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

The single nucleotide polymorphism rs7804356 located in the Src kinase-associated phosphoprotein 2 (SKAP2) gene is associated with type 1 diabetes (T1D) suggesting SKAP2 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.

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

Diabetes ◽

10.2337/db20-0092 ◽

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

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

BMC Pediatrics ◽

10.1186/s12887-020-02339-8 ◽

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.

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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

Experimental Diabetes Research ◽

10.1155/2012/896362 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 44

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.

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The role of islet lipid composition remodeling in regulation of beta-cell death via ADP-ribosyl-acceptor glycohydrolase ARH3 signaling in insulitis

10.1101/2020.03.23.004481 ◽

2020 ◽

Author(s):

Ernesto S. Nakayasu ◽

Cailin Deiter ◽

Jennifer E. Kyle ◽

Michelle A. Guney ◽

Dylan Sarbaugh ◽

...

Keyword(s):

Cell Death ◽

Type 1 Diabetes ◽

Lipid Metabolism ◽

Lipid Composition ◽

Antigen Processing ◽

Human Islets ◽

List Type ◽

Β Cell ◽

Induced Apoptosis

SummaryLipids have been implicated as mediators of insulitis and β-cell death in type 1 diabetes development, but the mechanisms underlying this association are poorly understood. Here, we investigated the changes in islet/β-cell lipid composition using three models of insulitis: human islets and EndoC-βH1 β-cells treated with the cytokines IL-1β and IFN-γ, and islets from non-obese diabetic mice. Across all three models, lipidomic analyses showed a consistent change in abundance of the lysophosphatidylcholine, phosphatidylcholine and triacylglycerol species. We also showed that lysophosphatidylcholine and its biosynthetic enzyme PLA2G6 are enriched in murine islets. We determined that the ADP-ribosyl-acceptor glycohydrolase ARH3 is regulated by cytokines downstream of PLA2G6, which in turn regulates proteins involved in apoptosis, lipid metabolism, antigen processing and presentation and chemokines. ARH3 reduced cytokine-induced apoptosis, which may represent a negative feedback mechanism. Overall, these data show the importance of lipid metabolism in regulating β-cell death in type 1 diabetes.HighlightsLipidomics of 3 insulitis models revealed commonly regulated lipid classes.Identification of 35 proteins regulated by cytokines via PLA2G6 signaling.ARH3 reduces cytokine-induced apoptosis via PLA2G6 regulation.ARH3 regulates the levels of proteins related to insulitis and type 1 diabetes.

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Erratum to “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”

Experimental Diabetes Research ◽

10.1155/2012/672865 ◽

2012 ◽

Vol 2012 ◽

pp. 1-1 ◽

Cited By ~ 4

Author(s):

Lotte B. Nielsen ◽

Cheng Wang ◽

Kaspar Sørensen ◽

Claus H. Bang-Berthelsen ◽

Lars Hansen ◽

...

Keyword(s):

Type 1 Diabetes ◽

Glycaemic Control ◽

Beta Cell ◽

Disease Progression ◽

Beta Cell Function ◽

Cell Function ◽

Healthy Controls ◽

Newly Diagnosed ◽

Circulating Levels

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Evaluating the Effect of Prebiotics on the Gut Microbiome Profile and β-cell Function in Youth with Newly-Diagnosed Type 1 Diabetes

10.1101/2020.10.05.20207142 ◽

2020 ◽

Author(s):

Heba M. Ismail ◽

Maria Spall ◽

Carmella Evans-Molina ◽

Linda A. DiMeglio

Keyword(s):

