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LIGHT/TNFSF14 is increased in patients with type 2 diabetes mellitus and promotes islet cell dysfunction and endothelial cell inflammation in vitro

View Article: PubMed Central - PubMed

ABSTRACT

Aims/hypothesis: Activation of inflammatory pathways is involved in the pathogenesis of type 2 diabetes mellitus. On the basis of its role in vascular inflammation and in metabolic disorders, we hypothesised that the TNF superfamily (TNFSF) member 14 (LIGHT/TNFSF14) could be involved in the pathogenesis of type 2 diabetes mellitus.

Methods: Plasma levels of LIGHT were measured in two cohorts of type 2 diabetes mellitus patients (191 Italian and 40 Norwegian). Human pancreatic islet cells and arterial endothelial cells were used to explore regulation and relevant effects of LIGHT in vitro.

Results: Our major findings were: (1) in both diabetic cohorts, plasma levels of LIGHT were significantly raised compared with sex- and age-matched healthy controls (n = 32); (2) enhanced release from activated platelets seems to be an important contributor to the raised LIGHT levels in type 2 diabetes mellitus; (3) in human pancreatic islet cells, inflammatory cytokines increased the release of LIGHT and upregulated mRNA and protein levels of the LIGHT receptors lymphotoxin β receptor (LTβR) and TNF receptor superfamily member 14 (HVEM/TNFRSF14); (4) in these cells, LIGHT attenuated the insulin release in response to high glucose at least partly via pro-apoptotic effects; and (5) in human arterial endothelial cells, glucose boosted inflammatory response to LIGHT, accompanied by an upregulation of mRNA levels of HVEM (also known as TNFRSF14) and LTβR (also known as LTBR).

Conclusions/interpretation: Our findings show that patients with type 2 diabetes mellitus are characterised by increased plasma LIGHT levels. Our in vitro findings suggest that LIGHT may contribute to the progression of type 2 diabetes mellitus by attenuating insulin secretion in pancreatic islet cells and by contributing to vascular inflammation.

Electronic supplementary material: The online version of this article (doi:10.1007/s00125-016-4036-y) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

No MeSH data available.


Related in: MedlinePlus

Release of LIGHT from platelets and PBMCs. (a) The spontaneous release of LIGHT in PRP from seven patients with type 2 diabetes mellitus (grey bars, Norwegian cohort) and six healthy controls (white bars). (b, c) The release of LIGHT in unstimulated PBMCs (white bars) and PBMCs stimulated with phytohaemagglutinin (PHA; 20 μg/ml, grey bars) after culturing for 20 h (b) and 48 h (c) in the same individuals as in (a). The Mann–Whitney U test was used to compare patients and healthy controls (a) and Wilcoxon signed rank test to compare PHA-stimulated and unstimulated cells (b, c). *p < 0.05 and **p < 0.01. DM, diabetic group
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Fig2: Release of LIGHT from platelets and PBMCs. (a) The spontaneous release of LIGHT in PRP from seven patients with type 2 diabetes mellitus (grey bars, Norwegian cohort) and six healthy controls (white bars). (b, c) The release of LIGHT in unstimulated PBMCs (white bars) and PBMCs stimulated with phytohaemagglutinin (PHA; 20 μg/ml, grey bars) after culturing for 20 h (b) and 48 h (c) in the same individuals as in (a). The Mann–Whitney U test was used to compare patients and healthy controls (a) and Wilcoxon signed rank test to compare PHA-stimulated and unstimulated cells (b, c). *p < 0.05 and **p < 0.01. DM, diabetic group

Mentions: Platelets are known as a cellular source of LIGHT in plasma [5] and, as shown in Fig. 2a, platelets (i.e. PRP) from patients with type 2 diabetes mellitus (n = 7) spontaneously released a significantly higher amount of LIGHT than platelets from healthy controls (n = 6) after both 10 and 90 min incubations. Based on plasma concentrations (∼15–25 pg/ml), these data suggest that platelets are an important cellular source of circulating LIGHT levels in our type 2 diabetes mellitus cohorts. In the Italian cohort, we previously measured urinary 11-dehydro-TXB2 excretion rate and soluble CD40 ligand (sCD40L) as markers of platelet activation [14]; both variables were correlated with plasma levels of LIGHT (r = 0.035, p = 0.055 and r = 0.277, p = 0.001, respectively), further supporting a link between platelet activation and circulating LIGHT levels. Somewhat surprisingly, however, there was no difference in LIGHT level between those who were treated with aspirin and those who were not in either the Italian cohort (median [25th–75th percentile]: 21.8 [15.3–43.7] pg/ml vs 24.1 [14.4–56.7] pg/ml, p = 0.91, aspirin users [n = 94] and non-users [97], respectively) or the Norwegian cohort (11.7 [10.0–19.2] pg/ml vs 12.6 [11.0–16.3] pg/ml, aspirin users [n = 17] and non-users [n = 23], respectively).Fig. 2


