Branched-Chain Amino Acids and Insulin Metabolism: The Insulin Resistance Atherosclerosis Study (IRAS)

Abstract

OBJECTIVERecent studies using untargeted metabolomics approaches have suggested that plasma branched-chain amino acids (BCAAs) are associated with incident diabetes. However, little is known about the role of plasma BCAAs in metabolic abnormalities underlying diabetes and whether these relationships are consistent across ethnic populations at high risk for diabetes. We investigated the associations of BCAAs with insulin sensitivity (SI), acute insulin response (AIR), and metabolic clearance of insulin (MCRI) in a multiethnic cohort.RESEARCH DESIGN AND METHODSIn 685 participants without diabetes of the Insulin Resistance Atherosclerosis Study (IRAS) (290 Caucasians, 165 African Americans, and 230 Hispanics), we measured plasma BCAAs (sum of valine, leucine, and isoleucine) by mass spectrometry and SI, AIR, and MCRI by frequently sampled intravenous glucose tolerance tests.RESULTSElevated plasma BCAAs were inversely associated with SI and MCRI and positively associated with fasting insulin in regression models adjusted for potential confounders (β = −0.0012 [95% CI −0.0018, −0.00059], P < 0.001 for SI; β = −0.0013 [95% CI −0.0018, −0.00082], P < 0.001 for MCRI; and β = 0.0015 [95% CI 0.0008, 0.0023], P < 0.001 for fasting insulin). The association of BCAA with SI was significantly modified by ethnicity, with the association only being significant in Caucasians and Hispanics. Elevated plasma BCAAs were associated with incident diabetes in Caucasians and Hispanics (multivariable-adjusted odds ratio per 1-SD increase in plasma BCAAs: 1.67 [95% CI 1.21, 2.29], P = 0.002) but not in African Americans. Plasma BCAAs were not associated with SI-adjusted AIR.CONCLUSIONSPlasma BCAAs are associated with incident diabetes and underlying metabolic abnormalities, although the associations were generally stronger in Caucasians and Hispanics.

Metabolomic profiling identifies potential pathways involved in the interaction of iron homeostasis with glucose metabolism

“…Sarcosine, alanine, glutamate, glycine, kynurenine, leucine, valine and a number of PCs were significantly different between a healthy population and the two MetS groups combined. These observed differences between healthy subjects and the MetS widely confirm published results [46], [47], [48], which renders validity to our study results. The association of metabolomic patterns with impaired glucose homeostasis could serve to identify pathways involved in the development of T2D.…”

“…Our data suggest that sarcosine, alanine, glutamate, glycine, kynurenine, branched-chain amino acids leucine and valine and a number of PCs may be involved in the pathophysiology of the MetS. A role for plasma branched-chain amino acids in T2D has been demonstrated previously which is also supported by our findings [47].…”

Fetal Serum Metabolites Are Independently Associated with Gestational Diabetes Mellitus

“…Some studies have reported that elevated plasma levels of branched-chain amino acids (BCAAs) also were associated with an increased risk of GDM [63,64] T2D [64,65], and insulin resistance [66]. In our present study, there were no significant differences in maternal plasma amino acid levels between GDM and non-GDM mothers.…”

Effect of metformin on myotube BCAA catabolism

“…9 Moreover, a report by Hasan et al 10 showed that high-fat fed male albino rats given metformin at 320 mg/day via oral gavage for 4 weeks exhibited rescued levels of muscle PGC-1α mRNA expression vs high-fat only rats. [13][14][15][16][17][18][19][20] Reduced BCAA catabolism has been suggested as a likely contributor to the accumulation of circulating BCAAs in obese and diabetic populations. 11 Similar findings have been obtained in rats given 300 mg/kg body weight which also induced PGC-1α expression in the soleus, white gastrocnemius, and red gastrocnemius vs saline-treated rats.…”