Are BCAAs Mere Biomarkers of Diabetes?

Abstract

Branched-chain amino acids (BCAAs; ie. leucine, isoleucine, and valine) are essential amino acids we need to ingest through our diet.While circulating BCAA levels were first found to be elevated in obese individuals back in 1969 by Felig and colleagues, 1 the potential role of BCAAs in obesity and diabetes development has been re-highlighted in the last decade. Using advanced metabolomic platforms, many independent investigators were able to reproduce the earlier finding and further demonstrate that not only plasma BCAAs, but also their partially oxidized intermediates such as α-keto acids and short-chain (C3-C5) acylcarnitines are increased in obese or insulin resistant/diabetic individuals, including Caucasians and Asians. 2-9Moreover, plasma BCAAs are found to be the earliest and the most predictive marker for future risk of diabetes, 10 and elevated plasma leucine levels precede the development of fatty liver, 11suggesting that circulating leucine is a predictive marker of hepatic steatosis. Interestingly, plasma BCAAs and their derived short-chain acylcarnitines are effectively lowered by bariatric surgery in obese and/or diabetic individuals. 5,8,12,13 Whether this normalized BCAA metabolism after RYGB surgery in morbidly obese patients contributes to improved insulin sensitivity and glycemic control or is just a secondary effect of the surgery needs to be examined further. Nonetheless, collectively these studies implicate a role of plasma BCAAs and their metabolites in the pathogenesis of insulin resistance and diabetes.The unresolved question in the field today is whether or not they are mere biomarkers or they are one of the potential culprits for derangement of glucose metabolism and development of obesity and insulin resistance/diabetes. While a number of studies demonstrate that either amino acid mixture or BCAA supplementation have beneficial effects on protein turnover and muscle wasting in patients with cirrhosis, kidney failure, cancer, or sepsis, [14][15][16][17][18][19][20][21][22][23][24][25] mounting evidence suggests that amino acids/BCAAs or their metabolized keto acids lead to hyperactivation of mTOR signaling, 7,26-28 induction of oxidative stress, 29-32 mitochondrial dysfunction, 33,34 apoptosis, 35,36 and more importantly, insulin resistance and/or impaired glucose metabolism. 7,[26][27][28][37][38][39][40][41][42][43][44] Consistent with these findings, recent studies demonstrate that a BCAA metabolite elevated in diabetic individuals can drive vascular fatty acid transport in muscle and induce insulin resistance in mice 44 and a defective muscle BCAA metabolism induces impaired lipid metabolism and insulin resistance.45 On the other hand, deprivation of a single or all three BCAAs improves insulin sensitivity and glycemic control in either chow-or High-Fat Diet (HFD)-fed, or genetically diabetic rodents.46-48 These findings strongly indicate not only a correlative, but also a causative role of circulating BCAAs and their oxidized intermediates in the development of insulin resistance ...