EVOO supplement prevents type 1 diabetes by modulating gut microbiota and serum metabolites in NOD mice.

AIMS: Extra virgin olive oil (EVOO) is the highest quality olive oil available and has been shown to regulate postprandial blood glucose in patients with type 1 diabetes (T1D). However, it remains uncertain whether EVOO can prevent the onset of T1D. In this study, we investigated the potential preventive effect of orally administered EVOO on T1D in non-obese diabetic (NOD) mice. MAIN METHODS: We analyzed changes in fecal microbes using 16 s rDNA sequencing and serum metabolites using Ultra High-Performance Liquid Chromatography and Quadrupole Time-of-Flight Mass Spectrometry (Q-TOF-MS). KEY FINDINGS: Our findings showed that EVOO supplementation in NOD mice slowed gastric emptying, reduced insulitis, and delayed T1D onset. Moreover, EVOO altered the composition of fecal microbes, increasing the Bacteroidetes/Firmicutes ratio, and promoting the growth of short-chain fatty acids (SCFAs)-producing bacteria, such as Lachnoclostridium and Ruminococcaceae_UCG-005. Moreover, it also increased beneficial serum metabolites, including unsaturated fatty acid and triterpenoid, which positively correlated with the increased SCFA-producing bacteria and negatively correlated with the disease indicators. Conversely, most decreased serum lipid metabolites, such as Oleamide, showed the opposite trend. SIGNIFICANCE: Our study demonstrates that EVOO may ameliorate pancreas inflammation and prevent T1D onset in NOD mice by modulating gut microbiota and serum metabolites.

Vitamin D in Prevention of Autoimmune Diseases.

Vitamin D is essential for the regulation of the immune system. In recent years, the role of vitamin D in the control of several autoimmune conditions such as inflammatory bowel disease (IBD), celiac disease, type 1 diabetes mellitus (T1DM), and others has been investigated. The aim of this review was to define the level of knowledge on vitamin D's role in these disorders, as well as the preventive and therapeutic role of vitamin D supplementation. Relevant studies published over the last 20 years were identified via a PubMed/Medline (http://www.ncbi.nlm.nih.gov/pubmed/) search using the keywords: vitamin D, autoimmune disease, and prevention. Vitamin D deficiency or impaired function of the enzymes necessary for its activity has been shown to affect the onset and severity of the autoimmune diseases examined. Vitamin D supplementation appears useful in the support therapy of IBD. Its role in celiac disease, autoimmune hepatitis, T1DM, and autoimmune thyroiditis is unclear. In conclusion, further studies are needed to define whether vitamin D is a cause or a result of the most common autoimmune, extra-skeletal diseases, such as IBD. Vitamin D should be provided to all newborns during their first year of life. Afterwards, the vitamin D supplementation regimen should be tailored to the presence of risk factors for vitamin D deficiency and/or specific disease.

Lactiplantibacillus plantarum 299v supplementation modulates ß-cell ER stress and antioxidative defense pathways and prevents type 1 diabetes in gluten-free BioBreeding rats.

The increasing incidence of Type 1 diabetes has coincided with the emergence of the low-fiber, high-gluten Western diet and other environmental factors linked to dysbiosis. Since Lactiplantibacillus plantarum 299 v (Lp299v) supplementation improves gut barrier function and reduces systemic inflammation, we studied its effects in spontaneously diabetic DRlyp/lyp rats provided a normal cereal diet (ND) or a gluten-free hydrolyzed casein diet (HCD). All rats provided ND developed diabetes (62.5±7.7 days); combining ND with Lp299v did not improve survival. Diabetes was delayed by HCD (72.2±9.4 days, p = .01) and further delayed by HCD+Lp299v (84.9±14.3 days, p < .001). HCD+Lp299v pups exhibited increased plasma propionate and butyrate levels, which correlated with enriched fecal Bifidobacteriaceae and Clostridiales taxa. Islet transcriptomic and histologic analyses at 40-days of age revealed that rats fed HCD expressed an autophagy profile, while those provided HCD+Lp299v expressed ER-associated protein degradation (ERAD) and antioxidative defense pathways, including Nrf2. Exposing insulinoma cells to propionate and butyrate promoted the antioxidative defense response but did not recapitulate the HCD+Lp299v islet ERAD transcriptomic profile. Here, both diet and microbiota influenced diabetes susceptibility. Moreover, Lp299v supplement modulated antioxidative defense and ER stress responses in ß-cells, potentially offering a new therapeutic direction to thwart diabetes progression and preserve insulin secretion.

