Abstract

Amino acids are increasingly recognised as modulators of nutrient disposal, including their role in regulating blood glucose through interactions with insulin signalling. More recently, cellular membrane transporters of amino acids have been shown to form a pivotal part of this regulation as they are primarily responsible for controlling cellular and circulating amino acid concentrations. The availability of amino acids regulated by transporters can amplify insulin secretion and modulate insulin signalling in various tissues. In addition, insulin itself can regulate the expression of numerous amino acid transporters. This review focuses on amino acid transporters linked to the regulation of insulin secretion and signalling with a focus on those of the small intestine, pancreatic β-islet cells and insulin-responsive tissues, liver and skeletal muscle. We summarise the role of the amino acid transporter B0AT1 (SLC6A19) and peptide transporter PEPT1 (SLC15A1) in the modulation of global insulin signalling via the liver-secreted hormone fibroblast growth factor 21 (FGF21). The role of vesicular vGLUT (SLC17) and mitochondrial SLC25 transporters in providing glutamate for the potentiation of insulin secretion is covered. We also survey the roles SNAT (SLC38) family and LAT1 (SLC7A5) amino acid transporters play in the regulation of and by insulin in numerous affective tissues. We hypothesise the small intestine amino acid transporter B0AT1 represents a crucial nexus between insulin, FGF21 and incretin hormone signalling pathways. The aim is to give an integrated overview of the important role amino acid transporters have been found to play in insulin-regulated nutrient signalling.

Introduction

Amino acids are vital nutrients for sustaining human life and are utilised by many essential biochemical pathways. These pathways depend on amino acid concentrations established using various inputs and outputs: dietary intake, protein synthesis, protein degradation, the synthesis of bioactive molecules and the catabolism and anabolism of amino acids in different tissues [1]. The pools of 20 canonical amino acids also serve as essential mediators of various intracellular and global signalling pathways. Nowhere has interest in amino acids been more apparent than in their emergence as modulators of insulin secretion and as targets of insulin signalling, the latter phenomenon being first recognised several decades ago in rodents and humans [2,3]. More recently, specific roles for amino acids have been elucidated in the regulation and reduction of glucose disposal [46], as co-activators of the major nutrient signalling pathway mTORC1 [711] and in the potentiation of insulin secretion [1214]. Furthermore, a rise in plasma amino acids, especially branched-chain amino acids (BCAAs, i.e. leucine, isoleucine, valine) and aromatic amino acids, have also been tightly associated with insulin resistance [5,6,15,16] and type II diabetes mellitus (TIIDM) [1720].

The movement of amino acids across the biological membranes of cells is controlled by integral membrane transporter proteins, also known as carriers. As a consequence, amino acid transporters are responsible for the modulation of cellular and circulating amino acids concentrations and also, therefore, any amino acids regulating insulin secretion and signalling. Simply stated, anywhere amino acids play an important role in regulating insulin; amino acid transporters will also play a vital role. That said, specific roles for amino acid transporters in insulin regulation is a more recently recognised phenomenon, the elucidation of which was previously limited by the incomplete catalogue of characterised human amino acid transporters [2123] and one requiring the increased convergence of two research fields: nutrient signalling and transporter physiology. The amino acid transporters covered here are all solute carriers (SLCs), utilising the electrochemical energy of ion gradients to drive metabolite transport in either the same (symporter) or opposite (antiporter/exchanger) direction across a membrane. They can also be facilitated diffusers, allowing substrate electrochemical gradients to drive transmembrane translocation. The human genome encodes 65 amino acid and peptide SLCs [1], classified throughout this review by their SLC designation in brackets following the introduction of their common protein name [22,24]. Advances in the characterisation of amino acid transporters highlighting their role in the regulation of insulin signalling are summarised in Figure 1 and Table 1 [48]. We begin with the emerging role of small intestine neutral amino acid/peptide transporters B0AT1 (SLC6A19) and PEPT1 (SLC15A1) in helping to uncover the role of insulin and the hormone fibroblast growth factor 21 (FGF21) in the initiation of dietary amino acid sensing. We then detail the role of vesicular glutamate transporters vGLUTs (SLC17), mitochondrial exchangers (SLC25) and glutamate transporter EAAT2 (SLC1A2) in the amplification of insulin secretion from pancreatic β-cells. Lastly, we examine evidence from amino acid transporters of the SLC38 family and the neutral amino acid exchanger LAT1-4F2hc (SLC7A5–SLC3A2) in regulating liver, skeletal muscle and pancreas insulin responses. We focus on research where a direct link between the regulation of insulin signalling and an amino acid transporter has been made. The purpose is to provide an up-to-date summary of the role of amino acid transporters in insulin-regulated metabolism and, where relevant, their potential as future treatment targets for metabolic disorders such as TIIDM.

Amino acid transporters in the regulation of insulin signalling.

Figure 1.
Amino acid transporters in the regulation of insulin signalling.

(A) Dietary intake gives rise to neutral AA and peptides that are first taken up by B0AT1 and PEPT1, respectively, from the lumen of the intestine. Intestinal L cells secrete GLP-1 and GIP due to increase in neutral AA or nutrients in general. Neutral AAs are then released into the circulation through LAT-1. (B,C) BCAAs and other AAs can activate mTOR/S6K pathway that results in insulin desensitisation under nutrient stress. Glutamine can serve as the substrates of GNG and contribute to EGP in the liver. On the other hand, low levels of AA can decrease mTOR/S6 signalling and up-regulate FGF21 that can subsequently increase Glc uptake and browning of WAT in adipose tissue after binding to FGFR1–4/β-Klotho. (D) In muscle, insulin up-regulates SNAT2 expression through endosomal pools. LAT1 and SNAT3 may also regulate intracellular AA levels that could regulate the uptake of glucose for storage. (E) In pancreas, SNAT3/5 mediates the uptake of glutamine which could provide a potential source of glutamate and finally loaded into vesicles by vGLUT1/2. The efflux of glutamate by EAAT2 is controversial (see text). SNAT2 is up-regulated during ER stress in response to hyper-production of insulin. Leucine entering pancreas through LAT1 allosterically regulates the production of glutamate in mitochondria. Glutamate is pumped out in the cytosol through AGC1 and can stimulate the secretion of insulin by glucose and hormonal mediated pathways. Black lines indicate the route and pathways. Broken lines indicate an as yet unknown mechanism; upward arrow indicates up-regulation or increased levels. Abbreviations: αKG, alpha-ketoglutarate; AA, amino acid; BCAA, branched-chain amino acids; cAMP, cyclic adenosine monophosphate; Cl, chloride ion; EGP, endogenous glucose production; FGF21, fibroblast growth factor 21; FGFR, fibroblast growth factor receptor; Glc, glucose; GDH, glutamate dehydrogenase; GIP, gastric inhibitory peptide; GLP-1, glucagon-like peptide 1; Gln, glutamine; Glu, glutamate; GNG, gluconeogenesis; g6p, glucose-6-phosphate; H, hydrogen ion; mTOR, mammalian target of rapamycin; Na, sodium ion; pKA, protein kinase A; TCA, tricarboxylic acid cycle; WAT, white adipose tissue.

Figure 1.
Amino acid transporters in the regulation of insulin signalling.

