IL-1β Inhibition in Cardiovascular Complications Associated to Diabetes Mellitus

Abstract

Diabetes mellitus (DM) is a chronic disease that affects nowadays millions of people worldwide. In adults, type 2 diabetes mellitus (T2DM) accounts for the majority of all diagnosed cases of diabetes. The course of the T2DM is characterized by insulin resistance and a progressive loss of β-cell mass. DM is associated with a number of related complications, among which cardiovascular complications and atherosclerosis are the main cause of morbidity and mortality in patients suffering from the disease. DM is acknowledged as a low-grade chronic inflammatory state characterized by the over-secretion of pro-inflammatory cytokines, including interleukin (IL)-1β, which reinforce inflammatory signals thus contributing to the development of complications. In this context, the pharmacological approaches to treat diabetes should not only correct hyperglycaemia, but also attenuate inflammation and prevent the development of metabolic and cardiovascular complications. Over the last years, novel biological drugs have been developed to antagonize the pathophysiological actions of IL-1β. The drugs currently used in clinical practice are anakinra, a recombinant form of the naturally occurring IL-1 receptor antagonist, the soluble decoy receptor rilonacept and the monoclonal antibodies canakinumab and gevokizumab. This review will summarize the main experimental and clinical findings obtained with pharmacological IL-1β inhibitors in the context of the cardiovascular complications of DM, and discuss the perspectives of IL-1β inhibitors as novel therapeutic tools for treating these patients.

Keywords: cardiovascular complications; diabetes; inflammation; interleukin-1 inhibitors; interleukin-1β.

FIGURE 1

Mechanisms by which IL-1β may directly promote vascular dysfunction and their inhibition by the IL-1Ra recombinant analog anakinra. In vascular smooth muscle cells (VSMC), IL-1β synergizes with extracellular high glucose (HG) to exacerbate pro-inflammatory signaling. iNOS, inducible nitric oxide synthase; Glut1, glucose transporter 1; IL-1R, interleukin-1 receptor; NADPH ox., NADPH oxidase; PPP, pentose phosphate pathway; ROS, reactive oxygen species.

FIGURE 2

IL-1β activation in cardiac damage. After cardiac injury such as AMI or I/R, exacerbated IL-1β signaling can induce NFκB and AP-1 activation and subsequent increase of pro-hypertrophic, contractile, inflammatory, apoptosis/necrosis, and fibrotic genes for autocrine and paracrine responses. These effects are reinforced in the diabetic myocardium, and can be stimulated by TNFα and TLRs signaling. However, some drugs may specifically target IL-1β actions by NLRP3, IL-1β, and IL-1R blockade. ECM, extra cellular matrix proteins.