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Therapeutic Approaches to Insulin Resistance and Type 2 Diabetes
Leonard, Siobhan
Type 2 diabetes is a chronic metabolic disorder primarily caused by a systemic insulin resistant state to which obesity is a major contributor. Increasing visceral adipose tissue augments adipokine secretion provoking an enduring low-grade inflammatory response that negatively impacts on the insulin signalling cascade. In an intervention study of a murine diet-induced model of type 2 diabetes, a novel compound, RTC-1, designed to reduce serum levels of one such adipokine, RBP, improved glucose handling and prevented weight gain. This compound also had a direct positive effect on glucose uptake in vitro, independent of its predicted mode of action. Through cellular analysis this study has established the mechanism by which this is achieved. RTC-1 was found to inhibit complex I of the mitochondrial respiratory chain (NADH:ubiquinone oxidoreductase), leading to a likely increase in the AMP to ATP ratio and the consequential activation of the cellular energy regulator, AMPK. This in turn stimulated the signalling pathway which enhanced the incorporation of the glucose transporter, GLUT4, into the plasma membrane. RTC-1 was also found to prevent adipogenesis and induced osteogenesis in an AMPK dependent manner. Additionally, RTC-1 was observed to provoke an increase in insulin sensitivity. In a separate project, the signalling capabilities of an orphan GPCR, GPR21, were investigated. Knockout studies have suggested a role for this receptor in macrophage infiltration into adipose tissue to augment insulin resistance through an unknown mechanism. Overexpression studies revealed GPR21 to be a constitutively active receptor, which couples Gαq type G proteins leading to the activation of the MAP kinases. Overexpression of GPR21 markedly attenuated insulin signalling and promoted macrophage migration. Interestingly, the effect of GPR21 on insulin signalling lessened in the presence of increasing concentrations of serum, inferring the possibility of a native regulatory ligand. Homology modelling and ligand docking studies led to the identification of a novel compound that interacted with GPR21. Its effects offered the potential as an anti-diabetic therapy as it was found to regulate GPR21-induced macrophage migration and to counteract the influence of GPR21 on the insulin signalling pathway.
Keyword(s): Therapeutic Approaches; Insulin Resistance; Type 2 Diabetes
Publication Date:
Type: Doctoral thesis
Peer-Reviewed: No
Institution: Maynooth University
Citation(s): Leonard, Siobhan (2015) Therapeutic Approaches to Insulin Resistance and Type 2 Diabetes. PhD thesis, National University of Ireland Maynooth.
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First Indexed: 2019-01-10 06:03:46 Last Updated: 2019-01-10 06:03:46