Amino acids do not merely represent precursors for de-novo protein synthesis, but also function as nutritional signals regulating various metabolic processes. Amino acids can act as potent hormone secretagogues, stimulating the secretion of insulin, glucagon, cortisol, insulin-like growth factor 1, and growth hormone. Furthermore, evidence points towards a key regulatory role for the essential amino acids, and leucine in particular, in gene transcription and translation. Leucine has an important function in intracellular signaling and is able to modulate skeletal muscle protein metabolism. Understanding the mechanisms by which leucine can alter metabolic signaling will be of great value for the development of effective nutritional and/or pharmacological interventions to prevent and/or treat chronic metabolic diseases. This review will discuss the potential of leucine to stimulate endogenous insulin release, inhibit muscle protein breakdown, and/or stimulate muscle protein synthesis in both health and disease. After speculating on the application of leucine as a pharmaconutrient in the prevention and treatment of sarcopenia and type 2 diabetes and the proposed efficacy of its use in sports practice, we will discuss the recent work investigating the clinical benefits of more prolonged leucine supplementation.
In addition to glucose, amino acids can also act as potent stimuli for the secretion of insulin from the pancreatic β-cell . In-vitro studies using incubated primary islet cells or β-cell lines have described strong insulinotropic properties for arginine, leucine, isoleucine, alanine, and phenylalanine. The various mechanisms by which these amino acids promote and/or enhance insulin secretion from the pancreatic β-cell are diverse and have not yet been fully elucidated . Similar to glucose-mediated insulin secretion, intracellular catabolism of the metabolizable amino acids in the pancreatic β-cell will increase the intracellular energy status (ATP/ADP ratio), which closes ATP-sensitive K+ channels, leading to the depolarization of the plasma membrane. The latter results in the opening of voltage-activated Ca2+ channels, resulting in the influx of Ca2+, which triggers insulin exocytosis. Leucine-induced insulin secretion is mediated both through its oxidative decarboxylation, as well as its ability to allosterically activate glutamate dehydrogenase [1,2]. A simplified overview on some of the proposed mechanisms by which glucose and leucine stimulate insulin secretion in the pancreatic β-cell is provided in Fig. 1.
In agreement with the data on incubated pancreatic β-cells, in-vivo human studies have reported elevated plasma insulin concentrations following intravenous amino acid administration . Nutritional studies in humans have already reported the synergistically stimulating effect of the combined ingestion of carbohydrate and protein on plasma insulin concentrations in the 1960s, which were later confirmed in both healthy and type 2 diabetic patients . We performed a series of studies to determine the in-vivo insulinotropic potential of the ingestion of various free amino acids and protein (hydrolysates) in combination with carbohydrate. In trying to define an optimal insulinotropic amino acid and/or protein (hydrolysate) mixture, when co-ingested with carbohydrate, we found a mixture containing a protein hydrolysate with the addition of free leucine to be most potential [4,5]. The latter was later shown to allow a two-fold to four-fold greater increase in postprandial insulin release in both healthy and type 2 diabetic patients when compared with the ingestion of carbohydrate only .
