Abstract
Although rodent studies suggest that trimethylamine N-oxide (TMAO) influences glucose homeostasis and risk of type 2 diabetes, evidence in humans is limited. To examine the associations of serial measures of plasma TMAO and related metabolite concentrations with incident type 2 diabetes, fasting plasma insulin and glucose levels, and the Gutt insulin sensitivity index (ISI). This prospective cohort design assessed the association of plasma TMAO and related metabolite concentrations with diabetes outcome, whereas a cross-sectional design assessed the association with insulin and glucose levels and Gutt ISI. The participants were a cohort of older US adults from the Cardiovascular Health Study (CHS). Data from June 1989 to May 1990, from November 1992 to June 1993, and from June 1995 to June 1997 were included, with follow-up through June 2010. Levels of TMAO and related metabolites were measured in CHS plasma samples. Data were analyzed from July 2019 to September 2020. Plasma concentrations of TMAO, carnitine, betaine, choline, crotonobetaine, and γ-butyrobetaine, measured by high-performance liquid chromatography and mass spectrometry. Linear regression for associations of TMAO and related metabolites with insulin and glucose levels and Gutt ISI, and proportional hazards regression for associations with diabetes. The study included 4442 participants without diabetes at baseline (mean [SD] age, 73 [6] years at entry; 2710 [61%] women). In multivariable analyses, plasma TMAO, carnitine, crotonobetaine, and γ-butyrobetaine concentrations were positively associated with fasting insulin level (insulin mean geometric ratio comparing fifth with first quintiles of metabolite concentration: 1.07 [95% CI, 1.04-1.10] for TMAO; 1.07 [95% CI, 1.03-1.10] for carnitine; 1.05 [95% CI, 1.02-1.08] for crotonobetaine; and 1.06 [95% CI, 1.02-1.09] for γ-butyrobetaine). In contrast, betaine and choline concentrations were associated with greater insulin sensitivity (mean difference in Gutt ISI comparing fifth with first quintiles: 6.46 [95% CI, 4.32-8.60] and 2.27 [95% CI, 0.16-4.38], respectively). Incident diabetes was identified in 661 participants during a median 12.1 (interquartile range, 6.9-17.1) years of follow-up. In multivariable analyses, TMAO and metabolites were not significantly associated with type 2 diabetes risk (hazard ratios of diabetes comparing fifth with first quintile: 1.20 [95% CI, 0.94-1.55] for TMAO; 0.96 [95% CI, 0.74-1.24] for choline; 0.88 [95% CI, 0.67-1.15] for betaine; 1.07 [95% CI, 0.83-1.37] for carnitine; 0.79 [95% CI, 0.60-1.04] for γ-butyrobetaine; and 1.06 [95% CI, 0.83-1.35] for crotonobetaine). Plasma TMAO and related metabolites were not significantly associated with type 2 diabetes among older adults. The metabolites TMAO, carnitine, γ-butyrobetaine, and crotonobetaine may be associated with insulin resistance, and betaine and choline may be associated with greater insulin sensitivity, but temporality of the associations was not established.
Highlights
Type 2 diabetes has reached epidemic proportions worldwide, with the number of adults having the disease doubling since 1980.1 a range of factors influence the risk of type 2 diabetes, strong evidence suggests that diabetes is largely attributable to lifestyle factors, including poor diet.[2]
Plasma trimethylamine N-oxide (TMAO), carnitine, crotonobetaine, and γ-butyrobetaine concentrations were positively associated with fasting insulin level
TMAO and metabolites were not significantly associated with type 2 diabetes risk
Summary
Type 2 diabetes has reached epidemic proportions worldwide, with the number of adults having the disease doubling since 1980.1 a range of factors influence the risk of type 2 diabetes (hereafter referred to as diabetes), strong evidence suggests that diabetes is largely attributable to lifestyle factors, including poor diet.[2]. Trimethylamine N-oxide (TMAO) is a metabolite derived predominantly from dietary precursors that include carnitine (primarily from red meat)[3,4] and choline (primarily from eggs and other animal products)[5,6] and from other dietary precursors such as phosphatidylcholine ( called lecithin), betaine (primarily from shellfish, wheat germ or bran, and spinach),[7] trimethyllysine,[8] and, to a lesser extent, carnitine-related compounds such as crotonobetaine and γ-butyrobetaine.[9] In the intestine, microorganisms release trimethylamine (TMA) from these precursors. The TMA is absorbed and metabolized into TMAO by the host hepatic flavin monooxygenases, primarily FMO3.5,10 circulating TMAO levels are an integrated measure of diet, microbiome, and host physiology. TMAO influences multiple atherosclerotic pathways[5,11,12,13]; in clinical samples of patients with prevalent risk factors, it is associated with risk of cardiovascular disease events.[6,14,15,16]
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