Mineralocorticoid receptors in the pathogenesis of insulin resistance and related disorders: from basic studies to clinical disease

Abstract

Aldosterone is a steroid hormone that regulates blood pressure and cardiovascular function by acting on renal and vascular mineralocorticoid receptors (MRs) to promote sodium retention and modulate endothelial function. Indeed, MRs are expressed in endothelial cells, vascular smooth muscle cells, adipocytes, immune cells, skeletal muscle cells, and cardiomyocytes. Excessive aldosterone and associated MR activation impair insulin secretion, insulin metabolic signaling to promote development of diabetes, and the related cardiometabolic syndrome. These adverse effects of aldosterone are mediated, in part, via increased inflammation, oxidative stress, dyslipidemia, and ectopic fat deposition. Therefore, inhibition of MR activation may have a beneficial effect in prevention of impaired insulin metabolic signaling, type 2 diabetes, and cardiometabolic disorders. This review highlights findings from the recent surge in research regarding MR-related cardiometabolic disorders as well as our contemporary understanding of the detrimental effects of excess MR activation on insulin metabolic signaling.

Keywords: diabetes; insulin resistance; mineralocorticoid receptors.

Figure 1.

Potential mechanisms for increased aldosterone and mineralocorticoid receptor (MR) activation in obesity, insulin resistance, and type 2 diabetes. Aldosterone is classically synthesized in the zona glomerulosa of the adrenal cortex. Aldosterone is also produced from adipose tissue by increased adipose-derived aldosterone secretagogues, aldosterone synthase, and cholesteryl ester-transfer protein inhibitors. Increased aldosterone levels and MR activation promote insulin resistance and type 2 diabetes, which further activate aldosterone/MR signaling and aggravate cardiometabolic syndrome.

Figure 2.

Proposed model for the inappropriate mineralocorticoid receptor (MR) activation in the development of insulin resistance. While membrane MR activation will promote free fatty acid uptake, activation of mammalian target of rapamycin/S6 kinase (mTOR/S6K) and PKC signaling, nuclear MR activation will induce oxidative stress, increased NF-κB signaling, inflammation. These abnormalities lead to impaired insulin metabolic signaling, systemic and tissue insulin resistance. eNOS, endothelial nitric oxide (NO) synthase.

Figure 3.

Mechanisms involved in tissue-specific mineralocorticoid receptor (MR) activation in insulin resistance. Inappropriate MR activation promotes systemic and tissue insulin resistance through reduced insulin secretion, inflammation, oxidative stress, lipid disorders, decreased insulin and glucose uptake, as well as impaired insulin metabolic signaling. These abnormalities are prevented by MR antagonists. eNOS, endothelial nitric oxide (NO) synthase.