Type 1 Diabetes ◽

Gut Microbiome ◽

Cell Function ◽

Human Study ◽

Newly Diagnosed ◽

Β Cell ◽

Microbiome Profile ◽

Β Cell Function ◽

Health Function

AbstractData show that disturbances in the gut microbiota play a role in glucose homeostasis, type 1 diabetes (T1D) risk and progression. The prebiotic high amylose maize starch (HAMS) alters the gut microbiome profile and metabolites favorably with an increase in bacteria producing short chain fatty acids (SCFAs) that have significant anti-inflammatory effects. HAMS also improves glycemia, insulin sensitivity and secretion in healthy non-diabetic adults. Additionally, a recent study testing an acetylated and butyrylated form of HAMS (HAMS-AB) that further increases SCFA production prevented T1D in a rodent model without adverse safety effects. The overall objective of this human study will be to assess how daily HAMS-AB consumption impacts the gut microbiome profile, SCFA production, β-cell heath, function and glycemia as well as immune responses in newly-diagnosed T1D youth. We hypothesize that HAMS-AB intake will improve the gut microbiome profile, increase SCFA production, improve β-cell health, function and glycemia as well as modulate the immune system. We describe here a pilot, randomized crossover trial of HAMS-AB in 12 newly-diagnosed T1D youth with residual β-cell function. In Aim 1, we will determine the effect of HAMS-AB on the gut microbiome profile and SCFA production; in Aim 2, we will determine the effect of HAMS-AB on β-cell health, function and glycemia; and in Aim 3, we will determine the peripheral blood effect of HAMS-AB on frequency, phenotype and function of specific T cell markers. We anticipate beneficial effects from a simple, inexpensive and safe dietary approach.

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4033 Evaluating the Effect of Prebiotics on the Gut Microbiome Profile and Beta-cell Function in Newly-Diagnosed Type 1 Diabetes

Journal of Clinical and Translational Science ◽

10.1017/cts.2020.126 ◽

2020 ◽

Vol 4 (s1) ◽

pp. 29-30

Author(s):

Heba M Ismail ◽

Carmella Evans-Molina ◽

Linda DiMeglio

Keyword(s):

Type 1 Diabetes ◽

Gut Microbiome ◽

Cell Function ◽

Short Chain Fatty Acids ◽

Newly Diagnosed ◽

Long Term Effects ◽

Β Cell ◽

Microbiome Profile ◽

Β Cell Function

OBJECTIVES/GOALS: Type 1 diabetes (T1D) results from the autoimmune destruction of insulin-producing β-cells. Emerging data suggest that differences in intestinal microbiota might be critically involved both in autoimmunity and in glucose homeostasis. The prebiotic high amylose maize starch (HAMS) alters the gut microbiome profile and metabolites positively by increasing production of beneficial short chain fatty acids (SCFAs) that have significant anti-inflammatory effects. HAMS also improves glycemia, insulin sensitivity and secretion in healthy non-diabetic adults. Further, an acetylated and butyrylated form of HAMS (HAMS-AB) that increases beneficial SCFA production, namely acetate and butyrate, has been safe and effective in disease prevention in mouse T1D models. The objective of the proposed study is to assess the effect of administering a prebiotic, such as HAMS-AB, on the gut microbiome profile, SCFA production, glycemia and β-cell function in humans with T1D. METHODS/STUDY POPULATION: We hypothesize that administration of HAMS-AB will (i) improve the gut microbiome profile in humans with T1D, (ii) increase SCFA production, and (iii) improve β-cell health, β-cell function and overall glycemia. We propose a pilot randomized controlled cross-over trial of HAMS-AB in 12 youth with newly-diagnosed T1D. We will use state-of-the-art markers to profile the gut microbiome (using 16S rRNA sequencing), measure stool SCFA levels (using gas chromatography), asses β-cell stress/death (by measuring proinsulin to C-peptide ratios) and glycemia (assessed by continuous glucose monitoring and HbA1c measurements). RESULTS/ANTICIPATED RESULTS: We expect that the use of HAMS-AB in newly diagnosed youth with type 1 diabetes will alter the gut microbiome profile (thus increasing the number of fermenters and SCFA levels), β-cell function and glycemia in humans with T1D. DISCUSSION/SIGNIFICANCE OF IMPACT: Given the unknown long-term effects of immune-modulatory therapy on those at risk for or those diagnosed with T1D, the use of a prebiotic such as HAMS-AB offers a simple, safe, yet inexpensive and tolerated dietary alternative approach to mitigating disease.

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