(A) Dietary intake gives rise to neutral AA and peptides that are first taken up by B0AT1 and PEPT1, respectively, from the lumen of the intestine. Intestinal L cells secrete GLP-1 and GIP due to increase in neutral AA or nutrients in general. Neutral AAs are then released into the circulation through LAT-1. (B,C) BCAAs and other AAs can activate mTOR/S6K pathway that results in insulin desensitisation under nutrient stress. Glutamine can serve as the substrates of GNG and contribute to EGP in the liver. On the other hand, low levels of AA can decrease mTOR/S6 signalling and up-regulate FGF21 that can subsequently increase Glc uptake and browning of WAT in adipose tissue after binding to FGFR1–4/β-Klotho. (D) In muscle, insulin up-regulates SNAT2 expression through endosomal pools. LAT1 and SNAT3 may also regulate intracellular AA levels that could regulate the uptake of glucose for storage. (E) In pancreas, SNAT3/5 mediates the uptake of glutamine which could provide a potential source of glutamate and finally loaded into vesicles by vGLUT1/2. The efflux of glutamate by EAAT2 is controversial (see text). SNAT2 is up-regulated during ER stress in response to hyper-production of insulin. Leucine entering pancreas through LAT1 allosterically regulates the production of glutamate in mitochondria. Glutamate is pumped out in the cytosol through AGC1 and can stimulate the secretion of insulin by glucose and hormonal mediated pathways. Black lines indicate the route and pathways. Broken lines indicate an as yet unknown mechanism; upward arrow indicates up-regulation or increased levels. Abbreviations: αKG, alpha-ketoglutarate; AA, amino acid; BCAA, branched-chain amino acids; cAMP, cyclic adenosine monophosphate; Cl, chloride ion; EGP, endogenous glucose production; FGF21, fibroblast growth factor 21; FGFR, fibroblast growth factor receptor; Glc, glucose; GDH, glutamate dehydrogenase; GIP, gastric inhibitory peptide; GLP-1, glucagon-like peptide 1; Gln, glutamine; Glu, glutamate; GNG, gluconeogenesis; g6p, glucose-6-phosphate; H, hydrogen ion; mTOR, mammalian target of rapamycin; Na, sodium ion; pKA, protein kinase A; TCA, tricarboxylic acid cycle; WAT, white adipose tissue.

Table 1
Amino acid transporters involved in the regulation of insulin secretion and signalling
Transporter Gene Accession number (UniProt) Location Substrates Tissue expression Mechanism KO phenotype relevant to insulin signalling Ref. 
B0AT1 SLC6A19 Q695T7 PM All neutral Intestine, stomach, kidney, liver, prostate S:1Na+ Up-regulated FGF21, GLP-1, GIP-1
Reduced body weight, postprandial glucose levels, insulin secretion
Altered gut microbiota 
[25,26
PEPT1 SLC15A1 P46059 PM Di- and tri-peptides Small intestine, kidney, pancreas, bile duct, liver S:H+ Reduced body weight gain on HFD, blunted GLP-1 secretion, reduced fat stores [27,28
vGLUT1 SLC17A7 Q9P2U7 Brain (neurons only), endocrine U or A:H+ (Cl)* Reduced incretin-mediated insulin secretion in global KO of vGLUT1. β-cell-specific KOs shown vGLUT1 and 2 are redundant and can both compensate for incretin-induced insulin secretion in a triple KO of all 3 vGLUTs [29,30
vGLUT2 SLC17A6 Q9P2U8 Brain (neurons only), endocrine U or A:H+ (Cl)* 
EAAT2 SLC1A2 P43004 PM D,E Brain (astrocytes, Bergmann glia, neurons), liver, pancreas S: 3Na+/1H+ A:1K+ Contradictory results. Glutamate content in secretory granules is higher than in WT mice. β-cell-specific KO mice show no effect [31,32
GC1 SLC25A22 Q9H936 Mitochondria IM E,D Ubiquitous S: 1H+ No KO phenotype [33
AGC1 SLC25A12 O75746 Mitochondria IM E,D Heart, skeletal muscle, brain, kidney, pancreas§ A:H+ (Ca2+) Deficiency in humans and mice leads to severe neurological symptoms; no pancreas-specific KO reported [3436
SNAT2 SLC38A2 Q96QD8 PM A,S,G,C,Q,N,H,P Ubiquitous S:1Na+ Sub-lethal due to cyanotic dyspnoea [37
SNAT3 SLC38A3 Q99624 PM Q,N,H Eye, liver, kidney, brain, pancreas, adipose, skeletal muscle S:Na+ A:H+ Stunted growth, hypoglycaemia, reduced hepatic amino acids, urea cycle dysregulation, death at 20 days [38,39
SNAT5 SLC38A5 Q8WUX1 PM Q,N,H,A Stomach, brain, liver, lung, small intestine, spleen, colon, kidney S:Na+ A:H+ Minimal abnormal phenotype, pancreatic α-cells proliferation inhibited during glucagon stimulation [4042
LAT1-4F2hc SLC7A5–SLC3A2 Q01650 PM H,M,L,I,V,F,Y,W Pancreatic β cells, brain, ovary, testis, placenta, spleen, colon, blood–brain barrier, foetal liver, activated lymphocytes, tumour cells Lethal phenotype [43,44
Transporter Gene Accession number (UniProt) Location Substrates Tissue expression Mechanism KO phenotype relevant to insulin signalling Ref. 
B0AT1 SLC6A19 Q695T7 PM All neutral Intestine, stomach, kidney, liver, prostate S:1Na+ Up-regulated FGF21, GLP-1, GIP-1
Reduced body weight, postprandial glucose levels, insulin secretion
Altered gut microbiota 
[25,26
PEPT1 SLC15A1 P46059 PM Di- and tri-peptides Small intestine, kidney, pancreas, bile duct, liver S:H+ Reduced body weight gain on HFD, blunted GLP-1 secretion, reduced fat stores [27,28
vGLUT1 SLC17A7 Q9P2U7 Brain (neurons only), endocrine U or A:H+ (Cl)* Reduced incretin-mediated insulin secretion in global KO of vGLUT1. β-cell-specific KOs shown vGLUT1 and 2 are redundant and can both compensate for incretin-induced insulin secretion in a triple KO of all 3 vGLUTs [29,30
vGLUT2 SLC17A6 Q9P2U8 Brain (neurons only), endocrine U or A:H+ (Cl)* 
EAAT2 SLC1A2 P43004 PM D,E Brain (astrocytes, Bergmann glia, neurons), liver, pancreas S: 3Na+/1H+ A:1K+ Contradictory results. Glutamate content in secretory granules is higher than in WT mice. β-cell-specific KO mice show no effect [31,32
GC1 SLC25A22 Q9H936 Mitochondria IM E,D Ubiquitous S: 1H+ No KO phenotype [33
AGC1 SLC25A12 O75746 Mitochondria IM E,D Heart, skeletal muscle, brain, kidney, pancreas§ A:H+ (Ca2+) Deficiency in humans and mice leads to severe neurological symptoms; no pancreas-specific KO reported [3436
SNAT2 SLC38A2 Q96QD8 PM A,S,G,C,Q,N,H,P Ubiquitous S:1Na+ Sub-lethal due to cyanotic dyspnoea [37
SNAT3 SLC38A3 Q99624 PM Q,N,H Eye, liver, kidney, brain, pancreas, adipose, skeletal muscle S:Na+ A:H+ Stunted growth, hypoglycaemia, reduced hepatic amino acids, urea cycle dysregulation, death at 20 days [38,39
SNAT5 SLC38A5 Q8WUX1 PM Q,N,H,A Stomach, brain, liver, lung, small intestine, spleen, colon, kidney S:Na+ A:H+ Minimal abnormal phenotype, pancreatic α-cells proliferation inhibited during glucagon stimulation [4042
LAT1-4F2hc SLC7A5–SLC3A2 Q01650 PM H,M,L,I,V,F,Y,W Pancreatic β cells, brain, ovary, testis, placenta, spleen, colon, blood–brain barrier, foetal liver, activated lymphocytes, tumour cells Lethal phenotype [43,44

Abbreviations: PM, plasma membrane; V, vesicular (membranes); IM, inner membrane; S, symport; A, antiport; U, uniport.

