Association of Branched-Chain Amino Acid Intake Trajectory in Adulthood with the Risk of Type 2 Diabetes and Its Related Risk Factors
Type 2 diabetes (T2D) is a growing global health concern, placing a significant burden on healthcare systems worldwide. Branched-chain amino acids (BCAAs), which include leucine, isoleucine, and valine, are essential amino acids that play a critical role in protein synthesis, glucose homeostasis, and nutrient-sensitive signaling pathways. While plasma BCAA levels have been shown to predict the development of T2D, the relationship between dietary BCAA intake and T2D risk remains inconsistent. Most studies on dietary BCAAs have relied on single or limited measurements, failing to account for the dynamic changes in BCAA intake over time and their potential impact on diabetes development. This study adopts a life-course approach, using multiple dietary BCAA measurements over 18 years to explore the association between BCAA intake trajectories and the risk of T2D and its related biomarkers.
The study utilized data from the China Health and Nutrition Survey (CHNS), which included 13,122 participants from 1991 to 2011. Participants were excluded based on several criteria: implausible energy intake, extreme outliers for BCAA intake, participation in only one survey, age under 18 at the first survey, pre-existing diabetes, and pregnancy. Dietary intake was assessed using a combination of three consecutive 24-hour recalls at the individual level and a household food inventory over the same 3-day period. BCAA content was calculated using the Chinese Food Composition Table and expressed as energy density (mg/kcal). Anthropometric variables were measured at each survey, and blood samples were collected in 2009 to assess biomarkers such as fasting glucose and hemoglobin A1c (HbA1c). T2D was identified through self-reported diabetes diagnosis, fasting blood glucose levels, HbA1c levels, or diabetes treatment.
The latent class mixed model (LCMM) was employed to identify BCAA intake trajectories over the 18-year period. Four distinct trajectories were identified: (1) “T1: light-stable,” characterized by stable low BCAA intake throughout adulthood; (2) “T2: heavy to light,” featuring high BCAA intake in early adulthood that declined with age; (3) “T3: moderate to heavy then decline,” with BCAA intake increasing to a peak in middle age before declining; and (4) “T4: light to moderate,” showing a gradual increase in BCAA intake throughout adulthood. These trajectories accounted for 62.6%, 5.1%, 6.6%, and 25.7% of participants, respectively.
The association between BCAA intake trajectories and T2D risk was analyzed using Cox multivariate regression models. Compared to the light-stable trajectory (T1), trajectories T3 and T4 were associated with a significantly higher risk of T2D. Specifically, T3 had a hazard ratio (HR) of 1.36 (95% CI: 1.04, 1.78), while T4 had an HR of 1.51 (95% CI: 1.30, 1.74). These findings highlight the adverse effects of increasing BCAA intake over time on T2D risk.
Subgroup analyses revealed significant differences in T2D-related biomarkers across the BCAA intake trajectories. Trajectories T3 and T4 were associated with higher levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), triacylglycerol, uric acid, lipoprotein A, and apolipoprotein B, as well as lower levels of high-density lipoprotein cholesterol (HDL-C). Although fasting glucose and HbA1c levels were not significantly different across trajectories, the trends suggested higher levels in T3 and T4 compared to T1 and T2.
Mediation analysis was conducted to explore whether the association between BCAA intake trajectories and T2D risk was mediated by specific biomarkers. The results indicated that total cholesterol, HDL-C, triacylglycerol, and apolipoprotein B partially mediated this association. The total effect of BCAA intake trajectories on T2D risk was estimated at 0.033, with indirect effects of 0.004 for total cholesterol, 0.005 for HDL-C, 0.005 for triacylglycerol, and 0.004 for apolipoprotein B. These biomarkers accounted for 12.1%, 15.2%, 15.2%, and 12.1% of the total effect, respectively.
The study underscores the importance of monitoring and managing BCAA intake throughout adulthood to mitigate the risk of T2D. Increasing BCAA intake over time, particularly in late adulthood, was associated with a higher risk of T2D, even when starting from a low baseline level. Conversely, reducing BCAA intake from high levels in early adulthood appeared to mitigate this risk. The findings suggest that intervention strategies aimed at controlling BCAA intake should be implemented early in adulthood to prevent the adverse effects associated with elevated BCAA levels.
The study also highlights the complex relationship between BCAA intake and lipid metabolism. BCAA supplementation has been shown to activate hepatic mammalian target of rapamycin (mTOR), which can block the transformation of free fatty acids (FFA) into triacylglycerol, leading to hyperlipidemia. In adipocytes, BCAAs activate adenosine monophosphate (AMP)-activated protein kinase (AMPKa2), stimulating lipolysis and increasing plasma FFAs, which can accumulate in the liver and contribute to insulin resistance and beta-cell dysfunction. These mechanisms provide a plausible explanation for the observed associations between BCAA intake trajectories, lipid biomarkers, and T2D risk.
In conclusion, this study provides valuable insights into the long-term effects of BCAA intake on T2D risk and its related biomarkers. The findings emphasize the need for early intervention strategies to control BCAA intake and reduce the risk of T2D. Future research should explore the relationship between BCAA intake and cardiovascular disease, as well as the broader implications of these findings for public health practice.
doi.org/10.1097/CM9.0000000000001526
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