scholarly journals SKAP2, a Candidate Gene for Type 1 Diabetes, Regulates β-Cell Apoptosis and Glycaemic Control in Newly Diagnosed Patients

Diabetes ◽  
2020 ◽  
pp. db200092
Author(s):  
Tina Fløyel ◽  
Kira Meyerovich ◽  
Michala C. Prause ◽  
Simranjeet Kaur ◽  
Caroline Frørup ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Glycaemic Control ◽  
Candidate Gene ◽  
Cell Apoptosis ◽  
Newly Diagnosed ◽  
Β Cell

scholarly journals SKAP2, a candidate gene for type 1 diabetes, regulates β-cell apoptosis and glycaemic control in newly diagnosed patients

2020 ◽  
Author(s):  
Ada Admin ◽  
Tina Fløyel ◽  
Kira Meyerovich ◽  
Michala C. Prause ◽  
Simranjeet Kaur ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Glycaemic Control ◽  
Candidate Gene ◽  
Cell Function ◽  
Human Islets ◽  
Newly Diagnosed ◽  
Β Cell ◽  
Functional Studies ◽  
Induced Apoptosis

The single nucleotide polymorphism rs7804356 located in the Src kinase-associated phosphoprotein 2<i> </i>(SKAP2) gene<i> </i>is associated with type 1 diabetes (T1D) suggesting <i>SKAP2</i> as a causal candidate gene. The objective of the study was to investigate if SKAP2 has a functional role in the β-cells in relation to T1D. In a cohort of children with newly diagnosed T1D, rs7804356 predicted glycaemic control and residual β-cell function during first year after diagnosis. In INS-1E cells and rat and human islets, pro-inflammatory cytokines reduced the content of SKAP2. Functional studies revealed that knockdown of SKAP2 aggravated cytokine-induced apoptosis in INS-1E cells and primary rat b-cells, suggesting an anti-apoptotic function of SKAP2. In support of this, overexpression of SKAP2 afforded protection against cytokine-induced apoptosis which correlated with reduced nuclear content of S536-phosphorylated NFκB subunit p65, lower nitric oxide production and diminished C/EBP-homologues protein (CHOP) expression indicative of decreased endoplasmic reticulum stress. Knockdown of CHOP partially counteracted the increase in cytokine-induced apoptosis caused by SKAP2 knockdown. In conclusion, our results suggest that SKAP2 controls β-cell sensitivity to cytokines possibly by affecting the NFκB-iNOS-ER stress pathway.

scholarly journals SKAP2, a candidate gene for type 1 diabetes, regulates β-cell apoptosis and glycaemic control in newly diagnosed patients

2020 ◽  
Author(s):  
Ada Admin ◽  
Tina Fløyel ◽  
Kira Meyerovich ◽  
Michala C. Prause ◽  
Simranjeet Kaur ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Glycaemic Control ◽  
Candidate Gene ◽  
Cell Function ◽  
Human Islets ◽  
Newly Diagnosed ◽  
Β Cell ◽  
Functional Studies ◽  
Induced Apoptosis

The single nucleotide polymorphism rs7804356 located in the Src kinase-associated phosphoprotein 2<i> </i>(SKAP2) gene<i> </i>is associated with type 1 diabetes (T1D) suggesting <i>SKAP2</i> as a causal candidate gene. The objective of the study was to investigate if SKAP2 has a functional role in the β-cells in relation to T1D. In a cohort of children with newly diagnosed T1D, rs7804356 predicted glycaemic control and residual β-cell function during first year after diagnosis. In INS-1E cells and rat and human islets, pro-inflammatory cytokines reduced the content of SKAP2. Functional studies revealed that knockdown of SKAP2 aggravated cytokine-induced apoptosis in INS-1E cells and primary rat b-cells, suggesting an anti-apoptotic function of SKAP2. In support of this, overexpression of SKAP2 afforded protection against cytokine-induced apoptosis which correlated with reduced nuclear content of S536-phosphorylated NFκB subunit p65, lower nitric oxide production and diminished C/EBP-homologues protein (CHOP) expression indicative of decreased endoplasmic reticulum stress. Knockdown of CHOP partially counteracted the increase in cytokine-induced apoptosis caused by SKAP2 knockdown. In conclusion, our results suggest that SKAP2 controls β-cell sensitivity to cytokines possibly by affecting the NFκB-iNOS-ER stress pathway.

