Increase of Neutrophil Extracellular Traps, Mitochondrial DNA and Nuclear DNA in Newly Diagnosed Type 1 Diabetes Children but Not in High-Risk Children

Neutrophil extracellular traps (NETs) and mitochondrial DNA (mtDNA) are inflammatory mediators involved in the development of type 1 diabetes (T1D). Pancreas-infiltrating neutrophils can release NETs, contributing to the inflammatory process. Levels of NETs are increased in serum from patients with T1D and mtDNA is increased in adult T1D patients. Our aim was to investigate extracellular DNA (NETs, mtDNA and nuclear DNA) in children with newly diagnosed T1D and in children at high risk of the disease. We also elucidated if extracellular DNA short after diagnosis could predict loss of endogenous insulin production. Samples were analysed for mtDNA and nuclear DNA using droplet digital PCR and NETs were assessed by a NET-remnants ELISA. In addition, in vitro assays for induction and degradation of NETs, as well as analyses of neutrophil elastase, HLA genotypes, levels of c-peptide, IL-1beta, IFN and autoantibodies (GADA, IA-2A, IAA and ZnT8A) were performed. In serum from children 10 days after T1D onset there was an increase in NETs (p=0.007), mtDNA (p<0.001) and nuclear DNA (p<0.001) compared to healthy children. The elevated levels were found only in younger children. In addition, mtDNA increased in consecutive samples short after onset (p=0.017). However, levels of extracellular DNA short after onset did not reflect future loss of endogenous insulin production. T1D serum induced NETs in vitro and did not deviate in the ability to degrade NETs. HLA genotypes and autoantibodies, except for ZnT8A, were not associated with extracellular DNA in T1D children. Serum from children with high risk of T1D showed fluctuating levels of extracellular DNA, sometimes increased compared to healthy children. Therefore, extracellular DNA in serum from autoantibody positive high-risk children does not seem to be a suitable biomarker candidate for prediction of T1D. In conclusion, we found increased levels of extracellular DNA in children with newly diagnosed T1D, which might be explained by an ongoing systemic inflammation.

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Apoptosis and proliferation ofperipheral blood T-cells as alternative processes in pathogenesis of diabetes mellitus type 1

Medical alphabet ◽

10.33667/2078-5631-2019-1-4(379)-16-20 ◽

2019 ◽

Vol 1 (4) ◽

pp. 16-20 ◽

Cited By ~ 1

Author(s):

A. V. Lugovaya ◽

N. M. Kalinina ◽

V. Ph. Mitreikin ◽

Yu. P. Kovaltchuk ◽

A. V. Artyomova ◽

...

Keyword(s):

Diabetes Mellitus ◽

T Cells ◽

High Risk ◽

Peripheral Blood ◽

Cellular Response ◽

Proliferative Potential ◽

Autoreactive T Cells ◽

Alternative Processes

Apoptosis, along with proliferation, is a form of lymphocyte response to activating stimuli. In the early stages of cell differentiation, the apoptotic response prevails and it results to the formation of tolerance to inductor antigen. Mature lymphocytes proliferate in response to stimulation and it means the initial stage in the development of the immune response. Since in this case apoptosis and proliferation acts as alternative processes, their ratio can serve as a measure of the effectiveness of the cellular response to activating signals. The resistance of autoreactive T-cells to apoptosis is the main key point in the development of type 1 diabetes mellitus (T1DM). Autoreactive T-cells migrates from the bloodstream to the islet tissue of the pancreas and take an active part in b cells destruction. The resistance of autoreactive effector T-cells to apoptosis may suggest their high proliferative potential. Therefore, the comparative evaluation of apoptosis and proliferation of peripheral blood lymphocytes can give a more complete picture of their functional state and thus will help to reveal the causes of ineffective peripheral blood T-ceiis apoptosis in patients with T1DM and will help to understand more deeply the pathogenesis of the disease. in this article, the features of proliferative response of peripheral blood T-cells in patients with T1DM and in individuals with high risk of developing T1DM have been studied. Apoptosis of T-cell subpopulations has been investigated. The correlation between the apoptotic markers and the intensity of spontaneous and activation- induced in vitro T-cells proliferation of was revealed. it was determined, that autoreactive peripheral blood T-cells were resistant to apoptosis and demonstrated the increased proliferative potential in patients with T1DM and in individuals with high risk of developing T1DM.

