FROM MICE TO MEN: Insights into the Insulin Resistance Syndromes

Abstract

The insulin resistance syndrome refers to a constellation of findings, including glucose intolerance, obesity, dyslipidemia, and hypertension, that promote the development of type 2 diabetes, cardiovascular disease, cancer, and other disorders. Defining the pathophysiological links between insulin resistance, the insulin resistance syndrome, and its sequelae is critical to understanding and treating these disorders. Over the past decade, two approaches have provided important insights into how changes in insulin signaling produce the spectrum of phenotypes associated with insulin resistance. First, studies using tissue-specific knockouts or tissue-specific reconstitution of the insulin receptor in vivo in mice have enabled us to deconstruct the insulin resistance syndromes by dissecting the contributions of different tissues to the insulin-resistant state. Second, in vivo and in vitro studies of the complex network of insulin signaling have provided insight into how insulin resistance can develop in some pathways whereas insulin sensitivity is maintained in others. These data, taken together, give us a framework for understanding the relationship between insulin resistance and the insulin resistance syndromes.

The pancreatic β-cell as a target of estrogens and xenoestrogens: Implications for blood glucose homeostasis and diabetes

“…Although it is not usually emphasized, during the prediabetic phase, when insulin resistance has developed, the -cell hyper secretes insulin to maintain normal blood glucose levels provoking hyperinsulinaemia (McGarry, 2002). This hyperinsulinemia may produce an excess of insulin signaling in the liver, kidneys and ovaries, leading to hypertriglyceridemia, increased sodium retention, hypertension, and hyperandrogenism (Biddinger & Kahn, 2006).…”

“…Excessive insulin signaling in the liver or endothelium produces dyslipidemia and in fat, it produces obesity, glucose intolerance, and dyslipedimia (Biddinger & Kahn, 2006). In addition, an excessive insulin signaling may provoke insulin resistance in the liver and muscle (Ueno et al, 2005) as well as -cell exhaustion (Aston-Mourney et al, 2008) and therefore, contributing to the development of type II diabetes (Figure 2).…”

“…Although it is not usually emphasized, during the prediabetic phase, when insulin resistance has developed, the -cell hyper secretes insulin to maintain normal blood glucose levels provoking hyperinsulinaemia (McGarry, 2002). This hyperinsulinemia may produce an excess of insulin signaling in the liver, kidneys and ovaries, leading to hypertriglyceridemia, increased sodium retention, hypertension, and hyperandrogenism (Biddinger & Kahn, 2006).Estrogens are hormones to be considered in blood glucose homeostasis, although in which conditions they exert a beneficial or detrimental action is still a matter of debate.A change in blood estrogens occurs during pregnancy as well as during the menstrual cycle in humans or the estrous cycle in rodents. At those physiological levels, E2 is thought to be involved in maintaining normal insulin sensitivity and to be beneficial for β-cell function (Livingstone & Collison, 2002;Louet et al, 2004).…”

Is there an Association between Variants in Candidate Insulin Pathway Genes IGF-I, IGFBP-3, INSR, and IRS2 and Risk of Colorectal Cancer in the Iranian Population?

“…Insulin binds to its cell surface receptor (INSR), which regulates its metabolic action through initiating a series of tyrosine residues phosphorylation (Kohanski, 1993;White, 1997;Zhang et al, 2010). Insulin receptor substrate-2 (IRS2) is one of the major substrate of INSR, given its key role as an adaptor to mediate insulin signals to the downstream molecules by binding to the p-85 subunit of phosphatidylinositol (PI)-3 kinase and activating the serine kinase PKB/Akt pathway (Biddinger et al, 2006;White, 2006). Additionally there are some inconsistent results about association between IRS2 haplotypes and obesity risk (Lautier et al, 2003).…”

Hyperinsulinemia and insulin resistance in Wrn null mice fed a diabetogenic diet

“…It is of interest that liver-specific insulin receptor knock out mice develop marked hyperinsulinemia, but have decreased levels of circulating free fatty acids and trigycerides (Biddinger and Kahn, 2006). In contrast, muscle-specific insulin receptor knock out mice have a three-fold increase in insulin-stimulated glucose transport in adipose tissue, with an increase in fat deposition and serum triglycerides and free fatty acids but not serum insulin (Biddinger and Kahn, 2006). The metabolic phenotype of Wrn null mice may represent a combination of the liver and muscle effects.…”