Activin A levels are associated with abnormal glucose regulation in patients with myocardial infarction: potential counteracting effects of activin A on inflammation

Abstract

Objective: On the basis of the role of activin A in inflammation, atherogenesis, and glucose homeostasis, we investigated whether activin A could be related to glucometabolic abnormalities in patients with acute myocardial infarction (MI).

Research design and methods: Activin A measurement and oral glucose tolerance tests (OGTTs) were performed in patients (n = 115) with acute MI, without previously known diabetes, and repeated after 3 months. Release of activin A and potential anti-inflammatory effects of activin A were measured in human endothelial cells. Activin A effects on insulin secretion and inflammation were tested in human pancreatic islet cells.

Results: 1) In patients with acute MI, serum levels of activin A were significantly higher in those with abnormal glucose regulation (AGR) compared with those with normal glucose regulation. Activin A levels were associated with the presence of AGR 3 months later (adjusted odds ratio 5.1 [95% CI 1.73-15.17], P = 0.003). 2) In endothelial cells, glucose enhanced the release of activin A, whereas activin A attenuated the release of interleukin (IL)-8 and enhanced the mRNA levels of the antioxidant metallothionein. 3) In islet cells, activin A attenuated the suppressive effect of inflammatory cytokines on insulin release, counteracted the ability of these inflammatory cytokines to induce mRNA expression of IL-8, and induced the expression of transforming growth factor-β.

Conclusions: We found a significant association between activin A and newly detected AGR in patients with acute MI. Our in vitro findings suggest that this association represents a counteracting mechanism to protect against inflammation, hyperglycemia, and oxidative stress.

FIG. 1.

Circulating activin A in patients with STEMI. Serum levels of activin A measured in patients with STEMI (n = 115) the first morning after primary PCI and in a stable phase after 3 months. Serum levels of activin A from patients (n = 72) with stable CAD are shown for comparison. Data are mean ± SEM.

FIG. 2.

Association between activin A and AGR. Activin A was measured in-hospital in patients with acute STEMI, classified 3 months later by an OGTT into AGR and normal glucose regulation. ORs of having AGR by quartiles of activin A are shown (P for trend; P = 0.012). The median value (arrow) was used as the cutoff for dichotomizing activin A into high and low levels.

FIG. 3.

Association between activin A levels and glucometabolic parameters during an OGTT. An OGTT was performed in stable patients (n = 46) 3 months after an acute STEMI. Glucose (A), insulin (B), and C-peptide (C) levels, measured 2 hours after glucose loading, in patients with high (≥75th percentile, 0.302 ng/mL) and low (<75th percentile) activin A measured at the same time point. Data are mean ± SEM.

FIG. 4.

Interaction between activin A and endothelial cells.A: The effect of various concentrations of glucose, insulin, or a combination thereof on activin A levels in HUVEC supernatants after culturing for 48 h as assessed by EIA measurements. Data are mean ± SEM (n = 4). *P < 0.05, **P < 0.01, and ***P < 0.001 vs. no glucose (two left panels). *P < 0.05 and **P < 0.01 vs. no insulin. †P < 0.05 vs. 5 nmol/L insulin (right panel). The effect of different concentrations of activin A on the spontaneous and IL-1β–stimulated (5 ng/mL) release of IL-8 (B) and the unstimulated expression of metallothionein (C) after culturing for 24 and 4 h, respectively. IL-8 was measured by EIA, and metallothionein was assessed by RT-PCR in relation to the control gene β-actin. Data are mean ± SEM (n = 5). *P < 0.05 vs. unstimulated (or IL-1β–stimulated) cells. MT, metallothionein.

FIG. 5.

Effects of activin A in human pancreatic islet cells. The effect of activin A (100 ng/mL), a mixture of inflammatory cytokines (IL-1β [10 ng/mL], IFN-γ [50 ng/mL], and TNF-α [10 ng/mL]), or a combination thereof on the capacity for glucose-stimulated insulin release, expressed as insulin stimulation index (culture time 1 h after determination of basal insulin secretion, A), and on mRNA levels of IL-8, IL-1β, monocyte chemoattractant protein-1, and TGF-β (culture time 24 h, B) in human pancreatic islet cells. mRNA was assessed by RT-PCR in relation to the control gene β-actin. Data are mean ± SEM (n = 4–6). *P < 0.05 and ***P < 0.001 vs. inflammatory cytokines without activin A. †P < 0.05 vs. control cells (vehicle). Act A, activin A; Ctr, control; Infl, inflammatory cytokines; MCP, monocyte chemoattractant protein.