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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

Circulating LIGHT levels in type 2 diabetes mellitus. (a) Plasma levels of LIGHT in 191 Italian type 2 diabetes patients and 32 healthy controls. (b, c) Correlations between plasma LIGHT levels and fasting glucose (b) and HbA1c (c). (d) Plasma levels of LIGHT in 40 Norwegian type 2 diabetes mellitus patients and 32 healthy controls. Correlations are given as Pearsons r between log10-transformed values while box plots represent median and 25th and 75th percentiles. The Mann–Whitney U test was used to compare patients and controls. **p < 0.01 vs controls. Ctrl, controls; DM, diabetic group
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Fig1: Circulating LIGHT levels in type 2 diabetes mellitus. (a) Plasma levels of LIGHT in 191 Italian type 2 diabetes patients and 32 healthy controls. (b, c) Correlations between plasma LIGHT levels and fasting glucose (b) and HbA1c (c). (d) Plasma levels of LIGHT in 40 Norwegian type 2 diabetes mellitus patients and 32 healthy controls. Correlations are given as Pearsons r between log10-transformed values while box plots represent median and 25th and 75th percentiles. The Mann–Whitney U test was used to compare patients and controls. **p < 0.01 vs controls. Ctrl, controls; DM, diabetic group

Mentions: Plasma levels of LIGHT were significantly raised in 191 patients with type 2 diabetes mellitus (Italian cohort) compared with 32 age- and sex-matched healthy controls (Fig. 1a). Within the Italian cohort, LIGHT was significantly correlated with glycaemic control as assessed by fasting plasma glucose (r = 0.27, p = 0.001; Fig. 1b) and HbA1c levels (r = 0.22, p < 0.006; Fig. 1c). When the patients were stratified according to time since diagnosis (≤1 year [n = 42], 2–9 years [n = 43] and ≥ 10 years [n = 40]), there was a gradual increase in LIGHT levels according to disease duration (ESM Fig. 1). However, whereas these three groups are comparable for most of the clinical characteristics, they were different in relation to age, ongoing aspirin treatment and glucose-lowering medication (ESM Table 1), weakening the impact of the association between LIGHT and disease duration.Fig. 1


LIGHT/TNFSF14 is increased in patients with type 2 diabetes mellitus and promotes islet cell dysfunction and endothelial cell inflammation in vitro
Circulating LIGHT levels in type 2 diabetes mellitus. (a) Plasma levels of LIGHT in 191 Italian type 2 diabetes patients and 32 healthy controls. (b, c) Correlations between plasma LIGHT levels and fasting glucose (b) and HbA1c (c). (d) Plasma levels of LIGHT in 40 Norwegian type 2 diabetes mellitus patients and 32 healthy controls. Correlations are given as Pearsons r between log10-transformed values while box plots represent median and 25th and 75th percentiles. The Mann–Whitney U test was used to compare patients and controls. **p < 0.01 vs controls. Ctrl, controls; DM, diabetic group
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Related In: Results  -  Collection

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Fig1: Circulating LIGHT levels in type 2 diabetes mellitus. (a) Plasma levels of LIGHT in 191 Italian type 2 diabetes patients and 32 healthy controls. (b, c) Correlations between plasma LIGHT levels and fasting glucose (b) and HbA1c (c). (d) Plasma levels of LIGHT in 40 Norwegian type 2 diabetes mellitus patients and 32 healthy controls. Correlations are given as Pearsons r between log10-transformed values while box plots represent median and 25th and 75th percentiles. The Mann–Whitney U test was used to compare patients and controls. **p < 0.01 vs controls. Ctrl, controls; DM, diabetic group
Mentions: Plasma levels of LIGHT were significantly raised in 191 patients with type 2 diabetes mellitus (Italian cohort) compared with 32 age- and sex-matched healthy controls (Fig. 1a). Within the Italian cohort, LIGHT was significantly correlated with glycaemic control as assessed by fasting plasma glucose (r = 0.27, p = 0.001; Fig. 1b) and HbA1c levels (r = 0.22, p < 0.006; Fig. 1c). When the patients were stratified according to time since diagnosis (≤1 year [n = 42], 2–9 years [n = 43] and ≥ 10 years [n = 40]), there was a gradual increase in LIGHT levels according to disease duration (ESM Fig. 1). However, whereas these three groups are comparable for most of the clinical characteristics, they were different in relation to age, ongoing aspirin treatment and glucose-lowering medication (ESM Table 1), weakening the impact of the association between LIGHT and disease duration.Fig. 1

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