*

Whether the transport mechanism involves proton antiport is suggested but unproven (see refs. [45,46]). The stoichiometry and the exact role of chloride as a substrate remain unclear.

Role in β-islet cells is disputed.

Also displays glutamate:glutamate exchange which limits the maximal rate of proton-equivalent transport.

§

Pancreas expression is low despite its functional importance; AGC2 (SLC25A13) has a higher pancreatic expression (see ref. [47]).

Exchanges cytosolic glutamate and a proton for mitochondrial aspartate under respiring conditions; depends on Ca2+ for substrate release.

Epithelial amino acid transporters B0AT1 (SLC6A19) and PEPT1 (SLC15A1)

Dietary protein restriction has gained increasing interest due to its significant beneficial impact on metabolic health, including improved glucose tolerance, energy expenditure and reduced body weight [4951]. Conversely, long-term high protein diets have been associated with the onset of insulin resistance [52,53]. Dietary protein restriction curtails the development of insulin resistance and hypertriglyceridaemia in mice by instigating the release of the hormone FGF21 in response to reduced hepatic amino acid supply [54,55]. FGF21 is an important metabolic regulator that improves insulin sensitivity, induces ketogenesis and inhibits gluconeogenesis [5658]. Recently, dietary intervention studies in mice highlighted the role of BCAAs in mediating the beneficial effects of protein restriction [59,60]. However, it was later shown that total amino acid restriction, not only BCAA restriction, from the diet was equally important for the beneficial effects of protein restriction. Maida et al. [60,61] showed that BCAA repletion in protein-restricted obese and wild-type (WT) mice restored liver mTORC1 levels but that FGF21 levels remained elevated. These results suggested the dietary loss of multiple amino acids, and not just BCAAs, are required to induce FGF21 and its beneficial metabolic effects. mTORC1 is a serine/threonine kinase that plays an important role in amino acid sensing and growth regulation (reviewed in detail [48,62,63]). mTORC1 is considered a negative regulator of insulin signalling in overfed subjects where overexpression of mTORC1 eventually leads to insulin desensitisation; mainly due to increase in BCAA supply [64]. Dietary restriction by single amino acids, particularly methionine and leucine, also lead to various degrees of up-regulated circulating FGF21 [54,60,61,6567].

Dietary protein is broken down into amino acids and peptides on the apical side of small intestine from where they are absorbed into the blood. The main BCAA transporter of the small intestine is the broad neutral (0) amino acid transporter (B0AT1) [68,69] (Figure 1A). It mediates the uptake of all neutral amino acids1 at the apical membrane of intestinal epithelial cells with transport driven by the symport of one sodium ion per amino acid [7074] (Table 1). It transports all neutral amino acids with similar Vmax2 values but variable Km values that range from 1 to 11 mM for neutral amino acids [71,72]. BCAAs and methionine show the highest affinity, whereas tryptophan is the least preferred substrate. The transporter is trafficked to the intestinal apical membrane by the ancillary proteins angiotensin-converting enzyme 2 (ACE2) and, to a lesser extent, aminopeptidase N [69,75,76]. B0AT1 is expressed in kidney epithelial cells where it is activated by the ACE2 homologue collectrin (TMEM27) [7779]. B0AT1 mRNA is also marginally expressed in pancreas, stomach, liver and colon [8082].

It was not until research beginning in 2011 that B0AT1 was recognised as the uptake pathway linking dietary neutral amino acid to the beneficial health effects of protein restriction mediated by increased insulin sensitivity and circulating FGF21 levels [25,26]. A global B0AT1 knock-out (KO) mouse showed reduced weight gain on a high-fat diet (HFD) and reduced expression of downstream mTORC1 targets in the intestine, liver, muscle and adipose tissue, indicative of lost BCAA activation [25,26]. B0AT1 (−/−) mice exhibited enhanced insulin sensitivity as measured by lower postprandial glucose levels in the absence of insulin secretion. These mice also replicated the effects of protein restriction by inducing the up-regulation of FGF21 in the liver and blood serum [25] with FGF21 levels comparable or higher to those observed in protein-restricted mice and rats [51]. Induction of FGF21 in mice liver also occurs during dietary methionine and leucine restriction but to a lesser extent than the B0AT1 (−/−) mouse ([8386] reviewed in refs. [8789]). Increased energy expenditure due to methionine restriction has been shown to occur only in male mice [86], but the sex-specific effects of FGF21-mediated protein and amino acid restriction in humans remain largely unstudied. Both methionine and leucine are major substrates of B0AT1 and the requirement of multiple neutral amino acids for effective and cumulative FGF21 induction is consistent with the transporter's role as the primary intestinal uptake pathway for neutral amino acids. The reduced plasma glucose recorded in these B0AT1 (−/−) mice seemed to be a result of a 50% reduction in intestinal uptake [26] but without any down-regulation of known sugar transporters [90]. However, the plasma glucose lowering effect of FGF21 has also been attributed to activation of brown adipose tissue (BAT), the browning of white adipose tissue (WAT) and increased hepatic energy consumption, particularly in obese and male rodents [58,9194]. The cause of blunted insulin secretion in B0AT1 (−/−) mice was unknown but possibly due to reduced postprandial glucose levels as a result of FGF21 up-regulation or delayed absorption of glucose or a combination of both (see Perspectives). As all studies involving B0AT1-mediated neutral amino acid restriction have been conducted in mice models caution is warranted when translating these results to human, especially as many of the metabolic effects of FGF21 observed in rodents has not been replicated in primates [reviewed in refs. [95,96]). The other significant phenotype of the B0AT1 (−/−) mouse is the stimulated secretion of the incretin hormones glucagon-like peptide (GLP-1) and gastric inhibitory polypeptide (GIP) [25,97], the role of which in potentiating insulin release is discussed in the next section.

Our laboratory and others have proposed the effects of dietary protein restriction in the B0AT1 (−/−) mouse could be replicated by inhibiting B0AT1, making it a potential target for the alleviation of metabolic disorders that would benefit from the dietary restriction of neutral amino acids, such as TIIDM [98] and phenylketonuria [99]. Several inhibitors of B0AT1 have been identified but none yet with clinical significance [98101]. B0AT1 (−/−) mice displayed hyper-excretion of neutral amino acids in urine but plasma levels remained normal, perhaps as a result of decreased oxidation of amino acids [1,26]. Mutations in human B0AT1 result in Hartnup disorder, which is characterised by malabsorption of amino acids [8082]. Other than the hyper-excretion of neutral amino acids, Hartnup disorder patients are mostly asymptomatic [102], possibly due to modern dietary protein intake being many times the daily requirements of 80–100 g [103]. Compensatory uptake is probably mediated by the peptide transporter PEPT1.

As the major small peptide transporter of the small intestine PEPT1 (SLC15A1) provides additional intestinal absorption capacity for neutral amino acids in the form of di- and tri-peptides [104] (Figure 1A). PEPT1 is a high-capacity, low-affinity transporter (Km of 0.2–10 mM) also expressed at limited levels in the colon, kidney, pancreas and bile duct epithelial cells [105108] (Table 1). It uses the H+ electrochemical gradient to cotransport peptides [104,109]. Previously, peptide uptake by PEPT1 was shown to stimulate GLP-1 secretion [110] and improved glucose homeostasis in healthy, obese and hyperglycaemic mice [111]. PEPT1 (−/−) mice also displayed reduced weight gain and fat deposits on an HFD [27]. In contrast with the phenotype of B0AT1 (−/−) mice, where increased GLP-1 levels were observed [25], the release of GLP-1 was blunted in PEPT1 (−/−) organoids [110]. This discrepancy of GLP-1 levels between PEPT1 (−/−) and B0AT1 (−/−) mice is most likely explained by the expression of PEPT1 in intestinal L cells and B0AT1 in intestinal K cells [112]. Intestinal L cells are located in the distal part of the intestine and are usually referred to as GLP-1-producing cells [113]. The absence of PEPT1 in the KO mouse probably ablates the ability of L cells to sense an increased gut protein load and secrete GLP-1 in response. On the other hand, the absence of B0AT1 would lead to an increase in protein load on the luminal side of the intestine, leading to GLP-1 release from L cells.