scholarly journals Systemic TNFα correlates with residual β-cell function in children and adolescents newly diagnosed with type 1 diabetes

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Anne Julie Overgaard ◽  
Jens Otto Broby Madsen ◽  
Flemming Pociot ◽  
Jesper Johannesen ◽  
Joachim Størling
Keyword(s):  
Type 1 Diabetes ◽  
Cell Function ◽  
Disease Onset ◽  
Newly Diagnosed ◽  
Β Cell ◽  
Entire Study ◽  
C Peptide ◽  
Disease Remission ◽  
Β Cell Function

Abstract Background Type 1 diabetes (T1D) is caused by immune-mediated destruction of the β-cells. After initiation of insulin therapy many patients experience a period of improved residual β-cell function leading to partial disease remission. Cytokines are important immune-modulatory molecules and contribute to β-cell damage in T1D. The patterns of systemic circulating cytokines during T1D remission are not clear but may constitute biomarkers of disease status and progression. In this study, we investigated if the plasma levels of various pro- and anti-inflammatory cytokines around time of diagnosis were predictors of remission and residual β-cell function in children with T1D followed for one year after disease onset. Methods In a cohort of 63 newly diagnosed children (33% females) with T1D with a mean age of 11.3 years (3.3–17.7), ten cytokines were measured of which eight were detectable in plasma samples by Mesoscale Discovery multiplex technology at study start and after 6 and 12 months. Linear regression models were used to evaluate association of cytokines with stimulated C-peptide. Results Systemic levels of tumor necrosis factor (TNF)-α, interleukin (IL)-2 and IL-6 inversely correlated with stimulated C-peptide levels over the entire study (P < 0.05). The concentrations of TNFα and IL-10 at study start predicted stimulated C-peptide level at 6 months (P = 0.011 and P = 0.043, respectively, adjusted for sex, age, HbA1c and stage of puberty). Conclusions In recent-onset T1D, systemic cytokine levels, and in particular that of TNFα, correlate with residual β-cell function and may serve as prognostic biomarkers of disease remission and progression to optimize treatment strategies. Trial Registration The study was performed according to the criteria of the Helsinki II Declaration and was approved by the Danish Capital Region Ethics Committee on Biomedical Research Ethics (journal number H-3-2014-052). The parents of all participants gave written consent.

Prognosis for residual islet β‐cell secretion function in young patients with newly diagnosed type 1 diabetes

2019 ◽  
Vol 11 (10) ◽  
pp. 818-825 ◽  
Author(s):  
Haitao Miao ◽  
Juanjuan Zhang ◽  
Bin Gu ◽  
Aibo Gao ◽  
Jie Hong ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Young Patients ◽  
Newly Diagnosed ◽  
Cell Secretion ◽  
Β Cell

Rotenone protects against β-cell apoptosis and attenuates type 1 diabetes mellitus

APOPTOSIS ◽  
2019 ◽  
Vol 24 (11-12) ◽  
pp. 879-891 ◽  
Author(s):  
Mengqiu Wu ◽  
Weiyi Chen ◽  
Shengnan Zhang ◽  
Songming Huang ◽  
Aihua Zhang ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Type 1 Diabetes Mellitus ◽  
Cell Apoptosis ◽  
Β Cell

scholarly journals Circulating Levels of MicroRNA from Children with Newly Diagnosed Type 1 Diabetes and Healthy Controls: Evidence That miR-25 Associates to Residual Beta-Cell Function and Glycaemic Control during Disease Progression