LIGHT/TNFSF14 is increased in patients with type 2 diabetes mellitus and promotes islet cell dysfunction and endothelial cell inflammation in vitro
Release of LIGHT from platelets and PBMCs. (a) The spontaneous release of LIGHT in PRP from seven patients with type 2 diabetes mellitus (grey bars, Norwegian cohort) and six healthy controls (white bars). (b, c) The release of LIGHT in unstimulated PBMCs (white bars) and PBMCs stimulated with phytohaemagglutinin (PHA; 20 μg/ml, grey bars) after culturing for 20 h (b) and 48 h (c) in the same individuals as in (a). The Mann–Whitney U test was used to compare patients and healthy controls (a) and Wilcoxon signed rank test to compare PHA-stimulated and unstimulated cells (b, c). *p < 0.05 and **p < 0.01. DM, diabetic group
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5016561&req=5

Fig2: Release of LIGHT from platelets and PBMCs. (a) The spontaneous release of LIGHT in PRP from seven patients with type 2 diabetes mellitus (grey bars, Norwegian cohort) and six healthy controls (white bars). (b, c) The release of LIGHT in unstimulated PBMCs (white bars) and PBMCs stimulated with phytohaemagglutinin (PHA; 20 μg/ml, grey bars) after culturing for 20 h (b) and 48 h (c) in the same individuals as in (a). The Mann–Whitney U test was used to compare patients and healthy controls (a) and Wilcoxon signed rank test to compare PHA-stimulated and unstimulated cells (b, c). *p < 0.05 and **p < 0.01. DM, diabetic group
Mentions: Platelets are known as a cellular source of LIGHT in plasma [5] and, as shown in Fig. 2a, platelets (i.e. PRP) from patients with type 2 diabetes mellitus (n = 7) spontaneously released a significantly higher amount of LIGHT than platelets from healthy controls (n = 6) after both 10 and 90 min incubations. Based on plasma concentrations (∼15–25 pg/ml), these data suggest that platelets are an important cellular source of circulating LIGHT levels in our type 2 diabetes mellitus cohorts. In the Italian cohort, we previously measured urinary 11-dehydro-TXB2 excretion rate and soluble CD40 ligand (sCD40L) as markers of platelet activation [14]; both variables were correlated with plasma levels of LIGHT (r = 0.035, p = 0.055 and r = 0.277, p = 0.001, respectively), further supporting a link between platelet activation and circulating LIGHT levels. Somewhat surprisingly, however, there was no difference in LIGHT level between those who were treated with aspirin and those who were not in either the Italian cohort (median [25th–75th percentile]: 21.8 [15.3–43.7] pg/ml vs 24.1 [14.4–56.7] pg/ml, p = 0.91, aspirin users [n = 94] and non-users [97], respectively) or the Norwegian cohort (11.7 [10.0–19.2] pg/ml vs 12.6 [11.0–16.3] pg/ml, aspirin users [n = 17] and non-users [n = 23], respectively).Fig. 2

View Article: PubMed Central - PubMed

ABSTRACT

Aims/hypothesis: Activation of inflammatory pathways is involved in the pathogenesis of type 2 diabetes mellitus. On the basis of its role in vascular inflammation and in metabolic disorders, we hypothesised that the TNF superfamily (TNFSF) member 14 (LIGHT/TNFSF14) could be involved in the pathogenesis of type 2 diabetes mellitus.

Methods: Plasma levels of LIGHT were measured in two cohorts of type 2 diabetes mellitus patients (191 Italian and 40 Norwegian). Human pancreatic islet cells and arterial endothelial cells were used to explore regulation and relevant effects of LIGHT in vitro.

Results: Our major findings were: (1) in both diabetic cohorts, plasma levels of LIGHT were significantly raised compared with sex- and age-matched healthy controls (n&thinsp;=&thinsp;32); (2) enhanced release from activated platelets seems to be an important contributor to the raised LIGHT levels in type 2 diabetes mellitus; (3) in human pancreatic islet cells, inflammatory cytokines increased the release of LIGHT and upregulated mRNA and protein levels of the LIGHT receptors lymphotoxin &beta; receptor (LT&beta;R) and TNF receptor superfamily member 14 (HVEM/TNFRSF14); (4) in these cells, LIGHT attenuated the insulin release in response to high glucose at least partly via pro-apoptotic effects; and (5) in human arterial endothelial cells, glucose boosted inflammatory response to LIGHT, accompanied by an upregulation of mRNA levels of HVEM (also known as TNFRSF14) and LT&beta;R (also known as LTBR).

Conclusions/interpretation: Our findings show that patients with type 2 diabetes mellitus are characterised by increased plasma LIGHT levels. Our in vitro findings suggest that LIGHT may contribute to the progression of type 2 diabetes mellitus by attenuating insulin secretion in pancreatic islet cells and by contributing to vascular inflammation.

Electronic supplementary material: The online version of this article (doi:10.1007/s00125-016-4036-y) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

No MeSH data available.


Related in: MedlinePlus