reactions of an amino group of proteins with reducing sugars, have been identified and detected in vivo. However, the effect of glycation on protein aggregation has not been fully investigated. In this study, we aim to elucidate the impact of protein glycation on islet amyloid polypeptide (IAPP, also known as amylin) aggregation, which was strongly associated with T2D. We chemically synthesized glycated IAPP (AGE-IAPP) to mimic the consequence of this hormone peptide in a hyperglycemia (high blood sugar) environment. Our data revealed that AGE-IAPP formed amyloid faster than normal IAPP, and higher-molecular-weight AGE-IAPP oligomers were also observed in the early stage of aggregation. Circular dichroism spectra also indicated that AGE-IAPP exhibited faster conformational changes from random coil to its β-sheet fibrillar states. Moreover, AGE-IAPP can induce normal IAPP to expedite its aggregation process, and its fibrils can also act as templates to promote IAPP aggregation. AGE-IAPP, like normal IAPP, is capable of interacting with synthetic membranes and also exhibits cytotoxicity. Our studies demonstrated that glycation modification of IAPP promotes the amyloidogenic properties of IAPP, and it may play a role in accumulating additional amyloid during T2D progression.

β-Cell compensation concomitant with adaptive endoplasmic reticulum stress and β-cell neogenesis in a diet-induced type 2 diabetes model.

Insulin-secreting pancreatic β-cells adapt to obesity-related insulin resistance via increases in insulin secretion and β-cell mass. Failed β-cell compensation predicts the onset of type 2 diabetes (T2D). However, the mechanisms of β-cell compensation are not fully understood. Our previous study reported changes in β-cell mass during the progression of T2D in the Nile rat (NR; Arvicanthis niloticus) fed standard chow. In the present study, we measured other β-cell adaptive responses, including glucose metabolism and β-cell insulin secretion in NRs at different ages, thus characterizing NR at 2 months as a model of β-cell compensation followed by decompensation at 6 months. We observed increased proinsulin secretion in the transition from compensation to decompensation, which is indicative of impaired insulin processing. Subsequently, we compared adaptive unfolded protein response in β-cells and demonstrated a positive role of endoplasmic reticulum (ER) chaperones in insulin secretion. In addition, the incidence of insulin-positive neogenic but not proliferative cells increased during the compensation phase, suggesting nonproliferative β-cell growth as a mechanism of β-cell mass adaptation. In contrast, decreased neogenesis and β-cell dedifferentiation were observed in β-cell dysfunction. Furthermore, the progression of T2D and pathophysiological changes of β-cells were prevented by increasing fibre content of the diet. Novelty Our study characterized a novel model for β-cell compensation with adaptive responses in cell function and mass. The temporal association of adaptive ER chaperones with blood insulin and glucose suggests upregulated chaperone capacity as an adaptive mechanism. β-Cell neogenesis but not proliferation contributes to β-cell mass adaptation.

Increased β-cell proliferation before immune cell invasion prevents progression of type 1 diabetes.

Type 1 diabetes (T1D) is characterized by pancreatic islet infiltration by autoreactive immune cells and a near-total loss of β-cells1. Restoration of insulin-producing β-cells coupled with immunomodulation to suppress the autoimmune attack has emerged as a potential approach to counter T1D2–4. Here we report that enhancing β-cell mass early in life, in two models of female NOD mice, results in immunomodulation of T-cells, reduced islet infiltration and lower β-cell apoptosis, that together protect them from developing T1D. The animals displayed altered β-cell antigens, and islet transplantation studies showed prolonged graft survival in the NOD-LIRKO model. Adoptive transfer of splenocytes from the NOD-LIRKOs prevented development of diabetes in pre-diabetic NOD mice. A significant increase in the splenic CD4+CD25+FoxP3+ regulatory T-cell (Treg) population was observed to underlie the protected phenotype since Treg depletion rendered NOD-LIRKO mice diabetic. The increase in Tregs coupled with activation of TGF-β/SMAD3 signaling pathway in pathogenic T-cells favored reduced ability to kill β-cells. These data support a previously unidentified observation that initiating β-cell proliferation, alone, prior to islet infiltration by immune cells alters the identity of β-cells, decreases pathologic self-reactivity of effector cells and increases Tregs to prevent progression of T1D.

