- Title
- Relationship between plasma trimethylamine N-oxide levels and type 2 diabetes in a Saudi Arabian cohort
- Creator
- Kalagi, Nora Arfan
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2022
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- The increasing prevalence of type 2 diabetes (T2D) as an important public health issue continues to escalate that has been projected to increase further by 46% worldwide by the middle of 21st century. Multiple factors are involved in the disease occurrence and prognosis, most predominantly the contemporary changes in lifestyle habits, including poor dietary patterns and physical inactivity, which are also contributing to the rising prevalence of obesity. Therefore, a better understanding of disease susceptibility and environmental factors is essential to considerably minimise the growing burden and delay the disease onset or progression. The discovery of gut microbiota (GM) involvement in the development of cardiometabolic diseases has sparked immense interest in the last two decades. Its etiological role in T2D has been hypothesised, revealing an interaction between T2D and insulin resistance with the diversity of the GM profile. Trimethylamine N-oxide (TMAO), a GM-dependent metabolite, has been found to be implicated in the risk of promoting atherosclerosis and increasing cardiovascular disease risk. This observation has recently been extended to propose TMAO as an initiating or promoting metabolite involved in the pathophysiology of precursor conditions, including T2D, for the development of cardiovascular disease (CVD). TMAO is produced via GM fermentation of choline-containing dietary nutrients (L-carnitine, betaine, lecithin) to produce TMA, which is further oxidised by the hepatic flavin mono-oxygenase (FMO3) enzyme for conversion to TMAO. The association between TMAO and T2D has been confirmed in animal and human studies. TMAO levels were associated with increased glucose tolerance, fasting insulin levels, and adipose tissue inflammation in mice fed a high-fat diet, while in humans, high TMAO levels were linked to an increased risk of T2D development and complications. Circulating TMAO levels have been reported to vary among studies from different regions, attributed to distinct dietary patterns among the study populations. Diet rich in red meat, eggs, fish, dairy products, and a high-fat diet are among the major determinants of elevated TMAO levels in the blood. Some lifestyle behavioural changes and pharmacological interventions in response to T2D treatment have also been shown to affect the GM composition and subsequently TMAO production. This thesis aimed to investigate the relationship between TMAO levels and T2D in the Saudi Arabian (SA) population, where the lifestyle factors, including dietary patterns and physical activity levels, differ greatly compared to other already studied Asian, European, or North American populations. Three study designs were used to address the thesis primary objective. The foundations of the studies in this thesis arise from the systematic review conducted to map the evidence of different interventional studies on dietary supplements and pharmacological agents proposed to play a role in the modulation of TMAO levels in the blood and urine, reducing the risk of developing cardiometabolic diseases. The main aim of the systematic review was to understand the suggested pathways for TMAO production and excretion in humans and the effect of these interventions on TMAO levels. The literature was searched thoroughly in multiple databases, and identified studies were divided into two categories, six studies on dietary supplements and seven on pharmacological agents. Studies involving dietary supplements were mostly small-randomised controlled trials; however, those involving pharmacological agents were inconsistent and varied greatly in study design and duration, which limited their reliability with the reported outcomes. Dietary nutrients, including choline and L-carnitine, were found to be the major determinants of TMAO levels, suggesting the need to further investigate the relationship between plasma TMAO levels and chronic diseases in populations with differing lifestyle factors, particularly dietary patterns, and physical activity levels. A prospective, single-centre case-control study of n=297 SA participants, n=133 patients with T2D, and n=164 healthy individuals without T2D assessed the association between TMAO and T2D. Patients with T2D had significantly higher median (IQR) plasma TMAO [4.95 (2.84–8.35) μmol/L] levels compared to non-diabetic individuals [3.07 (2.05–4.82) μmol/L] (P<0.001). TMAO levels were significantly correlated with fasting plasma glucose, glycosylated haemoglobin (HbA1C), and triglyceride levels. Patients in the highest quartiles of TMAO levels (>6.40μmol/L) were presented with a poor metabolic profile compared to the other quartiles. TMAO Levels in SA were comparable to those reported in the United States populations but not to studies from China and Europe. This study demonstrated a significant association between plasma TMAO levels and T2D among the SA population, consistent with the previously reported findings in other countries. A cross-sectional study was conducted to further investigate the association between TMAO and T2D in patients who also progressed to have chronic kidney disease (CKD). Median TMAO levels in people with T2D and CKD were significantly higher [10.16 (5.86-17.45) μmol/L] than in those without CKD [4.69 (2.62-7.76) μmol/L] (P=0.002). Among these patients, the highest quartile of plasma TMAO levels was >8.38 μmol/L, and plasma TMAO levels were found to be correlated with blood and urinary levels of biomarkers of kidney function, including serum creatinine, estimated glomerular filtration rate (eGFR), blood urea nitrogen (BUN), and urinary albumin to creatinine ratio (UACR) levels. This study found a significant association between plasma TMAO levels and CKD (P<0.0001) in patients with T2D. Finally, the cross-sectional analysis of the same study participants from the case-control study was conducted to assess the association between TMAO levels and lifestyle factors in patients with or without T2D and to explore their influence on the association between TMAO and T2D. A null correlation between TMAO levels, dietary components, and physical activity levels was observed among patients with T2D. This study suggested the limited role of diet in influencing the association between TMAO and T2D and warrants further investigations into diabetes-induced changes to GM composition, kidney function, and liver enzymes in regulating the association between TMAO and T2D. This thesis provides further evidence for the association between circulating levels of TMAO and T2D, ruling out the involvement of dietary patterns and physical activity levels as confounders. This thesis also provides evidence for the successive increase of TMAO levels when T2D progresses to renal damage/failure. Longitudinal studies with a large sample size are warranted to determine the cause-consequence relationship between TMAO levels and chronic diseases and to establish TMAO as a predictor of chronic diseases, including diabetes mellitus, CKD, and CVD.
- Subject
- trimethylamine N-oxide; TMAO; diet; type 2 diabetes; chronic kidney disease
- Identifier
- http://hdl.handle.net/1959.13/1465412
- Identifier
- uon:47266
- Rights
- Copyright 2022 Nora Arfan Kalagi
- Language
- eng
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