Characterisation of the role of mitochondrial dysfunction and meta-inflammation as a shared pathogenic network in gestational diabetes mellitus

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McElwain, Colm
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University College Cork
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Background Gestational diabetes mellitus (GDM) is one of the most prevalent obstetric complications, with a growing incidence resulting from upward trends in global obesity and metabolic syndrome. GDM pathology is considered a state of exaggerated insulin resistance in pregnancy, mediated by pancreatic beta cell insufficiency, adipose dysregulation and systemic meta-inflammation. Although the pathophysiology of GDM is complex, adipose tissue dysfunction is an established cause of metabolic dysfunction and systemic insulin resistance. Furthermore, the placental microenvironment is highly sensitive to GDM physiology and there is significant evidence that the hyperglycaemic state of GDM drives placental dysfunction, in part mediated by exaggerated oxidative stress and inflammation. This thesis aims to characterise the role of systemic and local tissue mitochondrial dysfunction and meta-inflammation in promoting GDM pathology. Methods In this study, the inflammatory and metabolic profiles of omental visceral adipose tissue (VAT), placental tissue and fasting maternal blood were extensively studied to identifiy pathways which may drive insulin resistance in GDM and contribute to both acute and chronic adverse maternal and fetal outcomes. Samples were collected at term pregnancy from nulliparous women with normal glucose tolerant pregnancies and women diagnosed with GDM. Various immune-endocrine mediators were investigated in VAT, placental tissue and the maternal circulation including markers of mitochondrial dysfunction, monocyte/macrophage population frequency, hormones, inflammatory cytokines and insulin signalling transduction. Results Firstly, distinct phenotypes of GDM were confirmed, relating to both insulin-deficient and insulin-resistant pathologies. Insulin-deficient GDM participants had lower body mass indexes (BMIs) and were significantly hypoinsulinaemic compared to insulin-resistant GDM participants, who had elevated BMIs with substantial VAT dysfunction, including adipocyte hypoplasia and dysregulated insulin signalling capacity. The placental microenvironment was also negatively affected in GDM, with a potent pro-inflammatory secretome including increased release of IL-6, TNF-α and IL-18. This inflammatory phenotype was mirrored in the maternal circulation, confirming that systemic low-grade inflammation is present in term GDM physiology and is, in part, facilitated by placental signalling. Mitochondrial dysfunction was also confirmed in GDM participants, characterised by exaggerated mitochondrial superoxide production in placental macrophages and elevated circulating levels of cell-free mitochondrial DNA. Ex vivo mitochondrial antioxidant therapy attenuated excessive placental inflammation in GDM, proposing a promising therapeutic avenue for alleviating systemic inflammation in GDM patients. Conclusion In this thesis, we have provided substantial evidence of metabolic dysfunction and inflammation in the maternal circulation, omental VAT and placental tissue of women with GDM. This includes evidence of defects in adipocyte expansion and impaired insulin signal transduction, in addition to placental and systemic mitochondrial dysfunction and inflammation, which may ultimately orchestrate GDM pathophysiology. These findings identify novel pathological pathways in GDM, which may be further delineated to establish their potential as therapeutic targets to alleviate adverse maternal outcomes.
Gestational diabetes mellitus , Metabolic dysfunction , Inflammation , Adipose , Placenta
McElwain, C. 2023. Characterisation of the role of mitochondrial dysfunction and meta-inflammation as a shared pathogenic network in gestational diabetes mellitus. PhD Thesis, University College Cork.