Molecular Targets of inflammation in pancreatic endocrine cells in Type 1 Diabetes (T1D)

Abstract T1D (Type 1 Diabetes) is an autoimmune disorder caused by the immune-mediated destruction of insulin-producing beta cells in the pancreas. There are direct mechanisms that have been demonstrated to cause final beta cell demise, such as the pathways triggered by Fas engagement and Perforin release. However, focus should be placed on other indirect mechanisms, such as pro-inflammatory cytokines present in the beta cell niche early on, that progressively debilitate and alter beta cells from earlier phases of T1D progression, rendering them as helpless targets of the immune system at the end. Though beta cells may resist adverse stimuli in early phases of the autoimmune process, the complicity of both, direct and indirect deleterious mechanisms, leads to beta cell death. In an effort to identify those indirect mechanisms that chronically besiege beta cells from the T1D-prone NOD mouse model, we used the microarray technology. We have identified several candidate genes the expression of which is altered in the NOD islet prior to T1D onset. Several of these genes are related to cell cycle progression and are downregulated due to the insulitic attack to the islet. One of these genes is cyclin D-3, a Dtype cyclin that interacts with either Cdk4 or Cdk6 to promote G1/S cycle progression. We have reported that cyclin D3 protects beta cells against cytokine-induced apoptosis and is required for proper beta cell function in a cell-cycle independent fashion. Cdk11 is also affected by inflammation in islet cells and is a cyclin-dependent kinase which is involved in transcription, mitosis and apoptosis. The natural partners of Cdk11 are L-type cyclins. We have examined whether the immune function is affected in the relative absence of Cdk11.

Alterations in ventral attention network connectivity in individuals with prediabetes

ABSTRACT Objective: Type 2 diabetes (T2D) is associated with aberrant neural functioning; however, the point at which brain function alterations occur in the progression of T2D is unknown. Here, we tested for differences in functional connectivity in adults with prediabetes and healthy individuals. We hypothesized that prediabetes, defined by glycated hemoglobin (HbA1c) 5.7–6.4% would be associated with disruptions in default mode network (DMN) connectivity. Methods: Fourteen brain networks were tested in 88 adults (prediabetes: n = 44; HbA1c = 5.8±0.2%; healthy: n = 44; HbA1c = 4.7±0.2%) matched for sex, age, and BMI. Results: We did not find differences in DMN connectivity between groups. Individuals with prediabetes showed stronger connectivity between the ventral attention network and (1) a visual network (p FWE = 0.0001); (2) a somatosensory network (p FWE = 0.0027). Individuals with healthy HbA1c showed stronger connectivity of the ventral attention network and (1) cingulo-opercular network (p FWE = 0.002); (2) a thalamic-striatal-visual network (p FWE = 0.001). Conclusions: Relative to individuals with prediabetes, those with a healthy HbA1c showed stronger connectivity between brain networks underlying self-control and attention to stimuli. In contrast, those with prediabetes demonstrated stronger connectivity between brain networks associated with sensory and attention to stimuli. While T2D reported contribute to decreased DMN connectivity, prediabetes is characterized by a shift in functional connectivity from a self-control network towards increasing connectivity in sensory network.

Increased mast cell number is associated with a decrease in beta-cell mass and regeneration in type 2 diabetic rats

The role of mast cells (MCs) in type 2 diabetes (T2D) is not thoroughly studied as much as in T1D. Therefore in the current study we investigated correlation between these cells and various parameters of islets of Langerhans (IOL) in rats which were equally divided (n = 40) into; control and diabetic groups.We detected a significantly increased (p < 0.05) MC count (MCC) in the diabetic IOL compared to the control, together with a noticeable intra-islet seeding of these cells which displayed a tryptase positive immunostaining.A significant positive correlation (p < 0.05) between MCC and the % of glucagon cells per islet was detected in DM, unlike mass of the islets, mass of β-cells, and % of β-cells per islet which were negatively correlated with MCC. Similarly, there was a negative correlation between MCC with β-cell proliferation and neogenesis frequency in DM. This highlights the potential association between the increased MC number and the diminished islet`s mass as well as regeneration which may fasten the progression of T2D.