Preventive treatment with fish oil facilitates the antidepressant-like effect of antidepressant drugs in type-1 diabetes mellitus rats: Implication of serotonergic system.

Treating depression associated with type-1 diabetesmellitus(T1DM) is a major clinical challenge. Fish oil (FO), composed mostly of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), has been pointed out as quite promising for the treatment of depression given its neuroprotective property. Although DHA and EPA exert several physiological actions, DHA is known to play a critical role in postnatal brain development. This study aimed to investigate the effect of preventive treatment with FO (with more DHA in the composition) alone or associated with antidepressant drugs on depression-like behaviors and brain monoamines levels of juvenile induced-T1DM rats. Thus, prepubescent rats were submitted to a prolonged treatment with vehicle (VEH) or FO (50% of DHA and 20% EPA) starting 4 weeks before the induction of experimental T1DM (on day 28) by streptozotocin. When combined, the treatment with vehicle, fluoxetine (FLX, a selective serotonin reuptake inhibitor) or imipramine (IMI, a tricyclic antidepressant) started at week 6 (day 42) and lasted for 2 weeks (until day 56). The behavioral tests were conducted on days 55 and 56, followed by hippocampal and prefrontal cortex dissection for neurochemical analyses. Our results showed that induced-T1DM rats pretreated with FO showed a significant increase of EPA and DHA in plasma, indicative of an increase in the systemic availability of these acids. As previously observed, induced-T1DM rats presented increased immobility and decreased swimming and climbing frequencies in the modified forced swimming test, indicative of depressive-like behavior. Only the combined treatment - FO plus antidepressants (FLX or IMI - both in the highest dose) - was able to induce a significant improvement of depressive-like behaviors. Here, it is noteworthy that swimming behavior has been associated with an increase in serotonergic neurotransmission. Interestingly, our data showed that the combined treatment (FO + antidepressants - including the ineffective dose of FLX) was able to increase the swimming of animals more significantly compared to animals not pretreated with FO. In addition, confirming these assumptions, the decreased 5-HT levels in the hippocampus from induced-T1DM rats were increased after treatment with FLX (highest dose) or IMI (both doses), being this increase more pronounced in animal pretreated with FO. Intriguingly, in these animals pretreated with FO, the ineffective dose of FLX in association with FO was able to increase the levels of 5-HT. The decreased hippocampal levels of noradrenaline were increased only after IMI treatment, not being influenced by FO pretreatment. In conclusion, ours results pointed out that the choice of the DHA/EPA ratio may be an important factor to be considered for the FO antidepressant-like effectper se,but the FO treatment in this composition associated with the antidepressant drugs - especially that ones that increase preferentially the availability of 5-HT -, may represent a better alternative of treatment to individuals with T1DM-associated depression.

Supplementation with Bifidobacterium longum subspecies infantis EVC001 for mitigation of type 1 diabetes autoimmunity: the GPPAD-SINT1A randomised controlled trial protocol.

