By Steve Blechman

Branched-chain amino acids supplements (BCAAs) have been associated with insulin resistance in obese individuals. “Recently, the valine catabolite 3-hydroxyisobutyrate (3-HIB) was shown to promote insulin resistance in skeletal muscle by increasing lipid content in vivo.” The purpose of this study was to investigate the mechanistic effects of 3-HIB on skeletal muscle insulin signaling, metabolism, and related gene expression in vitro. These findings were recently published in the Journal of Nutrition Research (June 2019). This most recent study found that 3-HIB can reduce muscle insulin sensitivity and support a role of 3-HIB in the development of insulin resistance. This study is significant because it confirms the mechanism of 3-HIB and insulin resistance in muscle!

Research has shown that elevated levels of valine are present in the blood of diabetic rats, mice and humans. (Nat Rev Endocrinol, 2014). When the mice were fed a diet without valine, insulin sensitivity improved after only one day. Mice on the valine-free diet lasting an entire week decreased their blood glucose levels, indicating that there was improved insulin function. (Metabolism, 2014). It was reported in the journal Nature Medicine in 2015 that valine catabolite 3-hydroxyisobutyrate (3-HIB) promoted the accumulation of fat within muscle tissue by directly stimulating fatty uptake in the muscle. The intramuscular fat activates certain signaling cascades within the muscle cell that diminish insulin signaling, leading to insulin resistance. This study also found that inhibiting the production of 3-HIB prevented the uptake of fat. Other studies support the negative effect of 3-HIB on insulin signaling with elevated 3-HIB in the muscle of human subjects with diabetes. (J Lipid Res, 1989; Diabetologia, 2015). An article titled “Insulin Resistance, And What May Contribute To It” by Lila Abassi and published on the American Council on Science & Health website March 14, 2016 reported on “… a study published in Nature Medicine, [that] scientists have discovered that 3-hydroxyisobutyrate (3-HIB), one of the intermediate products in the breakdown of the BCAA valine, plays a role in the transport of fatty acids into skeletal muscle cells, which creates fatty muscles — a contributor to insulin resistance.” Abassi also also states, “Thus far, it has been a relative mystery as to how BCAAs play a role in insulin resistance. Skeletal muscles display resistance to insulin when there is excess fat inside their cells.” In closing of the article, Abassi said, “What the researchers found was that 3-HIB acted as a shuttle in muscle cells, allowing blood vessels in skeletal muscle tissue to move fat into skeletal muscle. The more 3-HIB, the more fat was transported — and conversely, when scientists blocked 3-HIB from being made, there was less uptake of fat into skeletal muscle.”

One of the authors of the study, Dr. Zoltan Arany, said to Abassi: “In this study we showed a new mechanism to explain how 3-HIB, by regulating the transport of fatty acids in and out of muscle, links the breakdown of branched-chained amino acids with fatty acid accumulation, showing how increased amino acid flux can cause diabetes.”

More recent studies have confirmed that the branched-chain amino acid valine metabolite 3-HIB is involved in the pathogenesis of insulin resistance in skeletal muscle and might be involved in insulin resistance in humans (Diabetes, July 2017; EbioMedicine, 2018; J Diab Rsch, 2018). Unlike valine, leucine has been shown to improve insulin function. Leucine consumption alone has been shown to rescue insulin-signaling deficiency (PLoS, 2011). A most recent study (Exp Clin Endocrinol Diabetes, 2018) found that oral administration of leucine improved endothelial function in healthy individuals when infused with glucose. Acute hyperglycemia impairs endothelial function in healthy individuals. This study found that leucine administration prevented hyperglycemia-mediated endothelial function. Unlike leucine, which avoids insulin resistance by increasing mitochondrial-driven fat loss, valine does not encourage mitochondrial biogenesis. Impaired mitochondrial function in skeletal muscle is one of the major predisposing factors to metabolic diseases, such as insulin resistance, type 2 diabetes and cardiovascular disease. Leucine supplementation increases insulin sensitivity by activating SIRT1 activity. SIRT1 is known to “promote mitochondrial biogenesis and oxidative capacity and prevent the mitochondrial dysfunction in skeletal muscle” (Journal of Nutrition and Metabolism, 2014). Leucine may also attenuate adiposity and promote weight loss during energy restriction (Nutrition 2006, Diabetes, 2007). These effects are in part by activating the SIRT1-dependent pathway, stimulating mitochondrial biogenesis and increased oxygen consumption (Nutrition Metabolism, 2008). Mitochondrial biogenesis and SIRT1 expression in skeletal muscle has also been shown to increase life span in middle-aged mice (Cell Metabolism, 2010). As far as isoleucine is concerned, unlike valine, it has been shown to improve insulin sensitivity by increasing glucose into muscle cells (Am J Physiol Endocrinol Metab, 2007).

It’s clear based on scientific research that the high-circulating BCAA valine is associated with obesity and diabetes. The latest available literature has shown that the branched-chain amino acid valine (catabolite 3-HIB) is most likely the probable cause of insulin resistance!

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