Insulin action, type 2 diabetes, and branched-chain amino acids: A two-way street

Abstract

Background: A strong association of obesity and insulin resistance with increased circulating levels of branched-chain and aromatic amino acids and decreased glycine levels has been recognized in human subjects for decades.

Scope of review: More recently, human metabolomics and genetic studies have confirmed and expanded upon these observations, accompanied by a surge in preclinical studies that have identified mechanisms involved in the perturbation of amino acid homeostasis- how these events are connected to dysregulated glucose and lipid metabolism, and how elevations in branched-chain amino acids (BCAA) may participate in the development of insulin resistance, type 2 diabetes (T2D), and other cardiometabolic diseases and conditions.

Major conclusions: In human cohorts, BCAA and related metabolites are now well established as among the strongest biomarkers of obesity, insulin resistance, T2D, and cardiovascular diseases. Lowering of BCAA and branched-chain ketoacid (BCKA) levels by feeding BCAA-restricted diet or by the activation of the rate-limiting enzyme in BCAA catabolism, branched-chain ketoacid dehydrogenase (BCKDH), in rodent models of obesity have clear salutary effects on glucose and lipid homeostasis, but BCAA restriction has more modest effects in short-term studies in human T2D subjects. Feeding of rats with diets enriched in sucrose or fructose result in the induction of the ChREBP transcription factor in the liver to increase expression of the BCKDH kinase (BDK) and suppress the expression of its phosphatase (PPM1K) resulting in the inactivation of BCKDH and activation of the key lipogenic enzyme ATP-citrate lyase (ACLY). These and other emergent links between BCAA, glucose, and lipid metabolism motivate ongoing studies of possible causal actions of BCAA and related metabolites in the development of cardiometabolic diseases.

Keywords: Branched-chain amino acids; Insulin resistance; Lipogenesis; Metabolic diseases; Nutrition.

Figure 1

Overview of the pathways of branched-chain amino acid (BCAA) catabolism. Following uptake into cells through the LAT1 or LAT2 transporters (SLC7a5 and SC7a8, respectively), the first common step in the catabolism of the BCAA (leucine, isoleucine, valine) is transamination to yield cognate α-ketoacids (α-ketoisocaproate (αKIC), α-ketomethylvalerate (αKMV), α-ketoisovalerate (αKIV)) and glutamate. Transamination can be catalyzed by a cytosolic form of branched-chain aminotransferase (BCATc), or alternatively, BCAA can be transported into the mitochondria by SLC25a44 to gain access to the mitochondrial isoform of BCAT (BCATm). The branched-chain α-ketoacids then engage with the rate-limiting enzyme of BCAA catabolism, the branched-chain ketoacid dehydrogenase complex (BCKDH), to form CoA-modified intermediates. BCKDH activity is controlled by reversible phosphorylation; phosphorylation by the BCKDH kinase (BDK) inhibits enzyme activity, whereas dephosphorylation of BCKDH by the PPm1K phosphatase activates the enzyme. The CoA-modified metabolites generated by BCKDH are readily converted to carnitine-modified metabolites that serve as convenient biomarkers of BCAA catabolism (e.g. C5-AC and C3-AC), TCA cycle intermediates such as acetyl CoA, succinyl CoA, or a free acid that can leave the cell have been ascribed functions in the regulation of transendothelial fatty acid transport, 3-OH isobutyrate (3-HIB). In white adipose tissue, odd chain metabolites produced from BCAA catabolism such as propionyl CoA can serve as substrates for the synthesis of monomethyl branched-chain fatty acids (mmBCFA) by fatty acid synthase (FASN).

Figure 2

Mechanism by which chronic elevations in BCAA drive glycine depletion. Increases in BCAA are associated with glycine depletion in humans and preclinical models of obesity and insulin resistance. A mechanism contributing to this reciprocal relationship is demonstrated where increased transamination of BCAA by branched-chain aminotransferase (BCAT) generates glutamate as a nitrogen sink. To dissipate the nitrogen load, the glutamate nitrogen is transferred to substrates that can exit the skeletal muscle to engage in hepatic urea cycle and gluconeogenic pathways, including glutamine formed by glutamine synthase (GS), and alanine produced by alanine transaminase (ALAT). Increased flux through these pathways caused by chronic elevations of BCAA depletes pyruvate, which is replenished by the conversion of glycine to serine and pyruvate by the actions of serine hydroxymethyltransferase (SHMT) and serine dehydratase (SDH), ultimately resulting in decreased tissue and serum glycine levels. Low glycine levels may contribute to mitochondrial lipid overload by limiting acyl-CoA export as acyl-glycine adducts. Experimental evidence for this model is provided in references 5 and 53.

Figure 3

BCAA, insulin resistance, and type 2 diabetes: a two-way street. In the early stages of development of type 2 diabetes (T2D), obesity and insulin resistance contribute to elevations in BCAA levels through the mechanisms summarized by panels in the top half of the figure, reading left to right. Once elevated, BCAA can in turn contribute to the development of disease phenotypes through the mechanisms summarized by panels in the bottom half of the figure, reading right to left.