INTRODUCTION: The Global Platform for the Prevention of Autoimmune Diabetes-SINT1A Study is designed as a randomised, placebo-controlled, double-blind, multicentre, multinational, primary prevention study aiming to assess whether daily administration of Bifidobacterium infantis from age 7 days to 6 weeks until age 12 months to children with elevated genetic risk for type 1 diabetes reduces the cumulative incidence of beta-cell autoantibodies in childhood. METHODS AND ANALYSIS: Infants aged 7 days to 6 weeks from Germany, Poland, Belgium, UK and Sweden are eligible for study participation if they have a >10.0% expected risk for developing multiple beta-cell autoantibodies by age 6 years as determined by genetic risk score or family history and HLA genotype. Infants are randomised 1:1 to daily administration of B. infantis EVC001 or placebo until age 12 months and followed for a maximum of 5.5 years thereafter. The primary outcome is the development of persistent confirmed multiple beta-cell autoantibodies. Secondary outcomes are (1) Any persistent confirmed beta-cell autoantibody, defined as at least one confirmed autoantibody in two consecutive samples, including insulin autoantibodies, glutamic acid decarboxylase, islet tyrosine phosphatase 2 or zinc transporter 8, (2) Diabetes, (3) Transglutaminase autoantibodies associated with coeliac disease, (4) Respiratory infection rate in first year of life during supplementation and (5) Safety. Exploratory outcomes include allergy, antibody response to vaccines, alterations of the gut microbiome or blood metabolome, stool pH and calprotectin. ETHICS AND DISSEMINATION: The study was approved by the local ethical committees of the Technical University Munich, Medical Faculty, the Technische Universität Dresden, the Medizinische Hochschule Hannover, the Medical University of Warsaw, EC Research UZ Leuven and the Swedish ethical review authority. The results will be disseminated through peer-reviewed journals and conference presentations and will be openly shared after completion of the study. TRIAL REGISTRATION NUMBER: NCT04769037.

Prevention strategies for type 1 diabetes: a story of promising efforts and unmet expectations.

A number of studies have investigated primary and secondary prevention strategies for type 1 diabetes (T1D), since early interventions might improve long-term outcomes through the amelioration of immune processes and the preservation of beta-cell mass. Primary prevention trials focus on genetically at-risk individuals prior to the appearance of autoimmunity, whereas secondary prevention trials aim to halt the progression of complete beta-cell destruction in subjects with established islet autoimmunity (IA). Different approaches have been tested so far, focusing on both pharmaceutical (insulin and monoclonal antibodies) and non-pharmaceutical (vitamin D, omega-3 fatty acids, probiotics, and nicotinamide) interventions, as well as on environmental factors that are believed to trigger autoimmunity in T1D (cow's milk, gluten, and bovine insulin). Albeit certain strategies have displayed efficacy in reducing IA development rates, most efforts have been unsuccessful in preventing the onset of the disease in high-risk individuals. Moreover, significant heterogeneity in study designs, included populations, and explored outcomes renders the interpretation of study results challenging. The aim of this narrative review is to present and critically evaluate primary and secondary prevention strategies for T1D, seeking to fill existing knowledge gaps and providing insight into future directions.

Use and abuse of dietary supplements in persons with diabetes.

The dietary supplement industry has estimated sales of over $30 billion in the US and over $100 billion globally. Many consumers believe that dietary supplements are safer and possibly more effective than drugs to treat diabetes. The sheer volume of the literature in this space makes compiling them into one review challenging, so much so that primarily narrative reviews currently exist. By applying the interactive database supplied by the Office of Dietary Supplements at the National Institutes of Health, we identified the top 100 ingredients that appeared most often in dietary supplement products. One-hundred different keyword searches using the ingredient name and the word diabetes were performed using a program developed to automatically scrape PubMed. Each search was retained in a separate Excel spreadsheet, which was then reviewed for inclusion or exclusion. The studies that met the inclusion criteria were evaluated for effect of reducing and controlling diabetes. The PubMed scrape resulted in 6217 studies. For each keyword search only the most recent 100 were retained, which refined the total to 1823 studies. Of these 425 met the screening criteria. The ingredients, fiber, selenium and zinc had the most studies associated with improvement in diabetes. Several popular supplement ingredients (phosphorus, pantothenic acid, calcium, magnesium, glutamine, isoleucine, tyrosine, choline, and creatine monohydrate) did not result in any studies meeting our screening criteria. Our study demonstrates how to automate reviews to filter and collapse literature in content areas that have an enormous volume of studies. The aggregated set of studies suggest there is little clinical evidence for the use of dietary supplements to reduce or control diabetes.

The Protective Role of Calbindin-D9k on Endoplasmic Reticulum Stress-Induced Beta Cell Death.

