Abstract
Changes in lifestyle in developed countries have triggered the prevalence of obesity and type 2 diabetes mellitus (T2DM) in the latest years. Consequently, these metabolic diseases associated to insulin resistance, and the morbidity associated with them, accounts for enormous costs for the health systems. The best way to face this problem is to identify potential therapeutic targets and/or early biomarkers to help in the treatment and in the early detection. In the insulin receptor signaling cascade, the activities of protein tyrosine kinases and phosphatases are coordinated, thus, protein tyrosine kinases amplify the insulin signaling response, whereas phosphatases are required for the regulation of the rate and duration of that response. The focus of this review is to summarize the impact of transmembrane receptor protein tyrosine phosphatase (RPTPs) in the insulin signaling cascade and secretion, and their implication in metabolic diseases such as obesity and T2DM.
Highlights
Type 2 diabetes mellitus (T2DM) and obesity are two major medical challenges of the 21st century with increasing prevalence during the last decades, reaching pandemic proportions [1]. Both metabolic diseases are associated to insulin resistance, and only a subset of obese people develops type 2 diabetes mellitus (T2DM), obesity is a major risk factor for T2DM, and rates of T2DM prevalence have paralleled those of obesity
protein tyrosine phosphatases (PTPs) (RPTPs) in the insulin signaling cascade and secretion, and their putative implication in metabolic diseases associated to insulin resistance such as obesity and T2DM
receptor protein tyrosine phosphatase (RPTPs)-ε decreased hepatic glucose output in hepatocytes and decreased in part insulin-induced suppression of the phosphoenolpyruvate carboxykinase (PECK) gene in primary hepatocytes and mouse liver. These results suggest that RPTP-ε is a negative regulator of insulin receptor signaling and participates in the regulation of hepatic glucose metabolism [47]
Summary
Both obesity and T2DM [2] are associated with the development of a chronic low-grade inflammation in adipose tissue, with local production of proinflammatory cytokines [3], such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) [4] that can interfere with insulin receptor signaling (see Figure 1) and cause insulin resistance [5] Many of these obesity/T2DM-generated inflammatory signals converge to activate serine kinases promoting Ser phosphorylation of IRS1 (pSerIRS1), that directly interferes with insulin action in adipose tissue both in pathological [6] and physiological conditions [7].
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