In addition to the role as precursors for de-novo protein synthesis, and their insulinotropic properties, some amino acids also seem to be able to stimulate protein anabolism in an insulin-independent manner . Essential amino acids, and leucine in particular, are capable of activating the mRNA translational machinery through the mammalian target of rapamycin (mTOR) [8,9]. mTOR is thought to serve as a convergence point for leucine-mediated effects on mRNA translation initiation and represents an interesting molecular target for the prevention of muscle loss. For a detailed description of the molecular pathways regulating muscle protein synthesis, a few key reviews are referenced [7,10,11]. In agreement, leucine administration has been shown to stimulate muscle protein synthesis and inhibit protein breakdown in both in-vitro  as well as in-vivo [13–18] rodent models. Earlier in-vivo human studies generally report inhibition of muscle protein breakdown following intravenous leucine administration, with no apparent effect on muscle protein synthesis rates. In contrast, others have reported an increase in muscle protein synthesis following administration of a flooding dose of leucine . From a more practical standpoint, numerous studies have reported an increase in muscle protein synthesis rate, inhibition of muscle protein breakdown, and/or a more positive net protein balance following the ingestion of protein and/or amino mixtures [19–25]. The latter has been associated with an increase in intracellular and/or extracellular leucine concentration, which is now believed to form the main stimulus driving the postprandial muscle protein synthetic response. The latter might also, at least partly, explain the greater stimulation of postprandial muscle protein synthesis following the ingestion of whey protein when compared with casein or casein hydrolysate . Differences in the stimulation of postprandial muscle protein synthesis were strongly correlated with the concurrent increase in plasma leucine concentration, suggesting that the greater leucine content in whey protein might be partly responsible for the greater anabolic properties. In short, protein ingestion increases muscle protein synthesis rates and inhibits muscle protein breakdown, thereby stimulating net muscle protein accretion. Leucine seems to be a key component responsible for stimulating postprandial muscle protein synthesis, and needs to be present in sufficient amounts to optimize the postprandial muscle protein synthetic response.
APPLICATIONS FOR LEUCINE ADMINISTRATION
The application of leucine as a pharmaconutrient to stimulate endogenous insulin release, inhibit muscle protein breakdown, and/or stimulate muscle protein synthesis has numerous potential applications in health and disease. So far, the potential impact of leucine administration has mainly been assessed in type 2 diabetes, sarcopenia, or sports practice setting.
Type 2 diabetes
Type 2 diabetes is characterized by a reduced sensitivity of peripheral tissues to circulating insulin levels, resulting in impaired glucose uptake and subsequent hyperglycemic blood glucose excursions . The insulinotropic properties of amino acids, and leucine in particular, may be of relevance as a means to stimulate endogenous insulin release and, as such, to improve postprandial glycemic control in type 2 diabetes patients . Although long-standing type 2 diabetes patients generally show a blunted insulinotropic response to carbohydrate intake, this response can be substantially increased by the co-ingestion of protein and/or amino acids [6,28]. Though the pancreatic ß-cell is no longer properly responding to glucose, its response to other stimuli (like amino acids) remains highly functional. Co-ingestion of protein with additional leucine can increase the insulin response to carbohydrate ingestion two-to-four fold in long-standing type 2 diabetes patients [6,22,28,29]. In fact, the insulin response has been shown to increase up to the level that is observed in healthy, normoglycemic controls ingesting the same amount of carbohydrate. The greater postprandial insulin response has been proven functional, stimulating blood glucose uptake, and reducing postprandial hyperglycemia in these patients . In follow-up studies, it was reported that co-ingestion of a small amount of protein hydrolysate and leucine with each main meal improves 24 h glycemic control by reducing the prevalence of postprandial hyperglycemia . As the application of protein and/or leucine to stimulate endogenous insulin release in type 2 diabetes has been proven quite effective, studies investigating the clinical benefits of prolonged protein and/or leucine supplementation in type 2 diabetes patients are warranted.