Intracellular calcium ion content is tightly regulated for the maintenance of cellular functions and cell survival. Calbindin-D9k (CaBP-9k) is responsible for regulating the distribution of cytosolic free-calcium ions. In this study, we aimed to investigate the effect of CaBP-9k on cell survival in pancreatic beta cells. Six-month-old wildtype CaBP-9k, CaBP-28k, and CaBP-9k/28k knockout (KO) mice were used to compare the pathological phenotypes of calcium-binding protein-deleted mice. Subsequently, the endoplasmic reticulum (ER) stress reducer tauroursodeoxycholic acid (TUDCA) was administered to wildtype and CaBP-9k KO mice. In vitro assessment of the role of CaBP-9k was performed following CaBP-9k overexpression and treatment with the ER stress inducer thapsigargin. Six-month-old CaBP-9k KO mice showed reduced islet volume and up-regulation of cell death markers resulting from ER stress, which led to pancreatic beta cell death. TUDCA treatment recovered islet volume, serum insulin level, and abdominal fat storage by CaBP-9k ablation. CaBP-9k overexpression elevated insulin secretion and recovered thapsigargin-induced ER stress in the INS-1E cell line. The results of this study show that CaBP-9k can protect pancreatic beta cell survival from ER stress and contribute to glucose homeostasis, which can reduce the risk of type 1 diabetes and provide the molecular basis for calcium supplementation to diabetic patients.

Low Methoxyl Pectin Protects against Autoimmune Diabetes and Associated Caecal Dysfunction.

SCOPE: This study aims to examine the protective effects of specific low-methoxyl pectin (LMP) on the development of type 1 diabetes (T1D). METHODS AND RESULTS: Female non-obese diabetic (NOD) mice are weaned onto either control or 5% LMP supplemented diets for up to 22 weeks of age. T1D incidence, gut barrier function, and pancreatic-gut immune responses are analyzed. LMP supplementation significantly dampened the onset of T1D in NOD mice. LMP supplementation induces caecal homeostasis, as indicated by the increasing SCFAs production, higher expression of tight junction proteins claudin 1, zonula occludens-2 in caecum. Furthermore, LMP-mediated caecal homeostasis impacts gut-pancreatic immunity, as evidenced by increased regulatory T cell population, modulated inflammatory cytokine expression, and suppressed NOD like receptor protein 3 (NLRP3) inflammasome activation in both caecum and pancreas. CONCLUSION: The data demonstrate that LMP limits T1D development by inducing caecal homeostasis to shape pancreatic immune environment, providing a scientific basis for using LMP as a novel functional supplementation to intervene T1D.

Boswellic extracts and 11-keto-ß-boswellic acids prevent type 1 and type 2 diabetes mellitus by suppressing the expression of proinflammatory cytokines.

