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.
Excess blood lipids increase the total intramyocellular (IMC) lipid content and ectopic fat storage resulting in lipotoxicity and insulin resistance in skeletal muscle, which is one of the main targets of insulin whose action is central for the maintenance of glucose homeostasis. Consumption of a diet high in fat and refined sugars, a Western Diet (WD), has been shown to activate mineralocorticoid receptors (MRs) to promote insulin resistance. However, our understanding of the precise mechanisms by which enhanced MR activation promotes skeletal muscle insulin resistance remains unclear. In this study we investigated the roles and mechanisms by which enhanced MR signaling in soleus muscle promotes ectopic lipid accumulation and related insulin resistance in diet-induced obesity. Six week-old C57BL6J mice were fed either a mouse chow diet or WD with or without spironolactone (1 mg/kg/day) for 16 weeks. Spironolactone attenuated 16 weeks of WD - induced in vivo glucose intolerance and improved soleus insulin metabolic signaling (protein kinase B and AMP kinase α pathways). Improved insulin sensitivity was accompanied by increased Glut-4 expression in conjunction with decreased IMC lipid content and reduced free fatty acid (FFA) levels and CD36 expression in soleus skeletal muscle tissue. Related to this, miR-99a was identified to negatively target CD36(www.targetscan.org/vert_72/) and elevated CD36 induced excessive FFA uptake, ectopic lipid accumulation, as well as systemic and tissue insulin resistance. Furthermore, in skeletal muscle cells spironolactone prevented enhanced MR signaling mediated reduction of miR-99a and related increased CD36. These data indicate that inhibition of MR activation with spironolactone reversed diet - induced reduction of miR-99a, thereby reducing CD36 expression, leading to reduced IMC lipid content and improved soleus insulin sensitivity. Presentation: Saturday, June 11, 2022 1:48 p.m. - 1:53 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
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