Cardiovascular complications in insulin resistance and endocrine diseases

Abstract

Cerebrovascular diseases, such as stroke and cardiovascular disease, are one of the leading causes of death in Japan. Type 2 diabetes is the most common form of diabetes and an important risk factor for these diseases. Among various pathological conditions associated with type 2 diabetes, insulin resistance has already been reported to be an important risk factor for diabetic complications. The major sites of insulin action in glucose metabolism in the body include the liver, skeletal muscle, and adipose tissue. However, insulin signaling molecules are also constitutively expressed in vascular endothelial cells, vascular smooth muscle, and monocytes/macrophages. Forkhead box class O family member proteins (FoxOs) of transcription factors play important roles in regulating glucose and lipid metabolism, oxidative stress response and redox signaling, and cell cycle progression and apoptosis. FoxOs in vascular endothelial cells strongly promote arteriosclerosis by suppressing nitric oxide production, enhancing inflammatory response, and promoting cellular senescence. In addition, primary aldosteronism and Cushing's syndrome are known to have adverse effects on the cardiovascular system, apart from hypertension, diabetes, and dyslipidemia. In the treatment of endocrine disorders, hormonal normalization by surgical treatment and receptor antagonists play an important role in preventing cardiovascular complications.

Exploring mechanisms of insulin action and strategies to treat diabetes

“…It was shown that gluconeogenesis is suppressed by insulin signaling mediated by IRS-1/2 in the proximal tubules, and impaired insulin signaling in the tissue leads to systemic insulin resistance [31]. We also showed that inactivation of the forkhead box O 1 (FoxO1), one of the key downstream molecules of insulin signaling [3,33], via interaction with peroxisome proliferator-activated receptor gamma coactivator (PGC) 1α, is important in this context [31], although the contribution of the mammalian target of rapamycin (mTOR) pathway was also proposed recently [28]. Insulin receptor is considered to be expressed in the basolateral side of the proximal tubules [34], but glucose reabsorbed by SGLT1/2 expressed on the luminal side of the proximal tubules was also shown to suppress gluconeogenesis via suppression of Sirtuin 1 activity (Fig.…”