β-islet cell glutamate transporters vGLUT (SLC17 family)

Both cytosolic glutamate and leucine can potentiate insulin secretion from pancreatic β-islet cells [114120]. The availability and effect of glutamate are determined by the complex intersection between glucose and amino acid metabolism, including the control of glutamate flux by various intracellular membrane transporters [121,122]. Although its role was previously questioned [123126], intracellular glutamate is now thought to provide a crucial link between glucose- and incretin-stimulated insulin secretion [119]. Critical players in this mechanism are the human vesicular glutamate transporters vGLUT1 (SLC17A7) and vGLUT2 (SLC17A6), which are responsible for loading glutamate into intracellular vesicles — a necessary event in the potentiation of insulin secretion [29,30] (Figure 1E). vGLUT1 and 2 are highly selective l-glutamate transporters [127,128] with a Km of 1–5 mM or slightly lower [129138] and they require Cl for transport activity [127131,136140] (Table 1). Both transporters were first identified as neuronal transporters, vGLUT2 has also been located outside the central nervous system in primary afferent neurons of the intestine and in pancreatic β-cell [30,137,141143]. In β-islet cells, it is vGLUT1- and 2-mediated loading of insulin granular vesicles that is essential for the potentiation of insulin secretion [29,30,119].

The primary stimulus for insulin release is the uptake of glucose into β-cells by the facilitated diffuser GLUT2. This stimulus sets off a regulatory cascade terminating in insulin release at the plasma membrane. Potentiation of this process by glutamate begins with the release of the incretin hormones GLP-1 and GIP from enteroendocrine L and K cells following a meal [113,144146]. Circulating GLP-1 and GIP bind the β-cells plasma membrane incretin receptor, leading to the cyclisation of AMP (cAMP) and instigating a PKA (protein kinase A) signalling cascade [147,148] (Figure 1E). PKA has numerous targets involved in the recruitment and fusion of insulin granules to the membrane [149,150]. Gheni et al. [30,151] identified cytosolic β-cells glutamate as an essential signal mediating incretin-induced potentiation of insulin secretion in rodent models of diabetes, obesity and in insulin-producing cell lines. Incretin signalling induced the loading of glutamate into secretory granules, which was subsequently necessary for enhanced insulin release. Furthermore, vGLUT1 was required for elevating glutamate concentrations in insulin-containing granules; an event that also preceded insulin release [29,30,151]. This amplification of insulin secretion did not occur when vGLUT1 was absent from β-cells as demonstrated using a SLC17A7 (−/−) mouse [30]; vGLUT2, however, can compensate for the loss of vGLUT1 [29]. Interestingly, the source of cytosolic glutamate required for potentiation was provided by the mitochondrial malate–aspartate shuttle, which indicated the important role of mitochondrial-cytosol glutamate flux in the process (see the following section). Membrane-permeable analogues of glutamate were shown to enhance insulin secretion, demonstrating the presence of the amino acid alone as necessary and sufficient in the pathway [30]. Glutamate-mediated potentiation of insulin secretion is impaired very early in the development of TIIDM in humans and rodent models [30,152156].

How glutamate uptake into secretory granules amplifies insulin secretion remains unresolved and is hampered by a lack of understanding of the transport mode vGLUT1 uses to load vesicles. Under most experimental conditions, the membrane potential (ΔΨ) is the major driving force [128130,138,140,157], suggesting the uniport of anionic glutamate. However, the proton gradient established by the V-ATPase can also drive vGLUT function, consistent with glutamate:H+ antiport mechanism [131,138140,157]. No testing of how the extent of glutamate loading or the physical properties of vesicles themselves affect insulin secretion has been conducted. The elevation of cytosolic glutamate required for secretory granule loading establishes the source of glutamate as an important question and highlights the roles of other β-cells amino acid transporters that will now be addressed.

Mitochondrial exchangers (SLC25 family): role in β-cells glutamate availability

Despite earlier evidence for direct glutamate uptake by plasma membrane transporters [158,159], substantial research now suggests synthesis from glucose as the major source of cytosolic glutamate in β-cells [30,31,160]. Intracellular β-cell glutamate can be synthesised from d-glucose via TCA (tricarboxylic acid cycle) cycle-derived α-ketoglutarate by utilising cytosolic/mitochondria aspartate aminotransferase 1 or mitochondrial glutamate dehydrogenase (GDH) (Figure 1E). Glutamine has also been proposed as a significant alternative source of cytosolic glutamate [29,40,122]. Both glutamate and glutamine provide reducing equivalents for NADH production in the TCA cycle and ultimately the synthesis of ATP to facilitate glucose-stimulated insulin secretion via closure of KATP channels (reviewed in ref. [161]). As a result, mitochondrial inner membrane carriers play a pivotal role in the maintenance of cytosolic and mitochondrial glutamate concentrations in β-cells required for potentiation of insulin secretion.

Glutamate transport across the mitochondrial inner membrane occurs via the malate–aspartate shuttle and the mitochondrial glutamate carrier (SLC25A22, GC1) [29,30,34,119,161167] (Figure 1E). The malate–aspartate shuttle involves two mitochondrial transporters: the malate-α-ketoglutarate antiporter (OGC, SLC25A11) and aspartate glutamate carrier 1 (AGC1, SLC25A12). All three exchangers are widely expressed, AGC1 more heavily in electrically excitable tissue but absent from liver, whereas glutamate carrier 1 (GC1) is prominent in the liver and pancreas but only weakly expressed in the brain [47] (Table 1). The physiological role of GC1 is to import cytosolic glutamate into the mitochondria along with H+ symport or OH antiport. Hence, GC1-mediated transport is electroneutral and exhibits a relatively high Km of ∼4–5 mM [167]. AGC1 exchanges an aspartate from the mitochondrial matrix with a glutamate and a proton from the cytosol [35]. The exported aspartate is converted by an aminotransferase GOT1 into oxaloacetate. Oxaloacetate, in turn, is converted into malate which serves as an exchange substrate of OGC. Upon transport back into the mitochondrial matrix, malate provides the reducing equivalent to produce NADH for oxidative phosphorylation. Glutamate is co-transported with a proton by AGC1, meaning each transport cycle is electrogenic if aspartate–glutamate are exchanged but is electroneutral if identical substrates are exchanged. When mitochondria are respiring glutamate uptake is heavily favoured by AGC1 and GC1, due to a strong negative potential and pH chemical gradient components of the proton motive force across the mitochondrial inner membrane [168].

