Mineralocorticoid Receptor Activation in Vascular Insulin Resistance and Dysfunction

Abstract

Systemic insulin resistance is characterized by reduced insulin metabolic signaling and glucose intolerance. Mineralocorticoid receptors (MRs), the principal receptors for the hormone aldosterone, play an important role in regulating renal sodium handling and blood pressure. Recent studies suggest that MRs also exist in tissues outside the kidney, including vascular endothelial cells, smooth muscle cells, fibroblasts, perivascular adipose tissue, and immune cells. Risk factors, including excessive salt intake/salt sensitivity, hypertension, and obesity, can lead to the activation of vascular MRs to promote inflammation, oxidative stress, remodeling, and fibrosis, as well as cardiovascular stiffening and microcirculatory impairment. These pathophysiological changes are associated with a diminished ability of insulin to initiate appropriate intracellular signaling events, resulting in a reduced glucose uptake within the microcirculation and related vascular insulin resistance. Therefore, the pharmacological inhibition of MR activation provides a potential therapeutic option for improving vascular function, glucose uptake, and vascular insulin sensitivity. This review highlights recent experimental and clinical data that support the contribution of abnormal MR activation to the development of vascular insulin resistance and dysfunction.

Interplay of Angiotensin Peptides, Vasopressin, and Insulin in the Heart: Experimental and Clinical Evidence of Altered Interactions in Obesity and Diabetes Mellitus

“…Experiments on isolated pancreatic islets revealed that aldosterone acting on mineralocorticoid receptors (MR) enhances glucose-induced insulin secretion and ROS production. The activation of MR also decreased the sensitivity to insulin in adipocytes and in skeletal muscles [116], and promoted the development of inflammation, oxidative stress, lipid disorders, and insulin resistance, thereby impairing vascular insulin metabolic signaling [15,117,118].…”

Interaction of Vasopressin with Hormones of the Hypothalamo-Pituitary-Adrenal Axis: Significance for Therapeutic Strategies in Cardiovascular and Metabolic Diseases

“…Action of aldosterone on T channels is presumably indirect, because the gene CACNA1h, which is coding for the CaV3.2 T type channel does not possess mineralocorticoid response element (MRE). Increased formation of reactive oxygen species (ROS) and their involvement in the regulation of affinity of steroid hormones to MR receptors should be also taken into consideration [63][64][65][66]. In the cardiovascular system the genomic and nongenomic effects of aldosterone are also modified by angiotensin II (Ang II) [35].…”

Gitelman syndrome combined with diabetes mellitus: A case report and literature review

“…Studies indicate that aldosterone excess can lead to insulin resistance. [32][33][34] Although metformin is clinically employed to address insulin resistance, given the patient's concurrent diabetic nephropathy and elevated lactate levels (2 mmol/L), Considering the potential risk of lactic acidosis, [35] the inclusion of metformin in this treatment has been withheld. SGLT-2 inhibitors lower blood glucose by inhibiting renal proximal tubular reabsorption of glucose and sodium, potentially exacerbating the patient's hypotensive symptoms (101/65 mm Hg).…”