BACKGROUND: Type 1 diabetes is an autoimmune disease directed to the pancreatic islets where inflammation leads to the death of insulin-producing ß cells and insulin deficiency. Type 2 diabetes, which is closely related to overweight, is characterized by insulin resistance. In both cases, proinflammatory cytokines play an important role by causing insulitis and insulin resistance. The gum resin of Boswellia species and its pharmacologically active compounds, including 11-keto-ß-boswellic acids have been shown to suppress the expression of proinflammatory cytokines in various immune-competent cells. PURPOSE: To review the present evidence of the therapeutic effects of boswellic extracts (BE) and/or 11-keto-ß-boswellic acids in the prevention/treatment of diabetes mellitus and to provide comprehensive insights into the underlying molecular mechanisms. METHODS: This review considers all available informations from preclinical and clinical studies concerning BEs, 11-keto-ß-boswellic acids, proinflammatory cytokines and diabetes mellitus collected via electronic search (PubMed) and related publications of the author. RESULTS: Type 1 diabetes: Studies in mice with autoimmune diabetes revealed that in the model of multiple injections of low doses of streptozotocin (MLD-STZ), an extract of the gum resin of Boswellia serrata and 11-keto-ß-boswellic acid (KBA) suppressed the increase in proinflammatory cytokines in the blood, infiltration of lymphocytes into pancreatic islets and increase in blood glucose. In a second model, i.e. the nonobese diabetic (NOD) mouse, KBA prevented the infiltration of lymphocytes into pancreatic islets. Regarding the clinical effects, a case report provided evidence that BE suppressed the blood levels of tyrosine phosphatase antibody (IA2-A), a marker for insulitis, in a patient with late-onset autoimmune diabetes of the adult (LADA). Type 2 diabetes: In a preclinical study in rats where obesity was alimentary induced, the administration of BE significantly reduced food intake, overweight, proinflammatory cytokines such as interleukin-1ß (IL-1ß), and tumor necrosis factor-α (TNF-α) and ameliorated the parameters of glucose and lipid metabolism. Similar results were obtained in a second animal study, where type 2 diabetes was induced by a combination of a high-fat/high-fructose diet and a single dose of streptozotocin. Two clinical trials with patients with type 2 diabetes receiving the resin of Boswellia serrata demonstrated improvement in the blood glucose, HbA1c and lipid parameters. CONCLUSION: Preclinical and clinical data suggest that BE and/or 11-keto-ß-boswellic acids by inhibiting the expression of proinflammatory cytokines from immune-competent cells, may prevent insulitis and insulin resistance in type 1 and type 2 diabetes, respectively, and therefore may be an option in the treatment/prevention of type 1 and type 2 diabetes. It is hypothesized that molecularly, BE and 11-keto-ß-boswellic acids act via interference with the IκB kinase/Nuclear Transcription Factor-κB (IKK/NF-κB) signaling pathway through inhibition of the phosphorylation activity of IKK. However, further investigations and well-designed clinical studies are required.

Heat-Shock Protein 70-Mediated Heat Preconditioning Attenuates Hepatic Carbohydrate and Oxidative Disturbances in Rats With Type 1 Diabetes.

OBJECTIVES: Heat preconditioning and heat-shock protein (HSP) synthesis have significant cytoprotective effects against the development of cellular injury caused by the application of a subsequent stressor, which were found to depend on the time period between the stressors. We aimed to determine the most efficient recovery time (6 h or 24 h) following heat-stress exposure and prior application of diabetic streptozotocin (STZ) on the moderation of carbohydrate and oxidative metabolic disturbances caused by diabetes. METHODS: Experiment animals (Wistar rats) were exposed to acute heat stress at 41±1°C for 45 min, followed by 6-h or 24-h recovery times at room temperature before sacrifice or STZ administration. RESULTS: Our findings indicate that acute heat stress with 6-h or 24-h recovery periods results in a significant rise in the hepatic heat-shock protein 70 (HSP70) levels (even more so after 24 h), glycogen breakdown and stable glycemia, followed by reduced glycolytic and gluconeogenic activity (after 24 h) (glucose-6-phosphatase, fructose-1,6-bisphosphatase); stimulates antioxidative activity (glutathione peroxidase, glutathione reductase) (after 6 h); and decreases glutathione and catalase activity (after 24 h). Heat preconditioning (with 6-h and 24-h recovery periods) prior to STZ-induced diabetes increases HSP70 levels and causes lower serum glucose levels, higher glycogen and glucose-6-phosphate levels, lower glucose-6-phosphatase levels and glycogen phosphorylase and hexokinase levels but also elevates glutathione reductase and glutathione peroxidase activity compared to untreated STZ animals. CONCLUSIONS: Based on our findings, heat preconditioning and HSP70 induction in rats with type 1 diabetes attenuates STZ-induced metabolic alterations in hepatic carbohydrate metabolism and oxidative states. These changes are more evident at 24 h recovery post-acute heat stress, based on the most evident accumulation of HSP70 in this time frame.

Artesunate prevents type 1 diabetes in NOD mice mainly by inducing protective IL-4-producing T cells and regulatory T cells.

