Susceptibility to Fatty Acid-Induced β-Cell Dysfunction Is Enhanced in Prediabetic Diabetes-Prone BioBreeding Rats: A Potential Link Between β-Cell Lipotoxicity and Islet Inflammation

β-Cell lipotoxicity is thought to play an important role in the development of type 2 diabetes. However, no study has examined its role in type 1 diabetes, which could be clinically relevant for slow-onset type 1 diabetes. Reports of enhanced cytokine toxicity in fat-laden islets are consistent with the hypothesis that lipid and cytokine toxicity may be synergistic. Thus, β-cell lipotoxicity could be enhanced in models of autoimmune diabetes. To determine this, we examined the effects of prolonged free fatty acids elevation on β-cell secretory function in the prediabetic diabetes-prone BioBreeding (dp-BB) rat, its diabetes-resistant BioBreeding (dr-BB) control, and normal Wistar-Furth (WF) rats. Rats received a 48-h iv infusion of saline or Intralipid plus heparin (IH) (to elevate free fatty acid levels ∼2-fold) followed by hyperglycemic clamp or islet secretion studies ex vivo. IH significantly decreased β-cell function, assessed both by the disposition index (insulin secretion corrected for IH-induced insulin resistance) and in isolated islets, in dp-BB, but not in dr-BB or WF, rats, and the effect of IH was inhibited by the antioxidant N-acetylcysteine. Furthermore, IH significantly increased islet cytokine mRNA and plasma cytokine levels (monocyte chemoattractant protein-1 and IL-10) in dp-BB, but not in dr-BB or WF, rats. All dp-BB rats had mononuclear infiltration of islets, which was absent in dr-BB and WF rats. In conclusion, the presence of insulitis was permissive for IH-induced β-cell dysfunction in the BB rat, which suggests a link between β-cell lipotoxicity and islet inflammation.

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Rapid Point-of-Care Test for Determination of C-Peptide Levels

Journal of Diabetes Science and Technology ◽

10.1177/1932296821995557 ◽

2021 ◽

pp. 193229682199555

Author(s):

Paturi V. Rao ◽

Eric Bean ◽

Dhanalakshmi Nair-Schaef ◽

Siting Chen ◽

Steven C. Kazmierczak ◽

...

Keyword(s):

Type 1 Diabetes ◽

Cell Function ◽

Late Onset ◽

Autoimmune Diabetes ◽

Point Of Care ◽

Cell Mass ◽

Hepatic Clearance ◽

Β Cell ◽

C Peptide

C-peptide is co-secreted with insulin and is not subject to hepatic clearance and thus reflects functional β-cell mass. Assessment of C-peptide levels can identify individuals at risk for or with type 1 diabetes with residual β-cell function in whom β cell-sparing interventions can be evaluated, and can aid in distinguishing type 2 diabetes from Latent Autoimmune Diabetes in Adults and late-onset type 1 diabetes. To facilitate C-peptide testing, we describe a quantitative point-of-care C-peptide test. C-peptide levels as low as 0.2 ng/ml were measurable in a fingerstick sample, and the test was accurate over a range of 0.17 to 12.0 ng/ml. This test exhibited a correlation of r = 0.98 with a high-sensitivity commercial ELISA assay and a correlation of r = 0.90 between matched serum and fingerstick samples.

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Neutrophil elastase triggers the development of autoimmune diabetes by exacerbating innate immune responses in pancreatic islets of non-obese diabetic mice

Clinical Science ◽

10.1042/cs20200021 ◽

2020 ◽

Vol 134 (13) ◽

pp. 1679-1696 ◽

Cited By ~ 1

Author(s):

Lingling Shu ◽

Ling Zhong ◽

Yang Xiao ◽

Xiaoping Wu ◽

Yang Liu ◽

...

