Insulin's actions on vascular tissues: Physiological effects and pathophysiological contributions to vascular complications of diabetes

Abstract

Background Insulin has been demonstrated to exert direct and indirect effects on vascular tissues. Its actions in vascular cells are mediated by two major pathways: the insulin receptor substrate 1/2-phosphoinositide-3 kinase/Akt (IRS1/2/PI3K/Akt) pathway and the Src/mitogen-activated protein kinase (MAPK) pathway, both of which contribute to the expression and distribution of metabolites, hormones, and cytokines. Scope of review In this review, we summarize the current understanding of insulin's physiological and pathophysiological actions and associated signaling pathways in vascular cells, mainly in endothelial cells (EC) and vascular smooth muscle cells (VSMC), and how these processes lead to selective insulin resistance. We also describe insulin's potential new signaling and biological effects derived from animal studies and cultured capillary and arterial EC, VSMC, and pericytes. We will not provide a detailed discussion of insulin's effects on the myocardium, insulin's structure, or its signaling pathways' various steps, since other articles in this issue discuss these areas in depth. Major conclusions Insulin mediates many important functions on vascular cells via its receptors and signaling cascades. Its direct actions on EC and VSMC are important for transporting and communicating nutrients, cytokines, hormones, and other signaling molecules. These vascular actions are also important for regulating systemic fuel metabolism and energetics. Inhibiting or enhancing these pathways leads to selective insulin resistance, exacerbating the development of endothelial dysfunction, atherosclerosis, restenosis, poor wound healing, and even myocardial dysfunction. Targeted therapies to improve selective insulin resistance in EC and VSMC are thus needed to specifically mitigate these pathological processes.

Regeneration of glomerular metabolism and function by podocyte pyruvate kinase M2 in diabetic nephropathy

“…In parallel with the metabolic changes, the initial elevation of VEGF expressions in the glomeruli at 4-months corresponded with the enlargement of glomeruli size, and subsequently, its reduction corresponded with the changes in glomerular and renal sizes, as observed in advanced diabetic rodent models and patients (18,(36)(37)(38). The initial elevation of VEGF in the diabetic glomeruli was not affect by PKM2 overexpression in the podocyte, and its expression was preserved in PPKM2Tg mice after 7-months of diabetes.…”

“…The continuous or deficient expression of VEGF can cause both metabolic and pathological dysfunctions in the glomeruli (52). Many hormonal and cytokine disorders have displayed similar patterns: for example, hyperinsulinemia with insulin resistance and deficiency in autoimmune diabetes can accelerate atherosclerosis (53)(54)(55), and either loss or chronic excessive production of cytokines can contribute to organ dysfunction (37,56,57).…”

Glucose and MMP-9 dual-responsive hydrogel with temperature sensitive self-adaptive shape and controlled drug release accelerates diabetic wound healing

“…8 B, the capillary density of the wounds in each group was quantitatively analysed on day 7. The hydrogel III and hydrogel IV groups had more new blood vessels, which was attributed to the promotion of cell proliferation and migration by hydrogels III–IV, and the long-term release of insulin promoted angiogenesis [ 57 ]. Re-epithelialisation is the thinning and maturation of epithelial structures and is an important stage of skin regeneration.…”

Akt: A Potential Drug Target for Metabolic Syndrome

“…The PI3K/Akt pathway is one of the core pathways that leads to endothelial dysfunction ( Fu et al, 2021 ). Physiological insulin signaling increases eNOS phosphorylation via the PI3K/Akt pathway.…”