Methanolic extract of Origanum vulgare ameliorates type 1 diabetes through antioxidant, anti-inflammatory and anti-apoptotic activity

Type 1 diabetes (T1D), an autoimmune inflammatory disorder, develops as a consequence of pancreatic β-cell destruction and results in hyperglycaemia. Since current T1D therapy mainly involves insulin replacement, the aim of the present study was to evaluate the therapeutic potential of Origanum vulgare L. ssp. hirtum (Greek oregano) leaf extract rich in biophenols for the treatment of T1D. The phytochemical profile of methanolic oregano extract (MOE) and aqueous oregano extract (AOE) was determined by liquid chromatography/electrospray ion-trap tandem MS (LC/DAD/ESI-MSn), while their main compounds were quantified by HPLC with diode array detection. After establishing their potent in vitro antioxidant activity, the extracts were administered to C57BL/6 mice treated with multiple low doses of streptozotocin for diabetes induction. While prophylactic AOE therapy had no impact on diabetes induction, MOE reduced diabetes incidence and preserved normal insulin secretion. In addition, MOE scavenged reactive oxygen and nitrogen species and, therefore, alleviated the need for the up-regulation of antioxidant enzymes. MOE treatment specifically attenuated the pro-inflammatory response mediated by T helper 17 cells and enhanced anti-inflammatory T helper 2 and T regulatory cells through the impact on specific signalling pathways and transcription factors. Importantly, MOE preserved β-cells from in vitro apoptosis via blockade of caspase 3. Finally, rosmarinic acid, a predominant compound in MOE, exhibited only partial protection from diabetes induction. In conclusion, acting as an antioxidant, immunomodulator and in an anti-apoptotic manner, MOE protected mice from diabetes development. Seemingly, there is more than one compound responsible for the beneficial effect of MOE.

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Human Mesenchymal Stem Cells Modulate Cellular Immune Response to Islet Antigen Glutamic Acid Decarboxylase in Type 1 Diabetes

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2009-2350 ◽

2010 ◽

Vol 95 (8) ◽

pp. 3788-3797 ◽

Cited By ~ 30

Author(s):

Maria M. Zanone ◽

Enrica Favaro ◽

Ilaria Miceli ◽

Giorgio Grassi ◽

Elisa Camussi ◽

...

Keyword(s):

Type 1 Diabetes ◽

Acid Decarboxylase ◽

Diabetic Patients ◽

Human Mscs ◽

T Helper ◽

Ifn Γ ◽

Islet Antigen ◽

Helper Type

Context: Mesenchymal stem cells (MSCs) exert an immunosuppressive effect on the immune system. However, studies on the immunomodulatory potential of MSCs in type 1 diabetes are lacking. Objective: We aimed to evaluate whether human MSCs may inhibit in vitro pancreatic islet antigen-specific T cell activation in type 1 diabetes. Design: Human MSCs were isolated and characterized. Peripheral blood mononuclear cells (PBMCs) were obtained from nine type 1 diabetic patients at disease onset and 13 healthy control subjects. IFN-γ, IL-10, and IL-4 enzyme-linked immunospot responses of lymphocytes incubated with glutamic acid decarboxylase 65 (GAD65) were investigated in PBMC cultures and PBMC/MSC cocultures. Levels of prostaglandin E2 (PGE2), IFN-γ, IL-4, and IL-10 in supernatants were measured by ELISA. PGE2 inhibition experiments with NS-398 and indomethacin were also performed. Results: Five diabetic patients were identified with a positive PBMC IFN-γ response to GAD65 and negative IL-10 and IL-4 response. PBMC/MSC cocultures resulted in a significant decrease in the number of spots and in detection of IL-4-secreting cells. PGE2 inhibitors abrogated the immune-suppressive effect, indicating an involvement of PGE2 production, and the constitutive production of PGE2 by MSCs was enhanced in PBMC/MSC coculture. Moreover, in GAD-responder patients, GAD-stimulated PBMC/MSC cocultures significantly decreased secretion of IFN-γ and IL-10 and increased secretion of IL-4. Conclusions: These results provide evidence that human MSCs abrogate in vitro a proinflammatory T helper type 1 response to an islet antigenic stimulus in type 1 diabetes. MSCs induce IL-4-producing cells, suggesting a possible switch to an antiinflammatory T helper type 2 signaling of T cells.

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Glycation of HDL blunts its anti-inflammatory and cholesterol efflux capacities in vitro, but has no effect in poorly controlled type 1 diabetes subjects

Journal of Diabetes and its Complications ◽

10.1016/j.jdiacomp.2020.107693 ◽

2020 ◽

Vol 34 (12) ◽

pp. 107693

Author(s):

Diego Gomes Kjerulf ◽

Shari Wang ◽

Mohamed Omer ◽

Asha Pathak ◽

Savitha Subramanian ◽

...