Both GC1 and AGC1 play substantial roles in glutamate-induced insulin secretion [31,33,34,36,169,170]. Although the increase in cytosolic glutamate from mitochondrial glucose oxidation has been demonstrated by several laboratories [30,33,118,119,162,171], the idea remained controversial for some time (see refs. [123,172]). Several lines of evidence have now confirmed mitochondrial glutamate synthesis as vital for the potentiation of β-cell insulin secretion. These are (1) the appearance of cytosolic [13C]-labelled glutamate isotopomers from [U-13C] glucose in metabolic flux experiments [169,173]; (2) inhibition or genetic silencing of AGC1 and malate–aspartate shuttle enzymes [29,36,162,174]; (3) GC1 ablation [33]; (4) demonstration of GDH as a key enzyme in mitochondrial glutamate synthesis for the potentiation of insulin secretion [165,175,176]. The physiological functioning of GC1 and AGC1 in respiring mitochondria leads to a net entry of glutamate into the mitochondrial matrix for GC1 and the recycling of glutamate as part of the malate–aspartate shuttle for AGC1. Glutamate production in the mitochondrial matrix by GDH could potentially provide an increase in cytosolic glutamate by increasing the overall rate of the shuttle and increasing the apparent steady-state concentration of all intermediates, including glutamate. Indeed, the evidence demonstrating a net accumulation of cytosolic glutamate from the malate–aspartate shuttle seems convincing [29,30]. However, an alternative mechanism for net glutamate production hypothesised mitochondria-exported isocitrate is oxidised in the cytosol to form α-ketoglutarate, which then undergoes transamination probably by utilising aspartate. This reactions series could provide an additional input into the malate–aspartate shuttle which would explain the simultaneous decrease in aspartate and increase in cytosolic glutamate following glucose stimulation of islet β-cells [177]. The importance of GDH for glucose-stimulated glutamate synthesis as a singular source for enhanced insulin secretion is also contradicted by several studies [177179]. For example, Li et al. [177] found in human GDH transgenic mice that both glutamine and oxidative deamination of glutamate by leucine-stimulated GDH was associated with enhanced insulin secretion, a process inhibited by high glucose. These results suggested alternative glutamate sources exist to enhance insulin secretion besides glucose-derived glutamate (see SLC38 and LAT1 sections).

It is important to emphasise these mitochondrial carriers are vital for the potentiation of insulin secretion but only indirectly through their role in balancing cytosolic to mitochondrial glutamate concentrations. Insulin secretion can be enhanced simply by the elevation of cytosolic glutamate independently of the source of that glutamate [123,165,172]. For example, supplementation of cytosolic glutamate using a membrane-permeable analogue enhances insulin secretion independently of glutamate supplied by the mitochondria [117,118,120,165].

Other β-islet cell glutamate transporters: EAAT2 (SLC1A2)

mRNA transcripts and protein of the glutamate transporter EAAT2 (SLC1A2) have been detected in the plasma and secretory granular membranes of β-cells [32,141,142,180]. The transporter is part of the SLC1 family of excitatory amino acid and small neutral amino acid transporters [181]. Primarily expressed in neuronal astrocytes, it is responsible for the reuptake of glutamate from excitatory synapses and accounts >90% of total glutamate uptake in the brain [182] (Table 1). EAAT2 accumulates glutamate using the symport of 3 Na+ molecules and one proton in exchange for one K+ molecule. It can transport both Cα enantiomers of aspartate in addition to glutamate and mediates an anion conductance, which is thermodynamically uncoupled from glutamate transport [183187].

EAAT2 has been hypothesised to play two roles in the mechanism of incretin-dependent insulin secretion [188] (Figure 1E). Feldmann et al. [162] showed potentiation of insulin release resulted from inhibition of EAAT2, which implied the transporter was effluxing glutamate at the plasma membrane. This reversal of the transporter from its normal role accumulating glutamate is difficult to reconcile with the known thermodynamic drivers of EAAT2 (see ref. [181]). A second potential role of EAAT2 was proposed by Gammelsaeter et al. [32] who showed that EAAT2 was co-expressed with vGLUT3 (SLC17A8) in secretory granules. An EAAT2 KO mouse displayed increased granular glutamate concentration but decreased the rate of insulin exocytosis. The authors hypothesised a co-ordinated role of EAAT2 and vGLUT3 in recycling glutamate through secretory granules to mediate insulin secretion [189]. Any role for EAAT2 in insulin secretion is, however, strongly disputed [31]. A pancreatic-specific KO of EAAT2 revealed no effect on β-cell viability or glucose-stimulated insulin secretion [31]. Furthermore, no EAAT2 protein or mRNA was detected in β-cells.

SLC38 family of neutral amino acid symporters

SLC38 family transporters mediate sodium-dependent influx and efflux of small neutral amino acids in all human tissues [190]. Three SLC38 members, SNAT2 (SLC38A2), SNAT3 (SLC38A3) and SNAT5 (SLC38A5) play direct roles in the regulation and mediation of insulin signalling. SNAT2 is a ubiquitously expressed sodium-dependent symporter of, predominately, small neutral amino acids alanine, serine, glycine and cysteine but can also transport glutamine, asparagine, methionine, proline and histidine [190,191] (Table 1). SNAT2 is regulated by various metabolic signals such as amino acid availability, amino acid starvation, hypertonic stress and insulin [192197]. An increase in amino acid uptake by insulin was first identified in rat skeletal muscle [192,198] and was subsequently shown to stimulate plasma clearance of leucine in humans [3]. Both increased glutamine uptake and SNAT2 plasma membrane expression occurred via rapid trafficking of transporter-containing endosomal pools to the plasma membrane following exposure to insulin in rat myocytes [192,193,199] (Figure 1D). Essential amino acids also increased SNAT2 mRNA expression in humans in an mTORC1-dependent manner [200]. Due to the co-stimulatory effects of insulin and leucine on mTOR signalling [9], these results suggest a common activation pathway for increased SNAT2 expression. Despite the evidence for insulin-induced increase in glutamine uptake [192,193], earlier insulin-induced increases in plasma clearance for non-SNAT2 substrates (e.g. leucine [3]) have not been explained. However, the up-regulation of other amino acid transporter mRNA such as LAT1 (SLC7A5), which transports leucine, has been noted in myocytes [200]. For an extensive overview of the role of SNAT2 and amino acids in skeletal muscle metabolism, the reader is directed to several excellent reviews [201,202].

SNAT2 also plays a potential role in the development of endoplasmic reticulum (ER) stress response in pancreatic β-islets during the progression of TIIDM in mice [203] (Figure 1E). Peripheral tissue insulin resistance increases β-cell synthesis of insulin and cell proliferation, thereby inducing the ER stress. The unfolded protein response (UPR) is also induced as a direct result of increased insulin synthesis [204]. Prolonged UPR activation leads to apoptosis, which limits circulating insulin levels and leads to TIIDM [5]. To overcome the translational repression associated with ER stress, an anabolic transcriptional pathway up-regulates the expression and activity of SNAT2 and other transporters. The up-regulation of SNAT2 was termed ‘self-defeating’ as the response leads to increased protein synthesis, thereby aggravating the ER stress, subsequent apoptosis of β-cells and exacerbating TIIDM progression [203].

