Fasting and meal-stimulated residual beta cell function is positively associated with serum concentrations of proinflammatory cytokines and negatively associated with anti-inflammatory and regulatory cytokines in patients with longer term type 1 diabetes

Pham, Minh N.; Kolb, Hubert; Battelino, Tadej; Ludvigsson, Johnny; Pozzilli, Paolo; Zivehe, Fariba; Roden, Michael; Mandrup-Poulsen, Thomas; Schloot, Nanette C.

doi:10.1007/s00125-013-2883-3

Cited by 8 publications

(7 citation statements)

References 31 publications

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“…Nevertheless, our findings suggest that sCD25 concentrations could be used as markers for C-peptide loss, and sCD25 could be an informative marker to monitor in immunotherapeutic trials to intervene in the progression of the disease after diagnosis. Our results also add to the large body of literature that indicates a role for immune activation and proinflammatory cytokines, such as TNF-α, IL-1 and IL-6, in the promotion of beta cell death in type 1 diabetes [49]. Rather than sCD25 itself being causal, we think it likely that a raised sCD25 concentration in some patients is a downstream consequence of an active autoimmune inflammatory process.…”

Section: Discussionsupporting

confidence: 63%

Plasma concentrations of soluble IL-2 receptor α (CD25) are increased in type 1 diabetes and associated with reduced C-peptide levels in young patients

et al. 2013

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Aims/hypothesisType 1 diabetes is a common autoimmune disease that has genetic and environmental determinants. Variations within the IL2 and IL2RA (also known as CD25) gene regions are associated with disease risk, and variation in expression or function of these proteins is likely to be causal. We aimed to investigate if circulating concentrations of the soluble form of CD25, sCD25, an established marker of immune activation and inflammation, were increased in individuals with type 1 diabetes and if this was associated with the concentration of C-peptide, a measure of insulin production that reflects the degree of autoimmune destruction of the insulin-producing beta cells.MethodsWe used immunoassays to measure sCD25 and C-peptide in peripheral blood plasma from patient and control samples.ResultsWe identified that sCD25 was increased in patients with type 1 diabetes compared with controls and replicated this result in an independent set of 86 adult patient and 80 age-matched control samples (p = 1.17 × 10−3). In 230 patients under 20 years of age, with median duration-of-disease of 6.1 years, concentrations of sCD25 were negatively associated with C-peptide concentrations (p = 4.8 × 10−3).Conclusions/interpretationThe 25% increase in sCD25 in patients, alongside the inverse association between sCD25 and C-peptide, probably reflect the adverse effects of an on-going, actively autoimmune and inflammatory immune system on beta cell function in patients.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-013-3113-8) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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Section: Discussionsupporting

confidence: 63%

Plasma concentrations of soluble IL-2 receptor α (CD25) are increased in type 1 diabetes and associated with reduced C-peptide levels in young patients

et al. 2013

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“…Islet inflammation was found to persists when there was still substantial beta cell mass present [38]. Indeed, we found in longer term patients with type 1 diabetes a positive association of residual beta cell function with pro-inflammatory immune mediators IL-6 and TNFα, whereas increased concentrations of anti-inflammatory/regulatory immune mediators (Il-1RA, IL-10, transforming growth factor-ß1 and -ß2) were seen in patients with low serum C-peptide concentrations and assumed little residual beta cell mass [40].…”

Section: Discussionmentioning

confidence: 59%

The Systemic Immune Network in Recent Onset Type 1 Diabetes: Central Role of Interleukin-1 Receptor Antagonist (DIATOR Trial)