Keyword(s):

Type 1 Diabetes ◽

Cholesterol Efflux ◽

Anti Inflammatory

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The Role of Age and Excess Body Mass Index in Progression to Type 1 Diabetes in At-Risk Adults

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2017-01490 ◽

2017 ◽

Vol 102 (12) ◽

pp. 4596-4603

Author(s):

Christine T Ferrara ◽

Susan M Geyer ◽

Carmella Evans-Molina ◽

Ingrid M Libman ◽

Dorothy J Becker ◽

...

Keyword(s):

Body Mass Index ◽

Type 1 Diabetes ◽

Body Mass ◽

Protective Factor ◽

Diabetes Incidence ◽

Increased Risk ◽

Diabetes Progression ◽

The Impact

Abstract Background Given the global rise in both type 1 diabetes incidence and obesity, the role of body mass index (BMI) on type 1 diabetes pathophysiology has gained great interest. Sustained excess BMI in pediatric participants of the TrialNet Pathway to Prevention (PTP) cohort increased risk for progression to type 1 diabetes, but the effects of age and obesity in adults remain largely unknown. Objective To determine the effect of age and sustained obesity on the risk for type 1 diabetes in adult participants in the TrialNet PTP cohort (i.e., nondiabetic autoantibody-positive relatives of patients with type 1 diabetes). Research Design and Methods Longitudinally accumulated BMI >25 kg/m2 was calculated to generate a cumulative excess BMI (ceBMI) for each participant, with ceBMI values ≥0 kg/m2 and ≥5 kg/m2 representing sustained overweight or obese status, respectively. Recursive partitioning analysis yielded sex- and age-specific thresholds for ceBMI that confer the greatest risk for type 1 diabetes progression. Results In this cohort of 665 adults (age 20 to 50 years; median follow-up, 3.9 years), 49 participants developed type 1 diabetes. Age was an independent protective factor for type 1 diabetes progression (hazard ratio, 0.95; P = 0.008), with a threshold of >35 years that reduced risk for type 1 diabetes. In men age >35 years and women age <35 years, sustained obesity (ceBMI ≥5 kg/m2) increased the risk for type 1 diabetes. Conclusions Age is an important factor for type 1 diabetes progression in adults and influences the impact of elevated BMI, indicating an interplay of excess weight, age, and sex in adult type 1 diabetes pathophysiology.

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Type 1 diabetes in 2017: global estimates of incident and prevalent cases in children and adults

Diabetologia ◽

10.1007/s00125-021-05571-8 ◽

2021 ◽

Author(s):

Anders Green ◽

Simone M. Hede ◽

Christopher C. Patterson ◽

Sarah H. Wild ◽

Giuseppina Imperatore ◽

...

Keyword(s):

Type 1 Diabetes ◽

Age Groups ◽

Incidence Rates ◽

Data Availability ◽

Sensitivity Analyses ◽

Estimation Methods ◽

Diabetes Incidence ◽

Incident Cases ◽

The Impact

Abstract Aims/hypothesis Data on type 1 diabetes incidence and prevalence are limited, particularly for adults. This study aims to estimate global numbers of incident and prevalent cases of type 1 diabetes in 2017 for all age groups, by country and areas defined by income and region. Methods Incidence rates of type 1 diabetes in children (available from 94 countries) from the IDF Atlas were used and extrapolated to countries without data. Age-specific incidence rates in adults (only known across full age range for fewer than ten countries) were obtained by applying scaling ratios for each adult age group relative to the incidence rate in children. Age-specific incidence rates were applied to population estimates to obtain incident case numbers. Duration of diabetes was estimated from available data and adjusted using differences in childhood mortality rate between countries from United Nations demographic data. Prevalent case numbers were derived by modelling the relationship between prevalence, incidence and disease duration. Sensitivity analyses were performed to quantify the impact of alternative assumptions and model inputs. Results Global numbers of incident and prevalent cases of type 1 diabetes were estimated to be 234,710 and 9,004,610, respectively, in 2017. High-income countries, with 17% of the global population, accounted for 49% of global incident cases and 52% of prevalent cases. Asia, which has the largest proportion of the world’s population (60%), had the largest number of incident (32%) and prevalent (31%) cases of type 1 diabetes. Globally, 6%, 35%, 43% and 16% of prevalent cases were in the age groups 0–14, 15–39, 40–64 and 65+ years, respectively. Based on sensitivity analyses, the estimates could deviate by ±15%. Conclusions/interpretation Globally, type 1 diabetes represents about 2% of the estimated total cases of diabetes, ranging from less than 1% in certain Pacific countries to more than 15% in Northern European populations in 2017. This study provides information for the development of healthcare and policy approaches to manage type 1 diabetes. The estimates need further validation due to limitations and assumptions related to data availability and estimation methods. Graphical abstract

