Elevated TMAO levels linked to higher diabetes risk, study finds

By Dr. Liji Thomas, MDReviewed by Benedette Cuffari, M.Sc.Jun 4 2024

A recent study published in the journal Nutrients investigates how the incidence of diabetes is associated with altered trimethylamine N-oxide (TMAO) levels.

Study: Dynamic changes in gut microbiota-derived metabolite trimethylamine-n-oxide and risk of type 2 diabetes mellitus: potential for dietary changes in diabetes prevention. Image Credit: Proxima Studio / Shutterstock.com

The role of TMAO in diabtes

Type 2 diabetes mellitus (T2DM) is a highly prevalent and potentially disabling medical condition that is closely related to lifestyle factors. Diet, for example, is a significant factor that could contribute to T2DM, as well as modulate the gut microbiota.

TMAO is a microbial metabolite with significant biological roles in cardiovascular health, inflammatory responses, renal function, platelet activation, and lipid metabolism. The primary dietary sources of TMAO include marine fish like cod and haddock, as well as shellfish. Choline, phosphatidylcholine, and L-carnitine, typically found in protein-rich foods like meat and eggs, are also precursor molecules for TMAO.

TMAO has been identified as a novel independent risk factor associated with atherosclerosis and cardiovascular disease (CVD).”

The biological mechanisms involved in the association between TMAO, atherosclerosis, and CVD may include fatty tissue inflammation and disruption of the insulin signaling pathway, the latter of which can lead to insulin resistance and diabetes.

About the study

The current study utilized longitudinal data obtained between 2019 and 2021 in the rural part of Fuxin County in China’s Liaoning Province. 1,515 individuals were included in the study, all of whom were 35 years of age or older, resided in Fuxin County for at least five years, and did not have diabetes at baseline.

Serum TMAO levels, as well as its precursors choline, betaine, and carnitine, were measured in all study participants in 2019 and 2021. Demographic information, lifestyle factors, and any history of disease were also obtained for all study participants.

What did the study show?

About 35% of the study participants were male, with a mean age of 59.2 years and a mean body mass index (BMI) of 24.8 kg/m². Median TMAO levels in males and females were 4.2 μmol/L and 4,3 μmol/L, respectively.

Between 2019 and 2021, 81 new T2DM diagnoses were made, which amounts to an incidence rate of 5.35%. At baseline, the median TMAO levels between the T2DM cases and controls were 4.09 μmol/L and 5.08 μmol/L, respectively.

At the second time point in 2021, T2DM cases had higher median TMAO levels than controls, at 4.5 μmol/L and 3.2 μmol/L, respectively. The change in TMAO levels (ΔTMAO) was -0.56 and -0.90 in cases and controls, respectively. Both choline and carnitine levels were significantly higher in the control cohort than in T2DM cases.

After adjusting for demographic and lifestyle factors, including the daily intake of foods rich in TMAO precursors, the highest quartile of ΔTMAO at baseline was associated with a threefold risk of T2DM as compared to the lowest quartile. Compared with the group with decreased TMAO levels, those with the greatest increases in TMAO were at a 3.7 times greater risk of T2DM.

Choline levels were associated with a higher T2DM risk. The third and fourth quartiles of serum choline, which reflected the lowest reduction in serum choline levels, were associated with a higher T2DM risk as compared with the first quartile or greatest reduction in serum choline levels.

More specifically, this risk increased by 3.4-fold in the third quartile compared to a 4.7-fold increase in the fourth quartile. Each rise in choline levels by one standard deviation was associated with an 80% risk of T2DM. Baseline levels of carnitine and betaine were not linked to T2DM risk.

A longitudinal increase in T2DM risk was observed in individuals with consistently high TMAO levels. This risk was eight-fold higher than study participants with only high baseline TMAO or high ΔTMAO.

Conclusions

The study findings corroborate previous studies in China and Saudi Arabia, as well as other experimental studies, reporting that TMAO contributes to the development of T2DM. Several biological pathways may be affected by high TMAO levels, including Fox01 and protein kinase R-like ER kinase (PERK) pathways, as well as bile acid synthesis, which subsequently reduces glucose sensitivity.

Inhibition of the TMAO-synthesizing enzyme flavin-containing monooxygenase 3 (FMO3) or changing the gut microbiome composition reduces PERK activation and Fox01 transcription. TMAO also triggers genes that inhibit the synthesis of liver glycogen while stimulating the production of glucose by the liver, thereby increasing serum glucose levels.

Previously, researchers have shown that TMAO levels rise in association with increased consumption of animal proteins and saturated fats. Dietary changes cause rapid and reproducible alterations in the gut microbiome; therefore, it is crucial to strategically intervene through dietary advice and other lifestyle interventions to normalize TMAO levels and ultimately prevent T2DM. This could include high-fiber diets, medicinal plants, whole grains, and energy restriction, all changing the microbiome composition and reducing high blood sugar levels.

The prospective nature of the current study, which has a well-managed follow-up period, supports the reliability of these findings. Nevertheless, future studies are needed to explore TMAO distribution in larger and more diverse populations with a more extended follow-up period.