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.

Increases in circulating levels of ketone bodies and cardiovascular protection with SGLT2 inhibitors: Is low‐grade inflammation the neglected component?

“…Overall, the cumulative anti‐inflammatory effect of SGLT2 inhibitors could be the result of four possible mechanisms: (1) increased plasma levels of anti‐inflammatory ketone bodies, such as BHB; (2) decreased interfacing of immune cells with glucose; (3) decreased secretion of insulin; and (4) decreased circulating levels of uric acid. These mechanisms are likely to be complementary, rather than mutually exclusive, all converging on one primary target, that is, IL‐1β, a major cytokine with a recognized role in the development of atherosclerosis and CV disease (Figure ). Finally, a glycaemia‐independent, molecule‐intrinsic, anti‐inflammatory mechanism has been proposed for canagliflozin and dapagliflozin, as has been shown in vitro in vascular endothelial cells and cardiofibroblast …”

“…For instance, relevant preclinical models indicate a potent anti‐inflammatory effect of BHB, and observational studies in patients subjected to ketogenic diets (KDs) are consistent with this observation . Accordingly, low‐grade inflammation (LGI) is a recognized factor that contributes to the development and progression of atherosclerosis and is more generally a relevant risk factor for CV disease and mortality . LGI is defined as a chronic, sterile, cold, systemic and multifactorial pro‐inflammatory status .…”

The Modifying Impact of Long-Term Endurance Training on Inflammatory Cytokine IL-1B Level and VO2max in Premenopausal Women with Abdominal Obesity

“…Besides inflammatory and respiratory diseases, inflammatory cytokines are also related to metabolic abnormalities, affecting obesity and body fat. Therefore, an increase in systematic levels of cytokines causes an increase in insulin resistance and glucose homeostasis disorders (6).…”

Diabetes mellitus tipo 2 y cardiopatía isquémica: fisiopatología, regulación génica y futuras opciones terapéuticas

“…[7][8][9] Sin embargo, se ha postulado que las personas con DM2 son propensas a las consecuencias asociadas a la disfunción endotelial. Esto implicaría un efecto potenciador entre DM2 y disfunción endotelial en la génesis y desarrollo de la cardiopatía isquémica [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] (Figura 1). Desde un punto de vista clínico, la detección de la interacción entre los factores de riesgo es importante porque identifica los objetivos terapéuticos clave, por tanto, las intervenciones dirigidas a dichos factores de riesgo son potencialmente más eficaces que el tratamiento de los factores de riesgo que no interactúan 9,11,16 .…”

“…Tanto la hiperglicemia como los AGEs se asocian con el incremento en la activación de los monocitos circulantes. Los monocitos cultivados en altas concentraciones de glucosa o aquellos aislados de pacientes con pobre control glicémico se encuentran en un estado activado e inflamatorio, lo que se evidencia con la sobreexpresión de citoquinas como interleukinas (IL) 1β e IL 6 junto a la expresión de moléculas quimoatractantes de monocitos 21,22 . Estos cambios inflamatorios se asocian con la activación de la proteína kinasa C (PKC), activación del NF-kB y el aumento de la generación de superóxido, los tres son responsables del estrés oxidativo que ocurre en presencia de la hiperglicemia.…”