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Beta cell antigens in type 1 diabetes: triggers in pathogenesis and therapeutic targets

F1000Research ◽

10.12688/f1000research.7411.1 ◽

2016 ◽

Vol 5 ◽

pp. 728 ◽

Cited By ~ 7

Author(s):

François-Xavier Mauvais ◽

Julien Diana ◽

Peter van Endert

Keyword(s):

Type 1 Diabetes ◽

Beta Cell ◽

Autoimmune Response ◽

Monitoring Tools ◽

Specific Cellular Immune Response ◽

Mechanistic Understanding ◽

Cellular Immune ◽

The Impact

Research focusing on type 1 diabetes (T1D) autoantigens aims to explore our understanding of these beta cell proteins in order to design assays for monitoring the pathogenic autoimmune response, as well as safe and efficient therapies preventing or stopping it. In this review, we will discuss progress made in the last 5 years with respect to mechanistic understanding, diagnostic monitoring, and therapeutic modulation of the autoantigen-specific cellular immune response in T1D. Some technical progress in monitoring tools has been made; however, the potential of recent technologies for highly multiplexed exploration of human cellular immune responses remains to be exploited in T1D research, as it may be the key to the identification of surrogate markers of disease progression that are still wanting. Detailed analysis of autoantigen recognition by T cells suggests an important role of non-conventional antigen presentation and processing in beta cell-directed autoimmunity, but the impact of this in human T1D has been little explored. Finally, therapeutic administration of autoantigens to T1D patients has produced disappointing results. The application of novel modes of autoantigen administration, careful translation of mechanistic understanding obtained in preclinical studies and in vitro with human cells, and combination therapies including CD3 antibodies may help to make autoantigen-based immunotherapy for T1D a success story in the future.

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Effect of Different Cereal Peptides on the Development of Type 1 Diabetes is Associated with Their Anti‐inflammatory Ability: In Vitro and In Vivo Studies

Molecular Nutrition & Food Research ◽

10.1002/mnfr.201800987 ◽

2019 ◽

Vol 63 (11) ◽

pp. 1800987 ◽

Cited By ~ 1

Author(s):

Suling Sun ◽

Hao Zhang ◽

Kai Shan ◽

Tianjun Sun ◽

Mengyuan Lin ◽

...

Keyword(s):

Type 1 Diabetes ◽

In Vivo Studies ◽

Anti Inflammatory

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Gut mucosa alterations and loss of segmented filamentous bacteria in type 1 diabetes are associated with inflammation rather than hyperglycaemia

Gut ◽

10.1136/gutjnl-2020-323664 ◽

2021 ◽

pp. gutjnl-2020-323664 ◽

Cited By ~ 1

Author(s):

Matthieu Rouland ◽

Lucie Beaudoin ◽

Ophélie Rouxel ◽

Léo Bertrand ◽

Lucie Cagninacci ◽

...

Keyword(s):

Type 1 Diabetes ◽

Epithelial Cell ◽

Cell Function ◽

Diabetes Incidence ◽

Filamentous Bacteria ◽

Segmented Filamentous Bacteria ◽

Gut Mucosa ◽

Anti Inflammatory

ObjectiveType 1 diabetes (T1D) is an autoimmune disease caused by the destruction of pancreatic β-cells producing insulin. Both T1D patients and animal models exhibit gut microbiota and mucosa alterations, although the exact cause for these remains poorly understood. We investigated the production of key cytokines controlling gut integrity, the abundance of segmented filamentous bacteria (SFB) involved in the production of these cytokines, and the respective role of autoimmune inflammation and hyperglycaemia.DesignWe used several mouse models of autoimmune T1D as well as mice rendered hyperglycaemic without inflammation to study gut mucosa and microbiota dysbiosis. We analysed cytokine expression in immune cells, epithelial cell function, SFB abundance and microbiota composition by 16S sequencing. We assessed the role of anti-tumour necrosis factor α on gut mucosa inflammation and T1D onset.ResultsWe show in models of autoimmune T1D a conserved loss of interleukin (IL)-17A, IL-22 and IL-23A in gut mucosa. Intestinal epithelial cell function was altered and gut integrity was impaired. These defects were associated with dysbiosis including progressive loss of SFB. Transfer of diabetogenic T-cells recapitulated these gut alterations, whereas induction of hyperglycaemia with no inflammation failed to do so. Moreover, anti-inflammatory treatment restored gut mucosa and immune cell function and dampened diabetes incidence.ConclusionOur results demonstrate that gut mucosa alterations and dysbiosis in T1D are primarily linked to inflammation rather than hyperglycaemia. Anti-inflammatory treatment preserves gut homeostasis and protective commensal flora reducing T1D incidence.

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