SNAT3 is a Na+-dependent symporter and H+ antiporter, transporting glutamine, asparagine and histidine with high expression in liver, kidney, rat brain, adipose tissue, eye and muscle [190,205] (Table 1). In the liver, SNAT3 is involved in glutamine uptake from periportal hepatocytes and the release of glutamine from the perivenous hepatocytes into circulation [206] (Figure 1B). Glutamine plays an important role in energy metabolism in the liver as one of the major sources for gluconeogenesis via α-ketoglutarate and the TCA cycle [207]. Ablation of SNAT3 in mice reduced the amount of intracellular glutamine and spared glutamine from gluconeogenesis due to the reduction in liver glutaminase 2 protein levels; the first step in the conversion pathway [38]. Reduction in gluconeogenesis is the probable cause of reduced plasma glucose (<2.8 mM) and subsequent decreased insulin levels. Unexpectedly, plasma glutamine levels in these mice seem to be unaltered whereas intracellular leucine levels were reduced [38]. One explanation for these results is that in WT animals, intracellular glutamine accumulation through SNAT3 is utilised as an efflux substrate by LAT1 in exchange for the uptake of leucine [208]. Hence, the loss of glutamine uptake in SNAT3 (−/−) mice resulted in a lost capacity for leucine accumulation. The decreased levels of intracellular leucine and plasma insulin also explain the reduced expression of downstream mTORC1 pathway targets in SNAT3 (−/−) mice, which could not otherwise be expected as glutamine cannot directly or sufficiently activate mTOR signalling [38]. Consistent with a significant role for SNAT3 in insulin-mediated gluconeogenesis, direct insulin application onto WT mouse hepatocytes displayed decreased SNAT3 mRNA [209]. This down-regulation would reduce the pool of glutamine available for hepatic glucose production. However, such a link may be tissue-specific as insulin perfusion does not affect SNAT3 function in muscle [210]. SNAT3 has also been reported as playing a role in β-cell glutamine acquisition [39]. In this context, SNAT3 may provide an additional extracellular source of glutamate for β-islet cells as a consequence of the intracellular conversion of glutamine to glutamate (see β-cell sections) [121,211,212].

SNAT5 has similar transport properties to SNAT3, also co-transporting one Na+ ion in exchange for a proton. It accepts glutamine, asparagine, histidine and alanine as major substrates and is expressed in intestine, kidney, retina, lung, pancreas and cervix [213]. It also has been shown to be responsible for the uptake of glutamine in hepatocytes [213,214]. SNAT5 has raised recent interest due to a role in the regulation of amino acid homeostasis by α-cell-liver glucagon signalling. We include this topic here because glucagon and insulin actions are intricately linked to the regulation of global metabolism. Elevated serum glucagon is also symptomatic of TIIDM progression [215,216]. SNAT5 was shown to be up-regulated at the plasma membrane of α-cells in an mTORC1-dependent manner [41,217]. This up-regulation was caused predominately by elevated circulating levels of glutamine and alanine, which induces increased glucagon secretion and expansion (hyperplasia) of α-cell numbers [41,42]. The more general elevation of circulating amino acids was induced by inhibition of the G-protein-coupled glucagon receptor (GCGR) in the liver. The normal activation of the GCGR in hepatocytes controls liver gluconeogenesis utilising amino acid catabolism in the process. Therefore, inhibition of the GCGR leads to a down-regulation of amino acid uptake and catabolism, and the concurrent elevation of plasma amino acid levels [41,42,218]. The process is hypothesised to work as a feedback loop for glucagon, linking amino acid utilisation in the liver to the sensing of specific elevated amino acids by α-cells in order to kick-start further glucagon release. This was confirmed by demonstrating that both GCGR (−/−) and SNAT5 (−/−) mice independently caused hyperplasia of pancreatic α-cells [41,218]. The SNAT5-dependent uptake of amino acids activates mTORC1 leading to cell proliferation and compensatory additional glucagon release. Unexplained by current understanding of this mechanism is how the SNAT5 substrates alanine and glutamine stimulate α-cells proliferation when they have not been shown as direct or sufficient activators of mTORC1. It is unknown if inhibiting SNAT5 may represent a potential treatment to alleviate hyperglycaemia as knocking out the transporter in mice reduces α-cell mass and glucagon secretion [41,219] and the interference with long-term glucagon signalling may entail adverse consequences (see ref. [215]). One publication has also implicated SNAT5 in β-cells as playing a substantial role in increasing intracellular glutamate and incretin-enhanced insulin release — potentially another alternative pathway for the β-cell acquisition of glutamate [40] (see β-cell sections). Intracellular glutamine may also serve as an efflux substrate for the neutral amino acid exchanger LAT1 in exchange for leucine (Figure 1E).

Neutral amino acid exchanger LAT1-4F2hc (SLC7A5–SLC3A1)

LAT1 (SLC7A5) is a major transporter of BCAAs in many non-epithelial cells and is involved in insulin secretion directly through its cytosolic accumulation of leucine [43] (Figure 1E). LAT1 is a heteromeric amino acid transporter requiring the ancillary subunit 4F2hc (SLC3A2) [220]. It exchanges neutral amino acids more rapidly than accumulative Na+-dependent amino acid transporters and is best viewed as a ‘harmoniser’ of cytosolic BCAA concentrations [1,68,221] (Table 1). The apparent affinity for large neutral amino acid such as leucine, isoleucine and methionine in vitro is 100-fold higher on the cytosolic side compared with the extracellular side [222]. LAT1 expression is ubiquitous but specifically noted in the brain, spleen, placenta, testis, colon, pancreas, adipocytes and skeletal muscle [223225].

It has been recently proposed that elevated levels of circulating BCAAs in TIIDM patients could be due to down-regulation of BCAAs catabolism in visceral adipose tissue and liver [226,227]. The increased levels of BCAAs act as anaplerotic substrates and cause an overload of mitochondrial substrates, which in turn could down-regulate oxidation of fatty acids in muscle [228,229]. Since LAT1 is the major transporter controlling intracellular BCAA concentrations in adipocytes, it is likely to play an important role in the efflux of BCAAs resulting from any down-regulated catabolism (Figure 1C). One study also highlighted the role of LAT-1 in muscle tissue by showing that glucose can reduce the mRNA levels of LAT1 in myocytes after inactivating the regulator of cellular energetics, 5′-adenosine monophosphate-activated protein kinase (AMPK) [230]. Down-regulation of LAT-1 could reduce the uptake of BCAAs in skeletal muscle and increase BCAA levels in plasma. This hypothesis requires testing in vivo to confirm its physiological significance.

Expression of LAT1 in β-cells facilitates leucine uptake, which acts as an allosteric activator of GDH [231,232], enhancing insulin secretion via increased glutamate mitochondrial production and islet cell proliferation [43,165,233]. Activation of mTORC1 signalling is also promoted by LAT1-mediated leucine uptake into β-cells [43]. The originally identified activator of GDH was the leucine analogue, and LAT1 substrate/inhibitor, BCH (2-aminobicyclo[2.2.1]heptane-2-carboxylic acid) [231,234237]. The importance of leucine-mediated GDH activation to insulin secretion is confirmed by children with hyperinsulinaemia hypoglycaemia familial 6 syndrome [121,176,238,239] (OMIM: 606762). Patients exhibit abnormal insulin secretion caused by dominant activating mutations in GDH, which replicates leucine-induced GDH potentiation of insulin secretion and can be exacerbated by leucine-induced hypersecretion of insulin. A likely candidate of obligatory efflux via LAT1 is glutamine, which is present at high cytosolic concentrations [240] (Figure 1E). The activation of GDH by leucine is well correlated with an increase in β-cell glutaminolysis, suggesting glutamine availability is being increased [231,234,243]. LAT1 and other SLC7 heteromeric amino acid transporters may also be directly responsible for mTORC1 activation due to their ability to be re-directed from the plasma membrane to lysosomes by the proteins LAPTM4b and girdin [241,242].

