BCAA insufficiency leads to premature ovarian insufficiency,40 and decreased serum BCAA levels have been observed in patients with chronic heart failure.41 A BCAA dysmetabolism model proposes that the accumulation of downstream metabolites (not BCAAs per se) promotes β-cell mitochondrial dysfunction, stress signaling, and apoptosis associated with T2D.29 Increased BCAA levels are more likely to mark the loss of insulin action than being causative. This evidence concerns the gene ARID4B and congestive heart failure.