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Exocrine pancreas function is impaired in adult relatives of patients with type 1 diabetes

Acta Diabetologica ◽

10.1007/s00592-021-01819-2 ◽

2021 ◽

Author(s):

Anna Giovenzana ◽

Federica Vecchio ◽

Federica Cugnata ◽

Alessandro Nonis ◽

Alessandra Mandelli ◽

...

Keyword(s):

At Risk ◽

Type 1 Diabetes ◽

High Risk ◽

Exocrine Pancreas ◽

Pancreatic Enzyme ◽

Low Risk ◽

C Peptide ◽

Hla Genotypes ◽

Pancreas Function

Abstract Aims Alterations of the exocrine pancreas have been reported in type 1 diabetes, but their contribution to the pathogenesis of the disease is poorly understood. Here, we investigated markers of exocrine pancreas dysfunction in individuals at-risk of developing type 1 diabetes. Methods Serum P-amylase and lipase levels were assessed in samples obtained from healthy controls, patients with new onset type 1 diabetes, relatives participating to the TrialNet Pathway to Prevention who were, at blood collection, autoantibody negative or positive for a single autoantibody (low-risk individuals), and positive for multiple autoantibodies (high-risk individuals). Linear mixed models were adopted to estimate variation of pancreatic enzymes among the groups and to evaluate the influence of high-risk HLA genotypes and residual beta cell function on exocrine pancreas function. Results In adults, but not children, reduced levels of P-amylase and lipase were shown in at-risk individuals, including (for P-amylase levels only) those at low-risk, and in T1Dnew. Furthermore, while high-risk HLA genotypes negatively affected P-amylase levels in autoantibody negative adult individuals, fasting C-peptide levels did not correlate with pancreatic enzyme levels. Conclusions Exocrine pancreas dysfunction precedes the onset of type 1 diabetes in adult at-risk individuals and may be unrelated to fasting C-peptide levels.

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Insulin-Like Growth Factor-1 at Diagnosis and during Subsequent Years in Adolescents with Type 1 Diabetes

Journal of Diabetes Research ◽

10.1155/2018/8623560 ◽

2018 ◽

Vol 2018 ◽

pp. 1-6 ◽

Cited By ~ 4

Author(s):

Simona I. Chisalita ◽

J. Ludvigsson

Keyword(s):

Type 1 Diabetes ◽

Insulin Secretion ◽

Insulin Treatment ◽

Insulin Dose ◽

Newly Diagnosed ◽

Blood Samples ◽

C Peptide ◽

Endogenous Insulin ◽

High Hba1c

Background. Type 1 diabetes (T1D) in adolescents is associated with alterations in the insulin-like factor system probably caused both by a deranged metabolism and insulinopenia in the portal vein. Objective. To study how the circulating IGF-1 is affected at diagnosis and during subsequent years in adolescents with T1D. Methods. Ten girls and ten boys with type 1 diabetes (T1D), aged 13.0 ± 1.4 (mean ± SD) years at diagnosis, took part in the study. Blood samples were drawn at diagnosis and after 3, 9, 18, and 48 months. HbA1c, total IGF-1, and C-peptide were measured. Results. At diagnosis, the patients had high HbA1c, low IGF-1, and measurable C-peptide. After the start of insulin treatment, maximal improvement in glycemic control and IGF-1 occurred within 3 months and then both tended to deteriorate, that is, HbA1c to increase and IGF-1 to decrease. C-peptide decreased with time, and after 4 years, half of the patients were C-peptide negative. At diagnosis, C-peptide correlated positively to IGF-1 (r=0.50; p<0.03). C-peptide correlated negatively with insulin dose (U/kg) after 18 and 48 months from diagnosis (r=−0.48; p<0.03 and r=−0.72; p<0.001, resp.). Conclusions. In conclusion, our results show that in newly diagnosed adolescents with type 1 diabetes and deranged metabolism, the IGF-1 level is low and rapidly improves with insulin treatment but later tends to decrease concomitantly with declining endogenous insulin secretion.