Type 1 diabetes (T1D) is an autoimmune disease characterized by the immune-mediated destruction of insulin-producing ß cells. Recent studies showed that in addition to malaria, artemisinin and its derivative, artesunate (AS), could alleviate several autoimmune diseases. However, whether AS has a role in the prevention or treatment of T1D is still unknown. Therefore, in this study we administrated AS or DMSO in the drinking water of nonobese diabetic (NOD) mice, a mouse model of T1D. We found that AS administration significantly prevented the incidence of T1D. The frequency of IL-4-producing CD4+ single-positive T cells and CD8+ T cells was significantly elevated, and IFN-γ-producing T cells were reduced in the spleen and pancreatic lymph nodes. In the pancreas, the skewing to IL-4-producing T cells was also observed. In addition, more regulatory T cells were found in the pancreas. mRNA levels of proinflammatory cytokines, including TNF-α and IL-6, were decreased. In addition, AS administration promoted the functional maturity of ß cells in vitro. Our findings demonstrate that AS administration can prevent T1D in NOD mice mainly by reducing autoimmune T cells and increasing protective T cells. Our data constitute the first functional study of AS in T1D, which may provide a new rationale for future translational studies.-Li, Z., Shi, X., Liu, J., Shao, F., Huang, G., Zhou, Z., Zheng, P. Artesunate prevents type 1 diabetes in NOD mice mainly by inducing protective IL-4-producing T cells and regulatory T cells.

The role of vitamin D in the pathogenesis and treatment of diabetes mellitus: a narrative review.

Diabetes mellitus, a metabolic disorder associated with chronic complications, is traditionally classified into two main subtypes. Type 1 diabetes mellitus (T1DM) results from gradual pancreatic islet ß cell autoimmune destruction, extending over months or years. Type 2 diabetes mellitus (T2DM) is a heterogeneous disorder, with both insulin resistance and impairment in insulin secretion contributing to its pathogenesis. Vitamin D is a fat-soluble vitamin with an established role in calcium metabolism. Recently, several studies have provided evidence suggesting a role for it in various non-skeletal metabolic conditions, including both types of diabetes mellitus. Preclinical studies of vitamin D action on insulin secretion, insulin action, inflammatory processes, and immune regulation, along with evidence of an increase of hypovitaminosis D worldwide, have prompted several epidemiological, observational, and supplementation clinical studies investigating a potential biological interaction between hypovitaminosis D and diabetes. This narrative review aims to summarize current knowledge on the effect of vitamin D on T1DM and T2DM pathogenesis, prevention, and treatment, as well as on micro- and macrovascular complications of the disease. Furthermore, on the basis of current existing evidence, we aim to highlight areas for potential future research.

Intake of polyunsaturated fatty acids and risk of preclinical and clinical type 1 diabetes in children-a systematic review and meta-analysis.

BACKGROUND/OBJECTIVES: The association between the intake of polyunsaturated fatty acids (PUFAs) and the risk of preclinical and clinical type 1 diabetes (T1D) in children has generated conflicting results. Thus, we aimed to evaluate the definite effects of PUFAs on the risk of preclinical and clinical T1D. SUBJECTS/METHODS: Three databases were systematically searched up to July 18, 2017 to identify relevant observational studies, without language restriction. Any study included should report the risk of preclinical or clinical T1D in children with PUFAs supplementation compared with the controls, and report relative risks (RRs) or odds ratios (ORs) or provide data for estimation. Pooled RRs (or ORs) with 95% confidence intervals (CI) were calculated using random-effects models irrespective of statistical heterogeneity assessed by I2 statistic. RESULTS: We identified seven studies (three prospective cohort studies and four case-control studies) on PUFAs intake during pregnancy or during early life in children. The pooled RR between the risk of preclinical T1D and n-3 PUFAs supplementation against controls was 0.98 (95%CI, 0.85-1.13), with no heterogeneity. The results were similar after the intake during pregnancy, but not during early life in children (pooled RR, 0.45; 95%CI, 0.21-0.96; P = 0.039). N-3 PUFAs supplementation was not associated with a significant reduction in the risk of clinical T1D in children (pooled RR, 0.87; 95%CI, 0.71-1.08), with substantial heterogeneity(I2 = 64.7%). No association was also found between n-6 PUFAs intake and the risk of preclinical (1.07; 0.97-1.017) or clinical T1D (1.05; 0.92-1.20) in children. CONCLUSIONS: The result of the meta-analysis does not support that n-3 or n-6 PUFAs supplementation in children affects the overall risk of preclinical or clinical T1D. However, n-3 PUFAs intake in early life might reduce the risk of preclinical T1D. Therefore, this finding should be verified by more and well-designed prospective research in the future.

