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Anti-inflammatory effects of exendin-4, a glucagon-like peptide-1 analog, on human peripheral lymphocytes in patients with type 2 diabetes.

He L, Wong CK, Cheung KK, Yau HC, Fu A, Zhao HL, Leung KM, Kong AP, Wong GW, Chan PK, Xu G, Chan JC - J Diabetes Investig (2013)

Bottom Line: Experimental studies suggest that glucagon-like peptide (GLP-1) might have immunomodulating effects.These changes were attenuated by exendin-4, possibly through the suppression of p38 MAPK.These results suggest that exendin-4 might downregulate pro-inflammatory responses and reduce oxidative stress by suppressing MAPK signaling pathways in type 2 diabetes.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine and Therapeutics The Chinese University of Hong Kong Shatin Hong Kong SAR China.

ABSTRACT

Aims/introduction: Type 2 diabetes is characterized by dysregulation of immunity, oxidative stress and reduced incretin effects. Experimental studies suggest that glucagon-like peptide (GLP-1) might have immunomodulating effects. We hypothesize that GLP-1 receptor agonist, exendin-4, might reduce inflammatory response in type 2 diabetes.

Materials and methods: Using peripheral blood mononuclear cells (PBMC) sampled from 10 type 2 diabetes and 10 sex- and age-matched control subjects and supernatants from PBMC culture, the expression of phospho-mitogen activated protein kinase (MAPK) signaling pathways in CD4+ T helper lymphocytes and monocytes was analyzed using flow cytometry. Cytokines/chemokines and superoxide anion before and after treatment with exendin-4 were measured by cytometric bead array and chemiluminesence assay, respectively.

Results: Compared with control subjects, PBMC from type 2 diabetes patients showed activated MAPK (P38, c-Jun NH2-terminal protein kinase and extracellular signal-regulated kinase) signaling pathway, elevated superoxide anion, increased pro-inflammatory cytokines (tumor necrosis factor-α, interleukin-1β, interleukin-6) and chemokines (CCL5/regulated on activation normal T-cell expressed and secreted and CXCL10/interferon-γ-induced protein 10). These changes were attenuated by exendin-4, possibly through the suppression of p38 MAPK.

Conclusions: These results suggest that exendin-4 might downregulate pro-inflammatory responses and reduce oxidative stress by suppressing MAPK signaling pathways in type 2 diabetes.

No MeSH data available.


Related in: MedlinePlus

Effects of exendin‐4 on the ex vivo production of pro‐inflammatory cytokines of controls (CTL) and patients with type 2 diabetes. Peripheral blood mononuclear cells from controls and type 2 diabetes patients were pretreated with U0126 (U0126 10 μmol/L), SB203580 (SB 10 μmol/L) for 1 h followed by incubation with or without exendin‐4 (Ex4; 50 nmol/L) for 24 h. Release of (a) tumor necrosis factor (TNF)‐α, (b) interleukin (IL)‐1β and (c) IL‐6 were determined by cytometric bead array using flow cytometry. Dimethyl sulfoxide (DMSO) (0.1%) was used as the vehicle control. Results are presented with box‐and‐whisker plots. *P < 0.05.
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jdi12063-fig-0001: Effects of exendin‐4 on the ex vivo production of pro‐inflammatory cytokines of controls (CTL) and patients with type 2 diabetes. Peripheral blood mononuclear cells from controls and type 2 diabetes patients were pretreated with U0126 (U0126 10 μmol/L), SB203580 (SB 10 μmol/L) for 1 h followed by incubation with or without exendin‐4 (Ex4; 50 nmol/L) for 24 h. Release of (a) tumor necrosis factor (TNF)‐α, (b) interleukin (IL)‐1β and (c) IL‐6 were determined by cytometric bead array using flow cytometry. Dimethyl sulfoxide (DMSO) (0.1%) was used as the vehicle control. Results are presented with box‐and‐whisker plots. *P < 0.05.

Mentions: Previous studies reported elevated serum levels of inflammatory cytokines including TNF‐α, IL‐6, IL‐1β and IL‐6 in newly diagnosed type 2 diabetes patients17. In this experiment, after 24 h of incubation with PBMC culture, we observed significantly higher levels of inflammatory cytokines (TNF‐α, IL‐6 and IL‐1β) in PBMC supernatants from patients with type 2 diabetes than controls (Figure 1). Treatment with exendin‐4 (50 nmol/L), U0126 (specific inhibitor of ERK signaling pathway) and SB 203580 (specific inhibitor of p38 MAPK signaling pathway) for 24 h significantly reduced cytokine levels in PBMC supernatants from patients with type 2 diabetes (all P < 0.05), but not in control subjects (all P > 0.05).


