Elevated level of neutral amino acids is an early indicator for the development of insulin resistance. It has been proposed that high level of neutral amino acids stimulates amino acid-sensing mTOR pathway, resulting in phosphorylation of downstream proteins, such as p70S6 kinase and insulin substrate receptor-1 (IRS-1), thereby inhibiting insulin signaling and insulin-stimulated glucose transport in muscle and adipose tissue.
We hypothesized that mouse with reduced plasma amino acids level could have improved insulin sensitivity and might be less prone to develop T2D. To test this hypothesis, we have employed B0AT1 (Slc6a19) knockout mice. B0AT1 is the major neutral amino acid transporter in the intestine and kidney. Glucose tolerance test and insulin tolerance test were used to test insulin sensitivity in 2 months and 6 months old B0AT1−/− and B0AT1+/+ mice. The results show that B0AT1−/− mice have better insulin sensitivity than B0AT1+/+ mice. Western blot results also indicate reduced mTOR pathway activity in B0AT1−/− mice in a variety of tissues. Furthermore, when kept on a high fat diet, B0AT1−/− mice gained 30% less weight than wild type littermates after 4 months feeding period. Higher levels of “starving hormone” FGF21 and incretin GLP-1 have also been found in B0AT1−/− mice, which we think the combination of these hormones generate insulin-independent phenotypes in B0AT1−/− mice like reduced adipose tissue, browning of subcutaneous adipose tissue and elevated ketone bodies production. Results so far support the idea that a reduction of neutral amino acids in the blood plasma can improve insulin sensitivity and develop anti-diabetic phenotypes in mice.