Immunomodulatory Effect of Vitamin D and Its Potential Role in the Prevention and Treatment of Type 1 Diabetes Mellitus-A Narrative Review.

Type 1 diabetes mellitus is a chronic autoimmune disease associated with degeneration of pancreatic ß-cells that results in an inability to produce insulin and the need for exogenous insulin administration. It is a significant global health problem as the incidence of this disorder is increasing worldwide. The causes are still poorly understood, although it certainly has genetic and environmental origins. Vitamin D formed profusely in the skin upon exposure to sunlight, as well as from dietary sources, exhibits an immunomodulatory effect based on gene transcription control. Indeed, vitamin D can downregulate mechanisms connected with adaptive immunity, induce immunological tolerance and decrease auto-aggression-related inflammation. These properties provide the basis for a preventive and therapeutic role of vitamin D. As many studies have demonstrated, appropriate supplementation with vitamin D reduces the risk of autoimmune diseases, including type 1 diabetes mellitus, and alleviates disease symptoms in patients. The aim of this narrative review is to present the molecular mechanisms for the vitamin D immunomodulatory effect as well as review human clinical studies on the use of vitamin D as adjuvant therapy in type 1 diabetes mellitus.

Prospects for primary prevention of type 1 diabetes by restoring a disappearing microbe.

Prevention of childhood-onset type 1 diabetes has become more urgent with its marked increased incidence in recent decades in the modern world. Temporally associated with the rising incidence of type 1 diabetes, as well as other autoimmune and allergic diseases in childhood in modern times, is the disappearance of Bifidobacterium and specifically Bifidobacterium longum subsp. infantis (B. infantis) predominance in the intestinal microbiota of breastfed, vaginally-delivered infants. B. infantis efficiently metabolizes human milk oligosaccharides (HMOs) without cross-feeding free sugar monomers to other commensals or pathogens and thereby dominates the intestinal microbiota of breastfed infants. Increased levels of short-chain fatty acids (SCFA), which stimulate both immunoregulation and healthy intestinal and pancreatic ß-cell function, are generated by B. infantis. Based on recent observations of the intestinal microbiota in early life in young children who develop type 1 diabetes and demonstration of the robust preventive effects of SCFA in animal models of autoimmune diabetes, we hypothesize that restoring a B. infantis-dominant microbiota early in infancy will prevent islet autoimmunity and childhood-onset type 1 diabetes.

L-serine supplementation lowers diabetes incidence and improves blood glucose homeostasis in NOD mice.

Sphingolipids are a diverse group of lipids with important roles in beta-cell biology regulating insulin folding and controlling apoptosis. Sphingolipid biosynthesis begins with the condensation of L-serine and palmitoyl-CoA. Here we tested the effect of L-serine supplementation on autoimmune diabetes development and blood glucose homeostasis in female NOD mice. We found that continuous supplementation of L-serine reduces diabetes incidence and insulitis score. In addition, L-serine treated mice had an improved glucose tolerance test, reduced HOMA-IR, and reduced blood glucose levels. L-serine led to a small reduction in body weight accompanied by reduced food and water intake. L-serine had no effect on pancreatic sphingolipids as measured by mass spectrometry. The data thus suggests that L-serine could be used as a therapeutic supplement in the treatment of Type 1 Diabetes and to improve blood glucose homeostasis.

Vitamin D and Diabetes Mellitus.