The loss of muscle mass and strength with aging, often referred to as sarcopenia, reduces the functional capacity and increases the risk of developing chronic metabolic disease . One of the main causes of sarcopenia seems to be the disruption in the regulation of muscle protein turnover [32,33]. Recent work indicates that the elderly are less sensitive to the main anabolic stimuli, that is, food intake and physical activity [34,35]. It has been suggested that increasing the leucine content of a meal can effectively compensate for the blunted muscle protein synthetic response to food intake in the elderly [19,24]. Recently, Katsanos et al. reported that increasing the leucine content of an amino acid mixture (from 26 to 41%; or 1.7 to 2.8 g leucine) normalizes the postprandial muscle protein synthetic response in the elderly when compared with young individuals. These findings are supported by Rieu et al., who observed higher muscle protein synthesis rates following consumption of leucine-enriched meals in elderly men. As a consequence, it has been proposed that increasing the leucine content of a meal (>2.8 g leucine) represents an effective dietary strategy to augment the muscle protein synthetic response to food intake in the elderly . Though the impact of leucine on muscle protein breakdown has been well established in rodent models [14–18], it remains to be assessed whether additional leucine administration can also inhibit muscle protein breakdown in vivo in humans. Though several studies have reported reduced muscle protein breakdown rates after intravenous infusion of leucine in vivo in humans , studies investigating the impact of leucine co-ingestion on postprandial muscle protein breakdown are scarce. It should be noted that muscle protein breakdown rates are typically reduced after meal ingestion, because of the accompanying insulin response , reducing the potential for (additional) leucine to further inhibit postprandial muscle protein breakdown. In contrast, the proposed impact of leucine co-ingestion on muscle protein breakdown might be of particular relevance in a more compromised elderly subpopulation where accelerated muscle protein breakdown (due to comorbidity and some level of cachexia) is likely prevalent . In short, the proposed anabolic properties of amino acids, and leucine in particular, may be of relevance as a means to augment postprandial muscle protein balance and, as such, to compensate for the blunted muscle protein synthetic response to food intake in the elderly population. Consequently, leucine supplementation has been proposed as an effective nutritional strategy to attenuate the loss of muscle mass with aging and, as such, to prevent and treat sarcopenia.
Sport and exercise
Exercise stimulates muscle protein synthesis and breakdown rates, albeit the latter to a lesser extent, resulting in a more positive protein balance . However, muscle protein balance following exercise will remain negative in the absence of food intake . Protein and/or amino acid ingestion following exercise inhibits protein breakdown, stimulates muscle protein synthesis, resulting in net muscle protein accretion . It is generally assumed that allowing muscle protein balance to become positive during recovery from exercise will improve postexercise recovery and is required to allow skeletal muscle adaptation to more prolonged exercise training . It is a popular belief that the anabolic properties of leucine can be used to further augment postexercise muscle protein accretion and, as such, to maximize the skeletal muscle adaptive response to exercise. Although it has been well established that amino acid and/or protein ingestion increases postexercise muscle protein synthesis rates , maximal protein synthesis rates are achieved after ingesting approximately 20 g protein [41▪]. In a series of studies in our laboratory, we tried to further augment the postexercise muscle protein synthetic response to exercise by co-ingesting additional leucine with ample amounts of dairy protein (∼0.2 g protein per kg bodyweight per h) in both young and elderly men [20,21,42]. Additional leucine ingestion during recovery from exercise did not further increase postexercise muscle protein synthesis rates. From these studies, it was concluded that exercise stimulates muscle protein synthesis to such an extent, that under conditions of sufficient protein provided, no surplus benefit from leucine co-ingestion should be expected. Though it could be speculated that leucine co-ingestion could further inhibit postexercise muscle protein breakdown, there are ample studies to suggest that protein breakdown is already maximally inhibited when protein plus carbohydrate are provided during recovery from exercise [43–45]. In short, despite its proposed anabolic properties, leucine co-ingestion following exercise does not seem to further increase postexercise muscle protein synthesis when ample dietary protein is already provided. Therefore, leucine supplementation is not likely to be of any benefit for the athlete.
CLINICAL BENEFITS OF LEUCINE SUPPLEMENTATION
Long-term leucine supplementation studies are warranted to address whether the proposed insulinotropic and/or anabolic properties of leucine will translate into clinical benefits. Recently, we finalized a long-term leucine supplementation study in 60 elderly type 2 diabetes patients [46▪]. Patients were administered 2.5 g leucine (or placebo) with each main meal (3 × 2.5 or 7.5 g leucine or placebo per day) during a 6-month intervention period. All patients maintained their normal oral glucose lowering medication and continued their normal habitual dietary and physical activity routines. Despite the prolonged intervention period, we observed no improvements in various indices of whole-body insulin sensitivity and glycemic control. So, despite the well established insulinotropic properties of leucine co-ingestion, we failed to detect any long-term improvements in glycemic control. These findings underline the apparent difficulty to directly translate the outcome of more acute studies on postprandial glycemic control to the impact of prolonged dietary intervention.
