Browsing by Author "Speelman, Tammy"

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    The effect of acute phase proteins on hepatic insulin signalling
    (Stellenbosch : Stellenbosch University, 2020-03) Speelman, Tammy; Verhoog, Nicolette J. D.; Louw, Ann; Stellenbosch University. Faculty of Science. Dept. of Biochemistry.
    ENGLISH ABSTRACT: Insulin resistance is the main risk factor for the development of type-2 diabetes (T2D). It is described as perturbed insulin signalling in the peripheral target tissues (which include the liver, skeletal muscle and adipose tissue), resulting in deficient insulin action. In the liver, this leads to the inability of insulin to regulate glucose metabolism by decreasing hepatic glucose production (HGP), and thus decrease blood glucose concentrations, aiding in the progression to T2D. Numerous factors contribute to the development of insulin resistance, such as stress and obesity, however inflammation is known to play a key role. An increased inflammatory state is associated with enhanced production of acute phase proteins (APPs). Increased serum levels of APPs, such as plasminogen activator inhibitor-1 (PAI-1), serum amyloid A (SAA), and C-reactive protein (CRP) have additionally been associated with T2D and are commonly used as biological markers for this disease state. However, whether these APPs are more than just biological markers for T2D and could contribute to the development of insulin resistance has not yet been established. Although some studies support the possibility that PAI-1, SAA, and CRP impair insulin signalling, their role in the development of hepatic insulin resistance requires investigation. The aim of this study was thus to investigate the effect of PAI-1, SAA, and CRP on hepatic insulin signalling by investigating key proteins in the insulin signalling pathway which, comprise the insulin receptor (IR), insulin receptor substrate-2 (IRS-2), and the central protein, Akt, in a murine hepatoma and human liver carcinoma cell line, BWTG3 and HepG2, respectively. Additionally, HGP was investigated as well as the transcriptional regulation of G6Pase and PEPCK, two key enzymes involved in gluconeogenesis, which is an important process contributing to HGP. The overall results in this study showed that all three APPs impair hepatic insulin signalling in both liver cell models although to different degrees depending on the dose and length of exposure. Specifically, CRP was most effective in modulating the activation of key proteins (the IR and Akt) in the insulin signalling pathway, which subsequently correlated to its ability to increase G6Pase and PEPCK mRNA levels as well as HGP. The length of exposure played an integral role in this study as pro-longed exposure to PAI-1 and CRP enhanced their inhibitory effect on insulin signalling. This was not shown for SAA, which rather displayed dose-dependent effects. As far as could be determined, the results in this study is the first to support the role of PAI-1, SAA, and CRP in the development of hepatic insulin resistance as well as to directly compare the effects of these three APPs in the same experimental model. Although the molecular mechanism of these observed effects require further investigations, the findings in this study cement a foundation in the research linking APPs to hepatic insulin resistance.