Exposure to disinfection byproducts and risk of type 2 diabetes: a nested case-control study in the HUNT and Lifelines cohorts.

Environmental chemicals acting as metabolic disruptors have been implicated with diabetogenesis, but evidence is weak among short-lived chemicals, such as disinfection byproducts (trihalomethanes, THM composed of chloroform, TCM and brominated trihalomethanes, BrTHM). We assessed whether THM were associated with type 2 diabetes (T2D) and we explored alterations in metabolic profiles due to THM exposures or T2D status. A prospective 1:1 matched case-control study (n = 430) and a cross-sectional 1:1 matched case-control study (n = 362) nested within the HUNT cohort (Norway) and the Lifelines cohort (Netherlands), respectively, were set up. Urinary biomarkers of THM exposure and mass spectrometry-based serum metabolomics were measured. Associations between THM, clinical markers, metabolites and disease status were evaluated using logistic regressions with Least Absolute Shrinkage and Selection Operator procedure. Low median THM exposures (ng/g, IQR) were measured in both cohorts (cases and controls of HUNT and Lifelines, respectively, 193 (76, 470), 208 (77, 502) and 292 (162, 595), 342 (180, 602). Neither BrTHM (OR = 0.87; 95% CI: 0.67, 1.11 | OR = 1.09; 95% CI: 0.73, 1.61), nor TCM (OR = 1.03; 95% CI: 0.88, 1.2 | OR = 1.03; 95% CI: 0.79, 1.35) were associated with incident or prevalent T2D, respectively. Metabolomics showed 48 metabolites associated with incident T2D after adjusting for sex, age and BMI, whereas a total of 244 metabolites were associated with prevalent T2D. A total of 34 metabolites were associated with the progression of T2D. In data driven logistic regression, novel biomarkers, such as cinnamoylglycine or 1-methylurate, being protective of T2D were identified. The incident T2D risk prediction model (HUNT) predicted well incident Lifelines cases (AUC = 0.845; 95% CI: 0.72, 0.97). Such exposome-based approaches in cohort-nested studies are warranted to better understand the environmental origins of diabetogenesis.

Aldosterone induced up-expression of ICAM-1 and ET-1 in pancreatic islet endothelium may associate with progression of T2D

Previous studies have demonstrated that excess aldosterone impairs glucose metabolism. However, the underlying mechanism is still misty. Aldosterone has been proved a risk factor of fibrosis and inflammation. And the histology of islets from patients with type 2 diabetes (T2D) also displays inflammation and fibrosis. But it is unclear whether aldosterone has direct impact on islet inflammation and fibrosis in T2D. Islet endothelium plays a significant role in the maintenance of islet beta cell function and has a close relationship with islet fibrosis and inflammation. Therefore, we focused on the effect of aldosterone on the islet endothelium. In this study, we utilized a diabetic db/db mouse model and examined serum aldosterone levels, islet macrophages infiltration, and islet fibrosis. After we confirmed that there was an increased expression of intercellular cell adhesion molecule-1 (ICAM-1) and endothelin-1 (ET-1) in islet of diabetic mice compared with wild type mice. We next determined that aldosterone increased expression of ICAM-1 and ET-1 in both mRNA and protein levels in islet endothelium in vitro. And then we tested the expression of mineralocorticoid receptor (MR) in islet endothelium in vitro and in vivo. Our results showed that aldosterone can up-regulate the expression levels of ICAM-1 and ET-1 through MR. These findings suggest excess aldosterone might participate in islet inflammation and fibrosis in T2D.

Dynamic Immune Phenotypes of B and T Helper Cells Mark Distinct Stages of T1D Progression.