Few studies have addressed the potential impact of prolonged leucine supplementation on muscle mass and strength in the elderly. Borsheim et al. reported a greater than 20% increase in strength in elderly patients following 16 weeks of essential amino acid supplementation (providing 2.8 g leucine, twice daily). In addition, Dillon et al. supplemented elderly women with 15 g essential amino acids per day (providing 4.0 g leucine per day) for 12 weeks, and reported an approximately 4% increase in muscle mass (representing 1.7 kg lean tissue). As both studies do not report data on total energy intake and/or habitual diet, we can only speculate on whether the benefits of essential amino acid supplementation were attributed to an increase in total amino acid/protein intake and/or to the anabolic properties of leucine and/or other specific essential amino acids. In our laboratory, we investigated the impact of 3 months leucine supplementation with each main meal on muscle mass and strength in healthy, elderly men . Thirty healthy men were randomly assigned to either placebo or leucine supplementation during a 12-week intervention period. Patients were administered 2.5 g leucine (or placebo) with each main meal (3 × 2.5 or 7.5 g leucine or placebo per day). No changes in skeletal muscle mass or strength were observed over time in either the leucine or placebo supplemented group. Extrapolation of the acute stimulating properties of leucine ingestion (2.8 g) on postprandial muscle protein synthesis reported by Katsanos et al. towards the impact of prolonged leucine supplementation with each main meal should theoretically translate into an additional 1.7 kg lean muscle tissue gained over a 3-month intervention period. However, no changes in body composition and lean tissue mass were detected. There is no clear explanation for the apparent discrepancy between the acute and more prolonged effects of leucine supplementation on muscle protein metabolism. It might be speculated that 3 months leucine supplementation is insufficient to maximize the proposed benefits of prolonged leucine supplementation on muscle mass accretion. Furthermore, healthy elderly men habitually consume ample amounts of protein in their diet (∼1.0 g/kg per day), providing between 8 and 15 g leucine per day . The latter might explain why a further increase in leucine intake did not result in net muscle mass accretion.
Elderly type 2 diabetes patients generally experience a more rapid decline in skeletal muscle mass with aging . Because of both its insulinotropic and anabolic properties, leucine might be of even more relevance as a pharmaconutrient in elderly, type 2 diabetes patients . Therefore, we recently performed a study in which 60 elderly diabetes patients were supplemented with leucine or placebo during a 6-month intervention period [46▪]. In addition to assessing indices of whole-body insulin sensitivity and glycemic control, we also determined potential changes in skeletal muscle mass and strength. However, in line with the previous 3-month intervention study , we could not detect any measurable changes in whole-body or leg muscle mass or in type I or II muscle fiber size (Fig. 2).
Clearly, a greater postprandial muscle protein synthetic response observed following leucine co-ingestion does not necessarily translate into structural skeletal muscle hypertrophy during more prolonged intervention. Muscle mass maintenance is regulated by many other factors that all contribute to the regulation of muscle protein synthesis and breakdown. It could be speculated that long-term leucine supplementation is of more clinical relevance in frail and malnourished elderly and/or in specific clinical subpopulations that suffer from accelerated muscle mass loss.
Leucine has potent anabolic properties and can act as a strong insulin secretagogue. As such, leucine administration has been proposed as an effective nutritional strategy to augment postprandial muscle protein accretion and improve glycemic control. In accordance, postprandial muscle protein synthesis rates have been shown to increase following leucine co-ingestion in healthy, elderly men. However, additional leucine co-ingestion during postexercise recovery does not further increase muscle protein synthesis rates when ample dietary protein is already ingested. Leucine co-ingestion has been shown to substantially increase endogenous insulin release and can be applied to effectively improve postprandial glycemic control in type 2 diabetes patients. These recent studies suggest that leucine represents an effective pharmaconutrient in the prevention and treatment of sarcopenia and/or type 2 diabetes. Although there are numerous applications for the proposed benefits of leucine in health and disease, the clinical relevance of prolonged leucine supplementation has not been confirmed.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 95–96).
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