Vitamin D has been suggested as a protective compound for diabetes mellitus. Several mechanisms linking vitamin D to the regulation of the immune response support a role for vitamin D in the pathogenesis of autoimmune diabetes. Epidemiological evidence and observational studies suggesting that adequate vitamin D status is related to decreased risk of developing type 1 diabetes further corroborates this concept. However, only few and mostly underpowered randomized clinical trials have been conducted to test the effectiveness of vitamin D supplementation in autoimmune diabetes, with disappointing results. Similarly, recent evidence linking vitamin D action to insulin secretion and sensitivity led to the hypothesis that this compound may play a key role in the regulation of glucose homeostasis in both pre-diabetes and overt type 2 diabetes (T2D). However, the main clinical trials evaluating the efficacy of vitamin D supplementation for the control of glucose homeostasis in people at risk for or affected by T2D have yielded inconsistent results. The aim of this review is to summarize the rationale and results of randomized clinical trials testing vitamin D and its analogs in both autoimmune and T2D.

Pregnancy in Diabetes: challenges and opportunities for improving pregnancy outcomes.

Our aim was to review the data from the National Pregnancy in Diabetes (NPID) audit, and to identify the challenges and opportunities for improving pregnancy outcomes in women with diabetes. We reviewed three years of NPID data and relevant diabetes and obstetric literature, and found that there has been little change in pregnancy preparation or outcomes over the past 3 years, with substantial clinic-to clinic variations in care. Women with Type 2 diabetes remain less likely to take 5 mg preconception folic acid (22.8% vs. 41.8%; P < 0.05), and more likely to take potentially harmful medications (statin and/or ACE inhibitor 13.0% vs. 1.8%; P < 0.05) than women with Type 1 diabetes. However, women with Type 1 diabetes are less likely to achieve the recommended glucose control target of HbA1c < 48 mmol/mol (6.5%) (14.9% vs. 38.1%; P < 0.05). The following opportunities for improvement were identified. First, the need to integrate reproductive health into the diabetes care plans of all women with diabetes aged 15-50 years. Second, to develop more innovative approaches to improve uptake of pre-pregnancy care in women with Type 2 diabetes in primary care settings. Third, to integrate insulin pump, continuous glucose monitoring and automated insulin delivery technologies into the pre-pregnancy and antenatal care of women with Type 1 diabetes. Fourth, to improve postnatal care with personalized approaches targeting women with previous pregnancy loss, congenital anomaly and perinatal mortality. A nationwide commitment to delivering integrated reproductive and diabetes healthcare interventions is needed to improve the health outcomes of women with diabetes.

Protective effects of carbonyl iron against multiple low-dose streptozotocin-induced diabetes in rodents.

Particulate adjuvants have shown increasing promise as effective, safe, and durable agents for the stimulation of immunity, or alternatively, the suppression of autoimmunity. Here we examined the potential of the adjuvant carbonyl iron (CI) for the modulation of organ-specific autoimmune disease-type 1 diabetes (T1D). T1D was induced by multiple low doses of streptozotocin (MLDS) that initiates beta cell death and triggers immune cell infiltration into the pancreatic islets. The results of this study indicate that the single in vivo application of CI to MLDS-treated DA rats, CBA/H mice, or C57BL/6 mice successfully counteracted the development of insulitis and hyperglycemia. The protective action was obtained either when CI was applied 7 days before, simultaneously with the first dose of streptozotocin, or 1 day after MLDS treatment. Ex vivo cell analysis of C57BL/6 mice showed that CI treatment reduced the proportion of proinflammatory F4/80+ CD40+ M1 macrophages and activated T lymphocytes in the spleen. Moreover, the treatment down-regulated the number of inflammatory CD4+ IFN-γ+ cells in pancreatic lymph nodes, Peyer's patches, and pancreas-infiltrating mononuclear cells, while simultaneously potentiating proportion of CD4+ IL17+ cells. The regulatory arm of the immune system represented by CD3+ NK1.1+ (NKT) and CD4+ CD25+ FoxP3+ regulatory T cells was potentiated after CI treatment. In vitro analysis showed that CI down-regulated CD40 and CD80 expression on dendritic cells thus probably interfering with their antigen-presenting ability. In conclusion, particulate adjuvant CI seems to suppress the activation of the innate immune response, which further affects the adaptive immune response directed toward pancreatic beta cells.