Insulinotropic and muscle protein synthetic effects of branched-chain amino acids: potential therapy for type 2 diabetes and sarcopenia

Abstract

The loss of muscle mass and strength with aging (i.e., sarcopenia) has a negative effect on functional independence and overall quality of life. One main contributing factor to sarcopenia is the reduced ability to increase skeletal muscle protein synthesis in response to habitual feeding, possibly due to a reduction in postprandial insulin release and an increase in insulin resistance. Branched-chain amino acids (BCAA), primarily leucine, increases the activation of pathways involved in muscle protein synthesis through insulin-dependent and independent mechanisms, which may help counteract the "anabolic resistance" to feeding in older adults. Leucine exhibits strong insulinotropic characteristics, which may increase amino acid availability for muscle protein synthesis, reduce muscle protein breakdown, and enhance glucose disposal to help maintain blood glucose homeostasis.

Figure 1

Simplified overview of amino acid induced insulin secretion in the β-cell. Glucose is metabolized in the cell via glycolysis into pyruvate, which is subsequently metabolized further by the tricaboxylic acid cycle (TCA cycle) to form ATP. Increased ratios of ATP/ADP result in depolarization of the plasma membrane through closure of ATP-sensitive K⁺ channels. This depolarization opens voltage activated Ca²⁺ channels, leading to increased concentrations of intracellular Ca²⁺ ([Ca²⁺]_i) and subsequent insulin exocytosis. Intracellular catabolism of all metabolizable amino acids will increase the intracellular ATP/ADP ratio, thereby closing ATP-sensitive K⁺ channels, leading to the depolarization of the plasma membrane. Leucine both induces and enhances pancreatic β-cell insulin secretion through oxidative decarboxylation and allosteric activation of glutamate dehydrogenase (GDH) increasing ATP/ADP. Leucine can also be transaminated to α-ketoisocaproate (KIC) that is converted into acetyl-CoA before entering the TCA-cycle. Amino acids such as arginine can directly depolarize the plasma membrane of the β-cell, opening up voltage activated Ca²⁺ channels leading to insulin secretion. Adapted from Newsholme et al. [86].