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Lotte B. Nielsen ◽  
Cheng Wang ◽  
Kaspar Sørensen ◽  
Claus H. Bang-Berthelsen ◽  
Lars Hansen ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Glycaemic Control ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Control Group ◽  
Healthy Controls ◽  
Newly Diagnosed ◽  
New Onset

This study aims to identify key miRNAs in circulation, which predict ongoing beta-cell destruction and regeneration in children with newly diagnosed Type 1 Diabetes (T1D). We compared expression level of sera miRNAs from new onset T1D children and age-matched healthy controls and related the miRNAs expression levels to beta-cell function and glycaemic control. Global miRNA sequencing analyses were performed on sera pools from two T1D cohorts (n= 275 and 129, resp.) and one control group (n= 151). We identified twelve upregulated human miRNAs in T1D patients (miR-152, miR-30a-5p, miR-181a, miR-24, miR-148a, miR-210, miR-27a, miR-29a, miR-26a, miR-27b, miR-25, miR-200a); several of these miRNAs were linked to apoptosis and beta-cell networks. Furthermore, we identified miR-25 as negatively associated with residual beta-cell function (est.: −0.12,P= 0.0037), and positively associated with glycaemic control (HbA1c) (est.: 0.11,P= 0.0035) 3 months after onset. In conclusion this study demonstrates that miR-25 might be a “tissue-specific” miRNA for glycaemic control 3 months after diagnosis in new onset T1D children and therefore supports the role of circulating miRNAs as predictive biomarkers for tissue physiopathology and potential intervention targets.

Enterovirus infection, β-cell apoptosis and type 1 diabetes

2013 ◽  
Vol 34 (3) ◽  
pp. 153 ◽  
Author(s):  
Sandhya Nair ◽  
Ammira Akil ◽  
Maria E Craig
Keyword(s):  
Type 1 Diabetes ◽  
Cell Apoptosis ◽  
Enterovirus Infection ◽  
Β Cell

Type 1 Diabetic Serum Interferes with Pancreatic β-cell Ca2+ -Handling

2007 ◽  
Vol 27 (6) ◽  
pp. 321-326 ◽  
Author(s):  
N. Dekki ◽  
R. Nilsson ◽  
S. Norgren ◽  
S. M. Rössner ◽  
I. Appelskog ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Ethnic Background ◽  
Diabetic Patients ◽  
Pancreatic Β Cell ◽  
Newly Diagnosed ◽  
Β Cells ◽  
Β Cell ◽  
First Degree Relatives ◽  
Type 1 Diabetic Patients

The aim of this study was to clarify the frequency of patients with type 1 diabetes that have serum that increases pancreatic β-cell cytoplasmic free Ca2+ concentration, [Ca2+]i, and if such an effect is also present in serum from first-degree relatives. We also studied a possible link between the serum effect and ethnic background as well as presence of autoantibodies. Sera obtained from three different countries were investigated as follows: 82 Swedish Caucasians with newly diagnosed type 1 diabetes, 56 Americans with different duration of type 1 diabetes, 117 American first-degree relatives of type 1 diabetic patients with a mixed ethnic background and 31 Caucasian Finnish children with newly diagnosed type 1 diabetes. Changes in [Ca2+]i, upon depolarization, were measured in β-cells incubated overnight with sera from type 1 diabetic patients, first-degree relatives or healthy controls. Our data show that there is a group constituting approximately 30% of type 1 diabetic patients of different gender, age, ethnic background and duration of the disease, as well as first-degree relatives of type 1 diabetic patients, that have sera that interfere with pancreatic β-cell Ca2+-handling. This effect on β-cell [Ca2+]i could not be correlated to the presence of autoantibodies. In a defined subgroup of patients with type 1 diabetes and first-degree relatives a defect Ca2+-handling may aggravate development of β-cell destruction.

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