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

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.Type 2 diabetes is a chronic disease with rapidly increasing prevalence, and patients with type 2 diabetes have an increased risk of developing coronary artery disease (CAD) (1,2). The coexistence of type 2 diabetes and CAD is considerable, and type 2 diabetes has been rated as an equivalent of CAD. In contrast, many patients with established CAD have type 2 diabetes or its pre-states (3). Thus, a high prevalence of impaired glucose tolerance (IGT) and unknown type 2 diabetes has been reported in patients with CAD with no previous diagnosis of diabetes (4–6). Abnormal glucose regulation (AGR) (impaired fasting glucose [IFG], IGT, or type 2 diabetes) is approximately twice as common among patients with myocardial infarction (MI) as in population-based controls (7), and the presence of AGR is a strong risk factor for new cardiovascular events after acute MI (3,8,9).The association between cardiovascular disease and hyperglycemia may be explained by an accumulation of cardiovascular risk factors associated with the metabolic syndrome in patients with AGR (10). It may, however, also relate to mechanisms triggered by hyperglycemia and insulin resistance leading to cardiovascular damage before the onset of overt diabetes (7,11). Moreover, experimental and clinical data have illuminated a role of inflammation in atherogenesis, and it has been suggested that atherosclerosis, type 2 diabetes, and the metabolic syndrome are multifactorial diseases characterized by chronic inflammation (12). However, the reasons for the association between AGR and atherosclerotic disorders are not fully understood.Activin A, a member of the transforming growth factor (TGF)-β superfamily (13), has been recognized as a multifunctional cytokine with roles in regulation of wound repair, cell differentiation, and inflammation, and growing evidence implicates a role for activin A in inflammatory disorders potentially mediating both inflammatory and anti-inflammatory effects (14). Activin A also has been suggested to be important for glucose homeostasis, at least partly through direct stimulatory effects on pancreatic β-cells (15). However, reports on activin A levels in patients with type 2 diabetes are few and include a small number of patients (16,17). Furthermore, there are only a few reports on activin A levels during acute coronary syndrome (ACS) and no reports on patients with ST-elevation MI (STEMI) exclusively. Moreover, no data exist on the association between activin A and AGR in patients with CAD.On the basis of the role of activin A in inflammation, atherogenesis, and glucose homeostasis, we investigated whether activin A could be related to glucose abnormalities associated with STEMI, potentially representing a counteracting mechanism in response to AGR. This hypothesis was investigated by different approaches, including studies in a well-characterized population with STEMI and experimental studies in endothelial cells and pancreatic β-cells.