Anti-inflammatory effects of exendin-4, a glucagon-like peptide-1 analog, on human peripheral lymphocytes in patients with type 2 diabetes.

He L, Wong CK, Cheung KK, Yau HC, Fu A, Zhao HL, Leung KM, Kong AP, Wong GW, Chan PK, Xu G, Chan JC - J Diabetes Investig (2013)

Effects of exendin‐4 on the ex vivo production of pro‐inflammatory cytokines of controls (CTL) and patients with type 2 diabetes. Peripheral blood mononuclear cells from controls and type 2 diabetes patients were pretreated with U0126 (U0126 10 μmol/L), SB203580 (SB 10 μmol/L) for 1 h followed by incubation with or without exendin‐4 (Ex4; 50 nmol/L) for 24 h. Release of (a) tumor necrosis factor (TNF)‐α, (b) interleukin (IL)‐1β and (c) IL‐6 were determined by cytometric bead array using flow cytometry. Dimethyl sulfoxide (DMSO) (0.1%) was used as the vehicle control. Results are presented with box‐and‐whisker plots. *P < 0.05.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4020234&req=5

jdi12063-fig-0001: Effects of exendin‐4 on the ex vivo production of pro‐inflammatory cytokines of controls (CTL) and patients with type 2 diabetes. Peripheral blood mononuclear cells from controls and type 2 diabetes patients were pretreated with U0126 (U0126 10 μmol/L), SB203580 (SB 10 μmol/L) for 1 h followed by incubation with or without exendin‐4 (Ex4; 50 nmol/L) for 24 h. Release of (a) tumor necrosis factor (TNF)‐α, (b) interleukin (IL)‐1β and (c) IL‐6 were determined by cytometric bead array using flow cytometry. Dimethyl sulfoxide (DMSO) (0.1%) was used as the vehicle control. Results are presented with box‐and‐whisker plots. *P < 0.05.
Mentions: Previous studies reported elevated serum levels of inflammatory cytokines including TNF‐α, IL‐6, IL‐1β and IL‐6 in newly diagnosed type 2 diabetes patients17. In this experiment, after 24 h of incubation with PBMC culture, we observed significantly higher levels of inflammatory cytokines (TNF‐α, IL‐6 and IL‐1β) in PBMC supernatants from patients with type 2 diabetes than controls (Figure 1). Treatment with exendin‐4 (50 nmol/L), U0126 (specific inhibitor of ERK signaling pathway) and SB 203580 (specific inhibitor of p38 MAPK signaling pathway) for 24 h significantly reduced cytokine levels in PBMC supernatants from patients with type 2 diabetes (all P < 0.05), but not in control subjects (all P > 0.05).

Bottom Line: Experimental studies suggest that glucagon-like peptide (GLP-1) might have immunomodulating effects.These changes were attenuated by exendin-4, possibly through the suppression of p38 MAPK.These results suggest that exendin-4 might downregulate pro-inflammatory responses and reduce oxidative stress by suppressing MAPK signaling pathways in type 2 diabetes.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine and Therapeutics The Chinese University of Hong Kong Shatin Hong Kong SAR China.

ABSTRACT

Aims/introduction: Type 2 diabetes is characterized by dysregulation of immunity, oxidative stress and reduced incretin effects. Experimental studies suggest that glucagon-like peptide (GLP-1) might have immunomodulating effects. We hypothesize that GLP-1 receptor agonist, exendin-4, might reduce inflammatory response in type 2 diabetes.

Materials and methods: Using peripheral blood mononuclear cells (PBMC) sampled from 10 type 2 diabetes and 10 sex- and age-matched control subjects and supernatants from PBMC culture, the expression of phospho-mitogen activated protein kinase (MAPK) signaling pathways in CD4+ T helper lymphocytes and monocytes was analyzed using flow cytometry. Cytokines/chemokines and superoxide anion before and after treatment with exendin-4 were measured by cytometric bead array and chemiluminesence assay, respectively.

Results: Compared with control subjects, PBMC from type 2 diabetes patients showed activated MAPK (P38, c-Jun NH2-terminal protein kinase and extracellular signal-regulated kinase) signaling pathway, elevated superoxide anion, increased pro-inflammatory cytokines (tumor necrosis factor-α, interleukin-1β, interleukin-6) and chemokines (CCL5/regulated on activation normal T-cell expressed and secreted and CXCL10/interferon-γ-induced protein 10). These changes were attenuated by exendin-4, possibly through the suppression of p38 MAPK.

Conclusions: These results suggest that exendin-4 might downregulate pro-inflammatory responses and reduce oxidative stress by suppressing MAPK signaling pathways in type 2 diabetes.

No MeSH data available.


Related in: MedlinePlus