Multiple studies of B- and T-cell compartments and their response to stimuli demonstrate alterations in established type 1 diabetes (T1D). Yet it is not known whether these alterations reflect immune mechanisms that initiate islet autoimmunity, promote disease progression, or are secondary to disease. To address these questions, we used samples from the TrialNet Pathway to Prevention study to investigate T-cell responses to interleukin (IL)-2 and regulatory T cell-mediated suppression, the composition of the B-cell compartment, and B-cell responses to B-cell receptor and IL-21 receptor engagement. These studies revealed stage-dependent T- and B-cell functional and immune phenotypes; namely, early features that differentiate autoantibody-positive at-risk first-degree relatives (FDRs) from autoantibody-negative FDRs and persisted through clinical diagnosis; late features that arose at or near T1D diagnosis; and dynamic features that were enhanced early and blunted at later disease stages, indicating evolving responses along the continuum of T1D. We further explored how these specific phenotypes are influenced by therapeutic interventions. Our integrated studies provide unique insights into stable and dynamic stage-specific immune states and define novel immune phenotypes of potential clinical relevance.

Partial remission and early stages of pediatric type 1 diabetes display immunoregulatory changes. A pilot study

Type 1 diabetes (T1D) is a chronic metabolic disease of unknown etiology that results from β-cell destruction. The onset of the disease, which arises after a long asymptomatic period of autoimmune attack, may be followed by a relapsing and remitting progression, a phenomenon that is most evident during the partial remission phase (PR). This stage lasts for a few months, shows minor requirements of exogenous insulin and could be explained by a recovery of immunological tolerance. This study aims to identify new biomarkers at early stages of pediatric T1D that reflect immunoregulatory changes. To that end, pediatric patients with T1D (n = 52) and age-related control subjects (n = 30) were recruited. Immune response-related molecules and lymphocyte subsets were determined starting at T1D onset and until the second year of progression. Results showed that circulating TGF-β levels decreased during PR, and that betatrophin concentration was increased in all the considered stages without differing among studied checkpoints. Moreover, an increase of regulatory T, B and NK subsets was found during T1D progression, probably reflecting an attempt to restore self-tolerance. By contrast, a reduction in monocyte levels was observed at the early stages of diabetes. The results reveal significant changes in immunological parameters during the different early stages of T1D in children, which could ultimately serve as potential biomarkers to characterize the progression of T1D.

Probiotics and Prebiotics for the Amelioration of Type 1 Diabetes: Present and Future Perspectives.

Type 1-diabetes (T1D) is an autoimmune disease characterized by immune-mediated destruction of pancreatic beta (β)-cells. Genetic and environmental interactions play an important role in immune system malfunction by priming an aggressive adaptive immune response against β-cells. The microbes inhabiting the human intestine closely interact with the enteric mucosal immune system. Gut microbiota colonization and immune system maturation occur in parallel during early years of life; hence, perturbations in the gut microbiota can impair the functions of immune cells and vice-versa. Abnormal gut microbiota perturbations (dysbiosis) are often detected in T1D subjects, particularly those diagnosed as multiple-autoantibody-positive as a result of an aggressive and adverse immunoresponse. The pathogenesis of T1D involves activation of self-reactive T-cells, resulting in the destruction of β-cells by CD8+ T-lymphocytes. It is also becoming clear that gut microbes interact closely with T-cells. The amelioration of gut dysbiosis using specific probiotics and prebiotics has been found to be associated with decline in the autoimmune response (with diminished inflammation) and gut integrity (through increased expression of tight-junction proteins in the intestinal epithelium). This review discusses the potential interactions between gut microbiota and immune mechanisms that are involved in the progression of T1D and contemplates the potential effects and prospects of gut microbiota modulators, including probiotic and prebiotic interventions, in the amelioration of T1D pathology, in both human and animal models.