Keyword(s):

Type 1 Diabetes ◽

Neutrophil Elastase ◽

Autoimmune Diabetes ◽

Nod Mice ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells ◽

Islet Inflammation ◽

The Impact

Abstract Type 1 diabetes is an autoimmune disease resulted from self-destruction of insulin-producing pancreatic β cells. However, the pathological pathways that trigger the autoimmune destruction remain poorly understood. Clinical studies have demonstrated close associations of neutrophils and neutrophil elastase (NE) with β-cell autoimmunity in patients with Type 1 diabetes. The present study aims to investigate the impact of NE inhibition on development of autoimmune diabetes in NOD mice. NE pharmacological inhibitor (sivelestat) or biological inhibitor (elafin) was supplemented into NOD mice to evaluate their effects on islet inflammation and diabetogenesis. The impact of NE inhibition on innate and adaptive immune cells was measured with flow cytometry and immunohistochemistry. A significant but transient increase in neutrophil infiltration accompanied with elevated NE activity was observed in the neonatal period of NOD mice. Treatment of NOD mice with sivelestat or elafin at the early age led to a marked reduction in spontaneous development of insulitis and autoimmune diabetes. Mechanistically, inhibition of NE significantly attenuated infiltration of macrophages and islet inflammation, thus ameliorating cytotoxic T cell-mediated autoimmune attack of pancreatic β cells. In vitro studies showed that NE directly induced inflammatory responses in both min6 β cells and RAW264.7 macrophages, and promoted macrophage migration. These findings support an important role of NE in triggering the onset and progression of β-cell autoimmunity, and suggest that pharmacological inhibition of NE may represent a promising therapeutic strategy for treatment of autoimmune diabetes.

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Faculty Opinions recommendation of Anti-thymocyte globulin/G-CSF treatment preserves β cell function in patients with established type 1 diabetes.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725276356.793502829 ◽

2015 ◽

Author(s):

Carla Greenbaum ◽

Sandra Lord

Keyword(s):

Type 1 Diabetes ◽

Cell Function ◽

Β Cell ◽

Β Cell Function

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Association of T-cell reactivity with β-cell function in recent onset type 1 diabetes patients

Journal of Autoimmunity ◽

10.1016/j.jaut.2009.08.004 ◽

2010 ◽

Vol 34 (2) ◽

pp. 127-135 ◽

Cited By ~ 27

Author(s):

Christian Pfleger ◽

Guido Meierhoff ◽

Hubert Kolb ◽

Nanette C. Schloot

Keyword(s):

Type 1 Diabetes ◽

T Cell ◽

Cell Function ◽

Β Cell ◽

Cell Reactivity ◽

Recent Onset ◽

Onset Type ◽

Β Cell Function ◽

T Cell Reactivity

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Autoreactive T effector memory differentiation mirrors β cell function in type 1 diabetes

Journal of Clinical Investigation ◽

10.1172/jci120555 ◽

2018 ◽

Vol 128 (8) ◽

pp. 3460-3474 ◽

Cited By ~ 21

Author(s):

Lorraine Yeo ◽

Alyssa Woodwyk ◽

Sanjana Sood ◽

Anna Lorenc ◽

Martin Eichmann ◽

...

Keyword(s):

Type 1 Diabetes ◽

Cell Function ◽

Effector Memory ◽

Β Cell ◽

Β Cell Function ◽

Memory Differentiation

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Residual β-cell function after 10 years of autoimmune type 1 diabetes: prevalence, possible determinants, and implications for metabolism

Annals of Translational Medicine ◽

10.21037/atm-20-7471 ◽

2021 ◽

Vol 9 (8) ◽

pp. 650-650

Author(s):

Jin Cheng ◽

Min Yin ◽

Xiaohan Tang ◽

Xiang Yan ◽

Yuting Xie ◽

...

Keyword(s):

Type 1 Diabetes ◽

Cell Function ◽

Diabetes Prevalence ◽

Β Cell ◽

Β Cell Function

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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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