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Case Reports That Illustrate the Efficacy of SGLT2 Inhibitors in the Type 1 Diabetic Patient

Case Reports in Endocrinology ◽

10.1155/2015/676191 ◽

2015 ◽

Vol 2015 ◽

pp. 1-4 ◽

Cited By ~ 2

Author(s):

David S. H. Bell

Keyword(s):

Type 2 Diabetes ◽

Type 1 Diabetes ◽

Case Reports ◽

Sglt2 Inhibitor ◽

Sglt2 Inhibitors ◽

Endogenous Insulin ◽

Large Randomized Clinical Trial ◽

Endogenous Insulin Production

SGLT2 inhibitors are only approved for use in adults with type 2 diabetes. However, because SGLT2 inhibitors have a mechanism of action that does not require the presence of endogenous insulin, these drugs should also be efficacious in type 1 diabetes where endogenous insulin production is greatly reduced or absent. Herein, I present five cases which illustrate the benefits of utilizing an SGLT2 inhibitor with type 1 diabetes. In these cases the use of SGLT2 inhibitors resulted not only in better glycemic control in most patients but also in some patients’ less hypoglycemia, weight loss, and decreased doses of insulin. In type 1 diabetesCandida albicansvaginitis and balanitis may occur more frequently than in type 2 diabetes. These cases show that a large randomized clinical trial of SGLT2 inhibitors in type 1 diabetes needs to be performed.

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Country-specific birth weight and length in type 1 diabetes high-risk HLA genotypes in combination with prenatal characteristics

Journal of Perinatology ◽

10.1038/jp.2011.26 ◽

2011 ◽

Vol 31 (12) ◽

pp. 764-769 ◽

Cited By ~ 6

Author(s):

Y Sterner ◽

◽

C Törn ◽

H-S Lee ◽

H Larsson ◽

...

Keyword(s):

Type 1 Diabetes ◽

Birth Weight ◽

High Risk ◽

Hla Genotypes ◽

Country Specific

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Monocytic Cytokines in Autoimmune Polyglandular Syndrome Type 2 Are Modulated by Vitamin D and HLA-DQ

Frontiers in Immunology ◽

10.3389/fimmu.2020.583709 ◽

2020 ◽

Vol 11 ◽

Author(s):

Anna U. Kraus ◽

Marissa Penna-Martinez ◽

Firouzeh Shoghi ◽

Gesine Meyer ◽

Klaus Badenhoop

Keyword(s):

Vitamin D ◽

Type 1 Diabetes ◽

High Risk ◽

Enzyme Linked Immunosorbent Assay ◽

Healthy Controls ◽

Autoimmune Polyglandular Syndrome ◽

Pathway Gene ◽

Hla Dq

ContextAutoimmune polyglandular syndrome (APS-2: autoimmune Addison’s disease or type 1 diabetes) is conferred by predisposing HLA molecules, vitamin D deficiency, and heritable susceptibility. Organ destruction is accompanied by cytokine alterations. We addressed the monocytic cytokines of two distinct APS-2 cohorts, effects of vitamin D and HLA DQ risk.MethodsAPS-2 patients (n = 30) and healthy controls (n = 30) were genotyped for HLA DQA1/DQB1 and their CD14+ monocytes stimulated with IL1β and/or 1,25(OH)2D3 for 24 h. Immune regulatory molecules (IL-6, IL-10, IL-23A, IL-15, CCL-2, PD-L1), vitamin D pathway gene transcripts (CYP24A1, CYP27B1, VDR), and CD14 were analyzed by enzyme-linked immunosorbent assay and RTqPCR.ResultsPro-inflammatory CCL-2 was higher in APS-2 patients than in controls (p = 0.001), whereas IL-6 showed a trend – (p = 0.1). In vitro treatment with 1,25(OH)2D3 reduced proinflammatory cytokines (IL-6, CCL-2, IL-23A, IL-15) whereas anti-inflammatory cytokines (IL-10 and PD-L1) rose both in APS-type 1 diabetes and APS-Addison´s disease. Patients with adrenal autoimmunity showed a stronger response to vitamin D. Expression of IL-23A and vitamin D pathway genes VDR and CYP27B1 varied by HLA genotype and was lower in healthy individuals with high-risk HLA (p = 0.0025; p = 0.04), while healthy controls with low-risk HLA showed a stronger IL-10 and CD14 expression (p = 0.01; p = 0.03).Conclusion1,25(OH)2D3 regulates the monocytic response in APS-2 disorders type 1 diabetes or Addison´s disease. The monocytic cytokine profile of individuals carrying HLA high-risk alleles is proinflammatory, enhances polyglandular autoimmunity and can be targeted by vitamin D.

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