A Map of Human Type 1 Diabetes Progression by Imaging Mass Cytometry

Type 1 diabetes (T1D) results from the autoimmune destruction of insulin-producing β cells. A comprehensive picture of the changes during T1D development is lacking due to limited sample availability, inability to sample longitudinally, and the paucity oftechnologies enabling comprehensive tissue profiling. Here, we analyzed 1,581 islets from 12 human donors, including eight with T1D, using imaging mass cytometry (IMC). IMC enabled simultaneous measurement of 35 biomarkers with single-cell and spatial resolution. We performed pseudotime analysis of islets through T1D progression from snapshot data to reconstruct the evolution of β cell loss and insulitis. Our analyses revealed that β cell destruction is preceded by a β cell marker loss and by recruitment of cytotoxic and helper Tcells. The approaches described herein demonstrate the value of IMC for improving our understanding of T1D pathogenesis, and our data lay the foundation for hypothesis generation and follow-on experiments.

CD11c+ Cells Are Gatekeepers for Lymphocyte Trafficking to Infiltrated Islets During Type 1 Diabetes.

Type 1 diabetes (T1D) is a T cell mediated autoimmune disease that affects more than 19 million people with incidence increasing rapidly worldwide. For T cells to effectively drive T1D, they must first traffic to the islets and extravasate through the islet vasculature. Understanding the cues that lead to T cell entry into inflamed islets is important because diagnosed T1D patients already have established immune infiltration of their islets. Here we show that CD11c+ cells are a key mediator of T cell trafficking to infiltrated islets in non-obese diabetic (NOD) mice. Using intravital 2-photon islet imaging we show that T cell extravasation into the islets is an extended process, with T cells arresting in the islet vasculature in close proximity to perivascular CD11c+ cells. Antigen is not required for T cell trafficking to infiltrated islets, but T cell chemokine receptor signaling is necessary. Using RNAseq, we show that islet CD11c+ cells express over 20 different chemokines that bind chemokine receptors expressed on islet T cells. One highly expressed chemokine-receptor pair is CXCL16-CXCR6. However, NOD. CXCR6−/− mice progressed normally to T1D and CXCR6 deficient T cells trafficked normally to the islets. Even with CXCR3 and CXCR6 dual deficiency, T cells trafficked to infiltrated islets. These data reinforce that chemokine receptor signaling is highly redundant for T cell trafficking to inflamed islets. Importantly, depletion of CD11c+ cells strongly inhibited T cell trafficking to infiltrated islets of NOD mice. We suggest that targeted depletion of CD11c+ cells associated with the islet vasculature may yield a therapeutic target to inhibit T cell trafficking to inflamed islets to prevent progression of T1D.

Nutritional Effects of Zinc on Metabolic Syndrome and Type 2 Diabetes: Mechanisms and Main Findings in Human Studies.

Zinc (Zn) plays crucial roles in mammalian metabolism. There is increasing interest about the potential beneficial effects of Zn on the prevention or treatment of non-communicable diseases. This review critically analyzes the information related to the role of Zn on the metabolic syndrome (MetS) as well as type 2 diabetes (T2D), and summarizes the biological basis of these potential effects of Zn. There are several mechanisms by which Zn may help to prevent the development or progression of MetS and T2D, respectively. Zn is involved in both insulin secretion and action in peripheral tissues. Specifically, Zn has insulin-mimetic properties that increase the activity of the insulin signaling pathway. Zn modulates long-chain polyunsaturated fatty acids levels through its action on the absorption of essential fatty acids in the intestine and its subsequent desaturation. Zn is also involved in both the assembly of chylomicrons and lipoproteins as well as their clearance, and thus, plays a role in lipolysis regulation. Finally, Zn has been found to play a role in redox metabolism, and in turn, on blood pressure. The evidence related to the association between Zn status and occurrence of MetS is inconsistent. Although there are several studies reporting an inverse relationship between Zn status or dietary Zn intake and MetS prevalence, others found a direct relationship between Zn status and MetS prevalence. Intervention studies also provide confusing information about this issue, making it hard to reach firm conclusions. Zn as part of the treatment for patients with T2D has been shown to have positive responses in terms of glucose control outcomes, but only among those with Zn deficiency.

