Insulin signaling, resistance, and metabolic syndrome: insights from mouse models into disease mechanisms

Abstract

Insulin resistance is a major underlying mechanism for the “metabolic syndrome”, which is also known as insulin resistance syndrome. Metabolic syndrome is increasing at an alarming rate, becoming a major public and clinical problem worldwide. Metabolic syndrome is represented by a group of interrelated disorders, including obesity, hyperglycemia, hyperlipidemia, and hypertension. It is also a significant risk factor for cardiovascular disease and increased morbidity and mortality. Animal studies demonstrate that insulin and its signaling cascade normally control cell growth, metabolism and survival through activation of mitogen-activated protein kinases (MAPKs) and phosphotidylinositide-3-kinase (PI3K), of which activation of PI-3K-associated with insulin receptor substrate-1 and -2 (IRS1, 2) and subsequent Akt→Foxo1 phosphorylation cascade has a central role in control of nutrient homeostasis and organ survival. Inactivation of Akt and activation of Foxo1, through suppression IRS1 and IRS2 in different organs following hyperinsulinemia, metabolic inflammation, and over nutrition may provide the underlying mechanisms for metabolic syndrome in humans. Targeting the IRS→Akt→Foxo1 signaling cascade will likely provide a strategy for therapeutic intervention in the treatment of type 2 diabetes and its complications. This review discusses the basis of insulin signaling, insulin resistance in different mouse models, and how a deficiency of insulin signaling components in different organs contributes to the feature of the metabolic syndrome. Emphasis will be placed on the role of IRS1, IRS2, and associated signaling pathways that couple to Akt and the forkhead/winged helix transcription factor Foxo1.

Metabolic syndrome in adults who received hematopoietic stem cell transplantation for acute childhood leukemia: an LEA study

“…The endothelial damage caused by alkylating agents or TBI exposure 29 has been frequently reported, [30][31][32] and could promote the development of MS. [33][34][35] Of the different MS components, the only significant impact noted was that of TBI on hyperglycemia (OR: 4.7, 95%CI: 1.24-17.85, P = 0.02). When insulin resistance is considered one of the main mechanisms involved in MS development, 36 it can be hypothesized that TBI exposure could promote secondary development of MS by this mechanism. Two major hypotheses have been proposed to explain the role of TBI on hyperglycemia: pancreatic irradiation could impair the β-cells ability to produce insulin and cause hyperglycemia by this way.…”

Potential biomarker of metformin action

“…Hyperglycemia in diabetic patients is caused mainly by unregulated HGP, although decreased glucose uptake and utilization in peripheral tissues such as muscle and adipose tissue due to insulin resistance also contribute to the development of hyperglycemia (Guo 2014). Since the main effect of metformin is to suppress glucose production in the liver (Hundal et al 2002, Takashima et al 2010 and CBP phosphorylation in WBCs reflect hepatic CBP phosphorylation (Fig.…”

Obesity and thyroid cancer

“…Blood glucose homeostasis in healthy subjects requires a very delicate adjustment of insulin production by pancreatic b-cells and insulinmediated glucose uptake in tissues (Kern et al 1990, Dimitriadis et al 2008. The first step in insulin receptor activation results in the phosphorylation and recruitment of several molecules which ultimately lead to the downstream upregulation of the AKT/mTOR/PI3K and ERK/ RAS/MAPK pathways, the two main signaling cascades involved in cancer proliferation and survival (Guo 2013). Hence, insulin receptors are also directly involved in the expression and effects of IGF1 and IGF2, both already related to thyroid cancers (Vella et al 2001).…”