An investigation into motility characteristics in THP-1 cells - relevance for type 2 diabetes mellitus
Cardiff Metropolitan University
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In recent times, it has become established that common obesity linked Type 2 Diabetes Mellitus (T2DM) is a disease with an underlying chronic systemic inflammatory component, a central feature of which is the infiltration of monocytes within insulin target and releasing tissues, and their differentiation and accumulation as pro-inflammatory polarised macrophages. As Advanced Glycation End-products (AGEs) accumulate within the blood and tissues of diabetics and have been linked with vascular complications and leukocyte dysfunction, the study focussed on their possible role in this process by assessing AGE impact on motility characteristics in monocytic cells. Furthermore, due to a major requirement for new, inexpensive, non-pharmaceutical T2DM interventions which can be easily adopted, the study also investigated the impact of the potential neutraceutical, conjugated linoleic acid (CLA), on monocytic motility, as evidence indicates CLA supplementation resembles the effects of thiazolidinediones (TZDs), including impacts on monocytemacrophage dynamics. A significant, transient -2-fold increase in F-actin was detected by flow cytometry in THP-1 cells following exposure to glycated Human Serum Albumin (gHSA). Exposure to the 10-trans 12-cis CLA isomer resulted in a similar pattern of F-actin formation, but following exposure to the 9-cis 11-trans isomer, no significant changes in F-actin were detected. No significant changes in surface CD11b expression were detected in response to any stimuli. Visualisation of F-actin organisation by fluorescence microscopy revealed an irregular distribution and evidence of membrane ruffling and distortion following treatment of THP-1 cells with both gHSA and 10-trans 12-cis CLA. F-actin distribution was uniform and non-distinct in cells exposed to 9-cis 11-trans CLA, corresponding to that observed in un-activated leukocytes. These data indicate that gHSA enhances features of monocytic motility, and therefore suggest that it stimulates the migration of circulating monocytes into tissues, highlighting another possible pro-diabetic role of AGEs. Furthermore, as AGEs are present within the blood, vasculature and tissues, these data suggest a potential mechanism of monocyte-macrophage migration in-which AGEs have a continuous role. Additionally, these data indicate that 10-trans 12-cis CLA enhances monocytic motility whereas 9-cis 11-trans CLA has no impact, strengthening evidence for a possible anti-diabetic role for the 9-cis 11-trans isomer. Based on these data, early and effective hyperglycaemic control would be strongly advocated to prevent disease exacerbation in T2DM, and it is recommended that 10-cis 12-trans CLA intake be minimised whereas 9-cis 11-trans CLA intake possibly be supplemented. Beyond this, the study also raises further questions concerning other factors in the T2DM phenotype which may be involved in regulating monocyte-macrophage dynamics, the nature and determination of the fate of migrating monocytes which expand macrophage populations in T2DM, and the role of monocytic cells in initiating and perpetuating the disease.
MSc Biomedical Science
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