A complex auxiliary: IL-17/Th17 signaling during type 1 diabetes progression

Type 1 diabetes (T1D) is an autoimmune disease centered around the loss of the beta cells of the islets of Langerhans, and consequent inability of the islets to produce the insulin necessary to maintain glycemic control. While most therapeutic approaches have been centered on insulin replacement, newer approaches to target the underlying immune response have become an area of focus. However, the immune landscape in T1D is extremely complex, and the roles played by individual cytokines during disease progression are incompletely understood, making the development of immunotherapies very difficult. In this review, we discuss the complex auxiliary role played by IL-17, both around the islet and in peripheral tissues such as the gut and kidney, which might influence T1D progression. Through our re-analysis of the key factors involved IL-17 signaling in recently published single-cell sequencing and sorted-cell bulk sequencing datasets, we find supporting evidence for the general existence of the signaling apparatus in islet endocrine cells. We also explore the emerging evidence of IL-17 serving as an influential factor in diabetic complications that affect distal tissues. While anti-IL-17 therapies are emerging as an option for psoriasis and other autoimmune disorders, we highlight here a number of questions that would need to be addressed before their potential applicability to treating T1D can be fully evaluated.

The pattern of plasma BCAA concentration and liver Bckdha gene expression in GK rats during T2D progression.

BackgroundThis study was conducted to measure the concentration of branched chain amino acid (BCAA) in different species and detect the expression pattern of the liver Bckdha gene in Goto‐Kakizaki (GK) rats during type 2 diabetes (T2D) progression.MethodsWe measured the concentration of BCAA in GK rats, induced T2D cynomolgus monkeys and T2D humans by liquid chromatography tandem mass spectrometry, and used real‐time quantitative PCR to analyze the gene expression of Bckdha and Bckdk, which encode the rate‐limiting enzymes in catabolism of, respectively, branched chain amino acids and branched chain α‐keto acid dehydrogenase kinase.ResultsIn this study, we showed that GK rat BCAA concentrations were significantly reduced at 4 and 8 weeks (P < 0.05 and P < 0.01, respectively), while the expression of Bckdha in GK rat liver was increased at 4 and 8 weeks (1.62‐fold and 1.93‐fold, respectively). The BCAA concentrations were significantly reduced in diet‐induced T2D cynomolgus monkeys (P < 0.01), but significantly increased in T2D humans (P < 0.001).ConclusionsOur results showed that BCAA concentrations changed at different times and by different amounts in different species and during different periods of T2D progress, and the significant changes of BCAA concentration in the three species indicated that BCAA might participate in the progress of T2D. The results suggested that the increased expression of Bckdha in GK rat liver might partially explain the reduced plasma BCAA concentration at 4 and 8 weeks. Further studies are required to investigate the exact mechanism of BCAA changes in non‐obese T2D.

A longitudinal plasma lipidomics dataset from children who developed islet autoimmunity and type 1 diabetes

Early prediction and prevention of type 1 diabetes (T1D) are currently unmet medical needs. Previous metabolomics studies suggest that children who develop T1D are characterised by a distinct metabolic profile already detectable during infancy, prior to the onset of islet autoimmunity. However, the specificity of persistent metabolic disturbances in relation T1D development has not yet been established. Here, we report a longitudinal plasma lipidomics dataset from (1) 40 children who progressed to T1D during follow-up, (2) 40 children who developed single islet autoantibody but did not develop T1D and (3) 40 matched controls (6 time points: 3, 6, 12, 18, 24 and 36 months of age). This dataset may help other researchers in studying age-dependent progression of islet autoimmunity and T1D as well as of the age-dependence of lipidomic profiles in general. Alternatively, this dataset could more broadly used for the development of methods for the analysis of longitudinal multivariate data.

Pancreatic β-Cell Rest Replenishes Insulin Secretory Capacity and Attenuates Diabetes in an Extreme Model of Obese Type 2 Diabetes.