et al. 2013

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BackgroundThe hypothesis was tested that the systemic immune milieu in recent-onset type 1 diabetes is associated with residual beta cell function and other metabolic patient characteristics.Methods and FindingsAll patients (n = 89, 40% female) of the Diabetes and Atorvastatin (DIATOR) Trial were analyzed at recruitment, i.e. prior to receiving the study medication. Inclusion criteria were insulin dependent diabetes for 2 weeks to 3 months, age range 18–39 years, and islet cell autoantibodies. Blood samples were analyzed for 14 immune mediators by standard methods. Concentrations of all mediators correlated with at least one other mediator (p<0.05, Spearman correlation) giving rise to a network. Interleukin 1 receptor antagonist (IL1-RA) held a central position and was associated with both pro- and anti-inflammatory mediators. Further central elements were the pro-inflammatory mediators CRP and IL-6, the soluble adhesion molecules sICAM-1 and E-selectin, and MCP-4 which held a central position in the chemokine network. The two Th1-associated mediators IFNγ and IP-10 remained outside the network but correlated with each other. All correlations were positive (r = 0.25–0.72), i.e., high levels of pro-inflammatory mediators were accompanied by increased levels of anti-inflammatory mediators. IL-1RA was the only mediator associated with fasting and liquid mixed meal stimulated C-peptide concentrations (r = 0.31 and 0.24, p = 0.003 and 0.025, after adjustment for age, sex, BMI). There were associations between the immune mediator network and BMI (IL-1RA, CRP, IL-6, MCP-4, MIP-1ß) but few or no associations with HbA1c, insulin dose, lipid parameters, age or sex.ConclusionsIn patients with recent onset type 1 diabetes, systemic acute phase proteins, cytokines, chemokines and soluble adhesion molecules form a network. Among the few central elements IL-1RA has a dominant role. IL-1RA is associated with all other groups of mediators and is the only mediator which correlates (positively) with residual beta cell function.Trial registrationClinicalTrials.gov registration number: NCT00974740

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“…Hyperglycemia, which activates several reactions, including oxidative stress and chronic or subclinical inflammation, is clearly recognized as the primary player in diabetic endothelial dysfunction and DN (35–37). …”

Section: Discussionmentioning

confidence: 99%

l-Citrulline Protects from Kidney Damage in Type 1 Diabetic Mice

et al. 2013

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Rationale: Diabetic nephropathy (DN) is a major cause of end-stage renal disease, associated with endothelial dysfunction. Chronic supplementation of l-arginine (l-arg), the substrate for endothelial nitric oxide synthase (eNOS), failed to improve vascular function. l-Citrulline (l-cit) supplementation not only increases l-arg synthesis, but also inhibits cytosolic arginase I, a competitor of eNOS for the use of l-arg, in the vasculature.Aims: To investigate whether l-cit treatment reduces DN in streptozotocin (STZ)-induced type 1 diabetes (T1D) in mice and rats and to study its effects on arginase II (ArgII) function, the main renal isoform.Methods: STZ-C57BL6 mice received l-cit or vehicle supplemented in the drinking water. For comparative analysis, diabetic ArgII knock out mice and l-cit-treated STZ-rats were evaluated.Results: l-Citrulline exerted protective effects in kidneys of STZ-rats, and markedly reduced urinary albumin excretion, tubulo-interstitial fibrosis, and kidney hypertrophy, observed in untreated diabetic mice. Intriguingly, l-cit treatment was accompanied by a sustained elevation of tubular ArgII at 16 weeks and significantly enhanced plasma levels of the anti-inflammatory cytokine IL-10. Diabetic ArgII knock out mice showed greater blood urea nitrogen levels, hypertrophy, and dilated tubules than diabetic wild type (WT) mice. Despite a marked reduction in collagen deposition in ArgII knock out mice, their albuminuria was not significantly different from diabetic WT animals. l-Cit also restored nitric oxide/reactive oxygen species balance and barrier function in high glucose-treated monolayers of human glomerular endothelial cells. Moreover, l-cit also has the ability to establish an anti-inflammatory profile, characterized by increased IL-10 and reduced IL-1β and IL-12(p70) generation in the human proximal tubular cells.Conclusion: l-Citrulline supplementation established an anti-inflammatory profile and significantly preserved the nephron function during T1D.

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Fasting and meal-stimulated residual beta cell function is positively associated with serum concentrations of proinflammatory cytokines and negatively associated with anti-inflammatory and regulatory cytokines in patients with longer term type 1 diabetes

Cited by 8 publications

References 31 publications

Plasma concentrations of soluble IL-2 receptor α (CD25) are increased in type 1 diabetes and associated with reduced C-peptide levels in young patients

Plasma concentrations of soluble IL-2 receptor α (CD25) are increased in type 1 diabetes and associated with reduced C-peptide levels in young patients

The Systemic Immune Network in Recent Onset Type 1 Diabetes: Central Role of Interleukin-1 Receptor Antagonist (DIATOR Trial)

l-Citrulline Protects from Kidney Damage in Type 1 Diabetic Mice

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