Gut microbiota metabolites, amino acid metabolites and improvements in insulin sensitivity and glucose metabolism: the POUNDS Lost trial

Abstract

Objective: Alterations in gut microbiota have been linked to host insulin resistance, diabetes and impaired amino acid metabolism. We investigated whether changes in gut microbiota-dependent metabolite of trimethylamine N-oxide (TMAO) and its nutrient precursors (choline and L-carnitine) were associated with improvements in glucose metabolism and diabetes-related amino acids in a weight-loss diet intervention.

Design: We included 504 overweight and obese adults who were randomly assigned to one of four energy-reduced diets varying in macronutrient intake. The 6-month changes (Δ) in TMAO, choline and L-carnitine levels after the intervention were calculated.

Results: Greater decreases in choline and L-carnitine were significantly (p<0.05) associated with greater improvements in fasting insulin concentrations and homeostasis model assessment of insulin resistance (HOMA-IR) at 6 months. The reduction of choline was significantly related to 2-year improvements in glucose and insulin resistance. We found significant linkages between dietary fat intake and ΔTMAO for changes in fasting glucose, insulin and HOMA-IR (pinteraction <0.05); a greater increase in TMAO was related to lesser improvements in the outcomes among participants who consumed a high-fat diet. In addition, ΔL-carnitine and Δcholine were significantly related to changes in amino acids (including branched-chain and aromatic amino acids). Interestingly, the associations of ΔTMAO, Δcholine and ΔL-carnitine with diabetes-related traits were independent of the changes in amino acids.

Conclusion: Our findings underscore the importance of changes in TMAO, choline and L-carnitine in improving insulin sensitivity during a weight-loss intervention for obese patients. Dietary fat intake may modify the associations of TMAO with insulin sensitivity and glucose metabolism.

Trial registration number: NCT00072995.

Keywords: amino acids; clinical trials; glucose metabolism; nutrition.

Conflict of interest statement

Competing interests: None declared.

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2019. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Figures

Figure 1

Trajectories of changes in insulin resistance over 2 years according to tertile (T) categories of 6-month changes in choline (panels A and B) and L-carnitine (panels C and D). Data are means ± SE values after adjusted for age, sex, ethnicity, diet group, parental history of diabetes, body mass index, value for the respective outcome traits at the baseline examination, and either choline or L-carnitine levels at baseline. For Δcholine, median (25th, 75th) values were T1: –1.9 (–2.9, –1.4) μM; T2: –0.2 (–0.5, 0.2) μM; T3: 1.6 (1.0, 2.1) μM, respectively. For ΔL-carnitine, median (25th, 75th) values were T1: –5.0 (–7.5, –3.4) μM, T2: 0.2 (–0.9, 1.1) μM, and T3: 4.6 (3.2, 6.7) μM, respectively.

Figure 2

Changes in glycemic and insulin measures at 6 months according to tertile (T) categories of changes in trimethylamine N-oxide (TMAO) in low- or high-fat diet group. Panel A: changes in fasting glucose; panel B: changes in hemoglobin A1c (HbA1c); panel C: changes in log-transformed fasting insulin; panel D: changes in log-transformed homeostasis model assessment-of-insulin resistance (HOMA-IR). Data are means ± SE values after adjusted for age, sex, ethnicity, and parental history of diabetes. For ΔTMAO, median (25th, 75th) values were T1 (white): –2.0 (–3.5, –1.2) μM, T2 (gray): 0 (–0.3, 0.3) μM, and T3 (black): 1.9 (1.3, 4.0) μM, respectively among the total participants.