The onset of common obesity-linked type 2 diabetes (T2D) is marked by exhaustive failure of pancreatic β-cell functional mass to compensate for insulin resistance and increased metabolic demand, leading to uncontrolled hyperglycemia. Here, the β-cell-deficient obese hyperglycemic/hyperinsulinemic KS db/db mouse model was used to assess consequential effects on β-cell functional recovery by lowering glucose homeostasis and/or improving insulin sensitivity after treatment with thiazolidinedione therapy or glucagon-like peptide 1 receptor agonism alone or in combination with sodium/glucose cotransporter 2 inhibition (SGLT-2i). SGLT-2i combination therapies improved glucose homeostasis, independent of changes in body weight, resulting in a synergistic increase in pancreatic insulin content marked by significant recovery of the β-cell mature insulin secretory population but with limited changes in β-cell mass and no indication of β-cell dedifferentiation. Restoration of β-cell insulin secretory capacity also restored biphasic insulin secretion. These data emphasize that by therapeutically alleviating the demand for insulin in vivo, irrespective of weight loss, endogenous β-cells recover significant function that can contribute to attenuating diabetes. Thus, this study provides evidence that alleviation of metabolic demand on the β-cell, rather than targeting the β-cell itself, could be effective in delaying the progression of T2D.

Dietary Cows' Milk Protein A1 Beta-Casein Increases the Incidence of T1D in NOD Mice.

The contribution of cows’ milk containing beta-casein protein A1 variant to the development of type 1 diabetes (T1D) has been controversial for decades. Despite epidemiological data demonstrating a relationship between A1 beta-casein consumption and T1D incidence, direct evidence is limited. We demonstrate that early life exposure to A1 beta-casein through the diet can modify progression to diabetes in non-obese diabetic (NOD) mice, with the effect apparent in later generations. Adult NOD mice from the F0 generation and all subsequent generations (F1 to F4) were fed either A1 or A2 beta-casein supplemented diets. Diabetes incidence in F0–F2 generations was similar in both cohorts of mice. However, diabetes incidence doubled in the F3 generation NOD mice fed an A1 beta-casein supplemented diet. In F4 NOD mice, subclinical insulitis and altered glucose handling was evident as early as 10 weeks of age in A1 fed mice only. A significant decrease in the proportion of non-conventional regulatory T cell subset defined as CD4+CD25−FoxP3+ was evident in the F4 generation of A1 fed mice. This feeding intervention study demonstrates that dietary A1 beta-casein may affect glucose homeostasis and T1D progression, although this effect takes generations to manifest.

Identifying people at risk of developing type 2 diabetes: A comparison of predictive analytics techniques and predictor variables

BackgroundThe present study aims to identify the patients at risk of type 2 diabetes (T2D). There is a body of literature that uses machine learning classification algorithms to predict development of T2D among patients. The current study compares the performance of these classification algorithms to identify patients who are at risk of developing T2D in short, medium and long terms. In addition, the list of predictor variables important for prediction for T2D progression is provided. MethodsThis study uses 10,911 records generated in 36 clinics from the 15th of November 2008–15th of November 2016. Syntactic minority oversampling and random under sampling were used to create a balanced dataset. The performance of Neural Networks, Support Vector Machines, Decision Tress and Logistic Regression to identify patients developing T2D in short, medium and long terms was compared. The measures were Area Under Curve, Sensitivity, Specificity, Matthew correlation coefficient and Mean Calibration Error. Through importance analysis and information fusion techniques the predictors of developing T2D were identified for short, medium and long-term risk analysis. ResultsThe findings show that the performance of analytics techniques depends on both period and purpose of prediction whether the prediction is to identify people who will not develop T2D or to determine at risk patients. Oversampling as opposed to under sampling improved performance. 16 predictors and their importance to determine patients at risk of T2D in short, medium and long terms were identified. ConclusionsThis study provides guidelines for an automated system to prompt patients for screening. Several predictors are reportable by patients, others can be examined by physicians or ordered for further lab examination, which offers a potential reduction of the burden placed upon the clinical settings.