Perspectives and future directions

Several lines of research over the past 20 years have demonstrated amino acid transport plays a significant role in modulating the stimulation and sensitivity of insulin in numerous tissues. One unresolved question is why incretin hormone release in the B0AT1 KO mouse does not lead to a stimulation of insulin release from the pancreas, as would be expected by our understanding of the canonical mechanisms of the incretin-insulin signalling? We hypothesise this could be due to the actions of increased circulating FGF21 in B0AT1 KO mice (Figure 2). Although direct administration of FGF21 was shown to stimulate insulin secretion in diabetic mice [244], no mechanism directly linking protein-restricted FGF21 levels and β-cell signalling has been established to our knowledge. Any such mechanism could form part of a wider adaptive response to protein restriction orchestrated by FGF21-insulin signalling cross-talk [245,246]. The insulin sensitisation effect of FGF21 results from enhanced glucose utilisation by WAT and cardiac tissue without any increase in plasma insulin concentration [66,86]. A very similar phenotype is observed in B0AT1 KO mice [25,26]. Increased insulin sensitivity thus requires secretion of FGF21 due to the upstream restriction of neutral amino acids, or a caloric:protein imbalance sensed by the liver. This mechanism is supported by the unique endocrine role of FGF21 being induced by both protein restriction [25,51,54,60,66,67,247,248] and carbohydrate overload [249,250] but not caloric variation per se, suggesting the imbalance in caloric:protein dietary ratio as the underlying stimulus [50,88,251]. It appears likely that most of the beneficial and anti-type II diabetic effects observed in B0AT1 KO mice are mediated by FGF21 and these effects are also missing from FGF21-deficient mice [51].

Global integration of dietary amino acid transport and FGF21-insulin networks.

Figure 2.
Global integration of dietary amino acid transport and FGF21-insulin networks.

Reduced uptake of neutral amino acids in the lumen of the intestine by B0AT1 causes protein restriction and secretion of FGF21 in the liver. FGF21 is the major mediator behind the global effects of protein restriction resulting in increased glucose uptake in heart and WAT and browning of WAT. We hypothesise that FGF21 acts directly at the pancreatic β-cells or indirectly through neuronal–endocrinal mechanisms to suppress insulin secretion at the same time as increasing insulin sensitivity through its known actions in cardiac and adipose tissue.

Figure 2.
Global integration of dietary amino acid transport and FGF21-insulin networks.

Reduced uptake of neutral amino acids in the lumen of the intestine by B0AT1 causes protein restriction and secretion of FGF21 in the liver. FGF21 is the major mediator behind the global effects of protein restriction resulting in increased glucose uptake in heart and WAT and browning of WAT. We hypothesise that FGF21 acts directly at the pancreatic β-cells or indirectly through neuronal–endocrinal mechanisms to suppress insulin secretion at the same time as increasing insulin sensitivity through its known actions in cardiac and adipose tissue.

Due to its established signalling roles in adipose tissue and the hypothalamus [87,88], it is also possible FGF21 suppression of insulin secretion is mediated through indirect autonomic nervous system or endocrinal signals, with FGF21 binding to a tissue-specific fibroblast growth factor receptor (FGFR)-β-Klotho receptor sub-type [252]. Alternatively, the lack of incretin effect could be caused by reduced leucine uptake in B0AT1 KO mice, or reduced β-cell mTORC1 signalling, and subsequent lack of allosteric GDH activation. The increase in insulin sensitivity observed in the absence of B0AT1 may be partially caused by a reduction in serum glucagon levels and the resulting reduction in liver gluconeogenesis.

The integrated regulation of insulin signalling and potential existence of an unexplored FGF21–amino acid–insulin pathway is interesting but hardly the only unresolved research problem raised by this review. The exploration of the role of various amino acid transporters in insulin-affected tissues such as skeletal muscle, adipose and liver, has barely begun and many novel areas of research connecting amino acid transporters to insulin controlled metabolism remain to be investigated. The necessity of mTORC1 signalling in conjunction with insulin response pathways in many cells makes amino acid transporters such as LAT1 and SNATs obvious focus for future research. The liver itself could represent the site for integration of amino acid endocrine signalling networks that signal energy balance and restriction of protein independent of dietary caloric content. As amino acid transporters represent the primary entry pathway into most tissues and are often metabolic bottlenecks, they represent many of the missing links in signalling networks that respond to protein restriction or modulate the downstream effect of insulin, FGF21 and other global endocrine hormones. Moreover, many of the important transporter-mediated effects outlined in this review have not yet been verified as biologically relevant in humans. For example, the research findings on B0AT1 in the small intestine, vGLUTs in β-cells, and SNAT5 in α-cells are so far confined to rodent models. As a result, the important roles several amino acid transporters play in global insulin signalling and the significant role of amino acids in global metabolism mean this field is likely to become increasingly significant for human medical research in coming years.

1

Neutral amino acids are the 15 of 20 proteinogenic amino acids which exist predominately as zwitterions and have no net elemental charge at physiological pH (7.2–7.4). They include: Leu, Ile, Met, Phe, Val, Trp, Tyr, Ala, Gly, Ser, Thr, Gln, Asn, Cys, Pro.

2

At various points, we use the technical measures of transport kinetics Vmax and Km: the former refers to the maximal rate of transport activity (capacity) the latter is the Michaelis constant, the substrate concentration required to induce the half maximal rate measure. Given certain assumptions, the Michaelis constant is a measure of relative transport affinity, with the lower the number the higher the transport affinity.

Abbreviations

     
  • AA

    amino acids

  •  
  • ACE2

    angiotensin-converting enzyme 2

  •  
  • AGC1

    aspartate glutamate carrier 1

  •  
  • AMPK

    5′-adenosine monophosphate-activated protein kinase

  •  
  • BAT

    brown adipose tissue

  •  
  • BCAA

    branched-chain amino acid

  •  
  • BCH

    2-aminobicyclo[2.2.1]heptane-2-carboxylic acid

  •  
  • ER

    endoplasmic reticulum

  •  
  • FGF21

    fibroblast growth factor 21

  •  
  • FGFR

    fibroblast growth factor receptor 1–4

  •  
  • GCGR

    G-protein-coupled glucagon receptor

  •  
  • GDH

    glutamate dehydrogenase

  •  
  • GIP

    gastric inhibitory peptide

  •  
  • GLP1

    glucagon-like peptide 1

  •  
  • HFD

    high-fat diet

  •  
  • IGF1

    insulin-like growth factor 1

  •  
  • KO

    knock-out

  •  
  • mTOR

    mammalian target of rapamycin

  •  
  • PKA

    protein kinase A

  •  
  • SLC

    solute carrier

  •  
  • TCA

    tricarboxylic acid

  •  
  • TIIDM

    type II diabetes mellitus

  •  
  • UPR

    unfolded protein response

  •  
  • WAT

    white adipose tissue

  •  
  • WT

    wild type

Funding

S.J.F. was funded by the Medical Advances Without Animals (MAWA) Fellowship [Grant reference S4104091]. K.J. was funded by the Australian National Health and Medical Research Council [NHMRC, Grant reference GNT 1128442].

Acknowledgements

The authors would like to acknowledge Professor Stefan Bröer and Ms Aditya Yadav for their suggestions and support in editing this review. The authors apologise to all colleagues whose work we were unable to cover in this review owing to space constraints.

Competing Interests

The Authors declare that there are no competing interests associated with the manuscript.

