Type II Diabetes Mellitus (T2D) and cardiovascular diseases (CVD) are non-communicable chronic diseases that involves impairments in glucose metabolism and vascular function. Multiple factors may increase the risk for T2D, including but not limited to genetics, obesity and lifestyle, such as physical inactivity and diet. The gut microbiota, the human's largest population of microorganisms, plays an essential role in health and disease. The physiology and function of the gastrointestinal tract can be influenced by the diet. Phosphatidylcholine (PC), a source of choline in the diet, is rich in Western-type diets. Gut microbiota metabolize choline to trimethylamine (TMA) which circulates and is oxidized in the liver to form trimethylamine N-oxide (TMAO). As a result, ingestion of PC or choline could increase levels of TMAO. Preclinical studies indicate a role of TMAO in the development of atherosclerosis. Likewise, multiple observations support a potential role of TMAO in the development of insulin resistance and T2D. Much of the research has been conducted on rodent models, while others are observational human studies. Whether acute and short-term increases in TMAO contribute to impairments in insulin sensitivity in humans remains unknown. To address this, we performed two studies utilizing a double-blind, placebo controlled, crossover design. Eligible participants consumed a 1000mg/day dose of choline bitartrate and placebo (maltodextrin) the night before each testing session (for the acute choline study) or for 4 weeks (for the short-term choline ingestion study). Oral glucose tolerance test, continuous glucose monitoring, flow-mediated dilation, and applanation tonometry was performed the day after the acute choline load and before and after the short-term choline ingestion period. We hypothesized that gut microbiota-generated increase in TMAO will impair insulin sensitivity, glucose tolerance, endothelial function and arterial stiffness in healthy sedentary humans. Following acute choline ingestion, significant increases in plasma TMAO (p = 0.013) and choline (p = 0.003) were evident. There was no statistically significant difference in insulin sensitivity, glucose tolerance or in any of the endothelial function and arterial stiffness measurements. Four weeks of 1000mg choline ingestion per day, significantly increased plasma (p = 0.042) and urine (p = 0.008) TMAO concentrations compared to the placebo. However, no significant differences were observed for any other measurements of insulin sensitivity, glucose tolerance, glycemic variability, endothelial function, and arterial stiffness. More research is needed to elucidate the mechanisms behind the mechanistic observations between elevated TMAO concentrations and T2D and CVD. / Doctor of Philosophy / Type 2 diabetes mellitus (T2D) and cardiovascular diseases (CVD) increase the risk of all-cause mortality. Choline is a nutrient that can be found in foods such as red meat, dairy, fish, and eggs. Choline is metabolized from bacteria in our gut and a metabolite called trimethylamine (TMA) is formed. TMA is then oxidized in the liver and trimethylamine-N-oxide (TMAO) is produced. A Western-type diet is rich in red meat, dairy, fish, and eggs and has been shown to increase production of the compound TMAO. Preclinical studies have suggested a causal role of TMAO in atherosclerosis and T2D and elevated plasma TMAO concentrations have been associated with an increased risk for CVD and T2D in observational studies. However, the causal nature of this relationship in humans is unknown. The studies described herein aimed to investigate the effects of increases in TMAO on insulin sensitivity and vascular function in healthy adults. The first study tested the effect of increasing TMAO on insulin sensitivity, glucose tolerance, and vascular function following an acute choline load (1000mg) and placebo (carbohydrate) the night before each testing session. In the second study, we examined the effect of increasing TMAO on insulin sensitivity, glucose tolerance, and vascular function in healthy adults, following a short-term choline load (1000mg/day) and placebo (carbohydrate) for 4 weeks. Acute and short-term choline ingestion significantly increased plasma TMAO concentrations. No significant differences were observed following acute or short-term choline ingestion for any measurement of insulin sensitivity, glucose tolerance 24-hout glycemic variability, vascular function., and arterial stiffness.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/117235 |
| Date | 19 December 2023 |
| Creators | Laskaridou, Eleni |
| Contributors | Human Nutrition, Foods and Exercise, Davy, Kevin P., Davy, Brenda M., Neilson, Andrew P., Hedrick, Valisa E. |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Language | English |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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