References

References
1
Bröer
,
S.
and
Bröer
,
A.
(
2017
)
Amino acid homeostasis and signalling in mammalian cells and organisms
.
Biochem. J.
474
,
1935
1963
2
Sinex
,
F.M.
,
Macmullen
,
J.
and
Hastings
,
A.B.
(
1952
)
The effect of insulin on the incorporation of C14 into the protein of rat diaphragm
.
J. Biol. Chem.
198
,
615
619
PMID:
[PubMed]
3
Castellino
,
P.
,
Luzi
,
L.
,
Simonson
,
D.C.
,
Haymond
,
M.
and
DeFronzo
,
R.A.
(
1987
)
Effect of insulin and plasma amino acid concentrations on leucine metabolism in man. Role of substrate availability on estimates of whole body protein synthesis
.
J. Clin. Invest.
80
,
1784
1793
4
Ahlborg
,
G.
,
Felig
,
P.
,
Hagenfeldt
,
L.
,
Hendler
,
R.
and
Wahren
,
J.
(
1974
)
Substrate turnover during prolonged exercise in man: splanchnic and leg metabolism of glucose, free fatty acids, and amino acids
.
J. Clin. Invest.
53
,
1080
1090
5
Newgard
,
C.B.
,
An
,
J.
,
Bain
,
J.R.
,
Muehlbauer
,
M.J.
,
Stevens
,
R.D.
,
Lien
,
L.F.
et al.  (
2009
)
A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance
.
Cell Metab.
9
,
311
326
6
Tai
,
E.S.
,
Tan
,
M.L.
,
Stevens
,
R.D.
,
Low
,
Y.L.
,
Muehlbauer
,
M.J.
,
Goh
,
D.L.
et al.  (
2010
)
Insulin resistance is associated with a metabolic profile of altered protein metabolism in Chinese and Asian-Indian men
.
Diabetologia
53
,
757
767
7
Kimball
,
S.R.
and
Jefferson
,
L.S.
(
2010
)
Control of translation initiation through integration of signals generated by hormones, nutrients, and exercise
.
J. Biol. Chem.
285
,
29027
29032
8
Anthony
,
J.C.
,
Reiter
,
A.K.
,
Anthony
,
T.G.
,
Crozier
,
S.J.
,
Lang
,
C.H.
,
MacLean
,
D.A.
et al.  (
2002
)
Orally administered leucine enhances protein synthesis in skeletal muscle of diabetic rats in the absence of increases in 4E-BP1 or S6K1 phosphorylation
.
Diabetes
51
,
928
936
9
Krause
,
U.
,
Bertrand
,
L.
,
Maisin
,
L.
,
Rosa
,
M.
and
Hue
,
L.
(
2002
)
Signalling pathways and combinatory effects of insulin and amino acids in isolated rat hepatocytes
.
Eur. J. Biochem.
269
,
3742
3750
10
Campbell
,
L.E.
,
Wang
,
X.
and
Proud
,
C.G.
(
1999
)
Nutrients differentially regulate multiple translation factors and their control by insulin
.
Biochem. J.
344
,
433
441
11
Hara
,
K.
,
Yonezawa
,
K.
,
Weng
,
Q.P.
,
Kozlowski
,
M.T.
,
Belham
,
C.
and
Avruch
,
J.
(
1998
)
Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism
.
J. Biol. Chem.
273
,
14484
14494
12
Newsholme
,
P.
,
Brennan
,
L.
and
Bender
,
K.
(
2006
)
Amino acid metabolism, β-cell function, and diabetes
.
Diabetes
55
,
S39
S47
13
Floyd JC
,
J.
,
Fajans
,
S.S.
,
Conn
,
J.W.
,
Knopf
,
R.F.
and
Rull
,
J.
(
1966
)
Stimulation of insulin secretion by amino acids
.
J. Clin. Invest.
45
,
1487
1502
14
Gannon
,
N.P.
and
Vaughan
,
R.A.
(
2016
)
Leucine-induced anabolic-catabolism: two sides of the same coin
.
Amino Acids
48
,
321
336
15
Wang
,
T.J.
,
Larson
,
M.G.
,
Vasan
,
R.S.
,
Cheng
,
S.
,
Rhee
,
E.P.
,
McCabe
,
E.
et al.  (
2011
)
Metabolite profiles and the risk of developing diabetes
.
Nat. Med.
17
,
448
453
16
Würtz
,
P.
,
Soininen
,
P.
,
Kangas
,
A.J.
,
Rönnemaa
,
T.
,
Lehtimäki
,
T.
,
Kähönen
,
M.
et al.  (
2013
)
Branched-chain and aromatic amino acids are predictors of insulin resistance in young adults
.
Diabetes Care
36
,
648
655
17
Giesbertz
,
P.
and
Daniel
,
H.
(
2016
)
Branched-chain amino acids as biomarkers in diabetes
.
Curr. Opin. Clin. Nutr. Metab. Care
19
,
48
54
18
Shah
,
S.H.
,
Crosslin
,
D.R.
,
Haynes
,
C.S.
,
Nelson
,
S.
,
Turer
,
C.B.
,
Stevens
,
R.D.
et al.  (
2012
)
Branched-chain amino acid levels are associated with improvement in insulin resistance with weight loss
.
Diabetologia
55
,
321
330
19
van Nielen
,
M.
,
Feskens
,
E.J.
,
Mensink
,
M.
,
Sluijs
,
I.
,
Molina
,
E.
,
Amiano
,
P.
et al.  (
2014
)
Dietary protein intake and incidence of type 2 diabetes in Europe: the EPIC-InterAct Case-Cohort Study
.
Diabetes Care
37
,
1854
1862
20
Menni
,
C.
,
Fauman
,
E.
,
Erte
,
I.
,
Perry
,
J.R.
,
Kastenmüller
,
G.
,
Shin
,
S.-Y.
et al.  (
2013
)
Biomarkers for type 2 diabetes and impaired fasting glucose using a nontargeted metabolomics approach
.
Diabetes
62
,
4270
21
Saier MH
,
J.
(
2016
)
Transport protein evolution deduced from analysis of sequence, topology and structure
.
Curr. Opin. Struct. Biol.
38
,
9
17
22
Perland
,
E.
and
Fredriksson
,
R.
(
2017
)
Classification systems of secondary active transporters
.
Trends Pharmacol. Sci.
38
,
305
315
23
César-Razquin
,
A.
,
Snijder
,
B.
,
Frappier-Brinton
,
T.
,
Isserlin
,
R.
,
Gyimesi
,
G.
,
Bai
,
X.
et al.  (
2015
)
A call for systematic research on solute carriers
.
Cell
162
,
478
487
24
Schlessinger
,
A.
,
Yee
,
S.W.
,
Sali
,
A.
and
Giacomini
,
K.M.
(
2013
)
SLC classification: an update
.
Clin. Pharmacol. Ther.
94
,
19
23
25
Jiang
,
Y.
,
Rose
,
A.J.
,
Sijmonsma
,
T.P.
,
Bröer
,
A.
,
Pfenninger
,
A.
,
Herzig
,
S.
et al.  (
2015
)
Mice lacking neutral amino acid transporter B(0)AT1 (Slc6a19) have elevated levels of FGF21 and GLP-1 and improved glycaemic control
.
Mol. Metab.
4
,
406
417
26
Bröer
,
A.
,
Juelich
,
T.
,
Vanslambrouck
,
J.M.
,
Tietze
,
N.
,
Solomon
,
P.S.
,
Holst
,
J.
et al.  (
2011
)
Impaired nutrient signaling and body weight control in a Na+ neutral amino acid cotransporter (Slc6a19)-deficient mouse
.
J. Biol. Chem.
286
,
26638
26651
27
Kolodziejczak
,
D.
,
Spanier
,
B.
,
Pais
,
R.
,
Kraiczy
,
J.
,
Stelzl
,
T.
,
Gedrich
,
K.
et al.  (
2013
)
Mice lacking the intestinal peptide transporter display reduced energy intake and a subtle maldigestion/malabsorption that protects them from diet-induced obesity
.
Am. J. Physiol. Gastrointest. Liver Physiol.
304
,
G897
G907
28
Nässl
,
A.M.
,
Rubio-Aliaga
,
I.
,
Fenselau
,
H.
,
Marth
,
M.K.
,
Kottra
,
G.
and
Daniel
,
H.
(
2011
)
Amino acid absorption and homeostasis in mice lacking the intestinal peptide transporter PEPT1
.
Am. J. Physiol. Gastrointest. Liver Physiol.
301
,
G128
G137
29
Murao
,
N.
,
Yokoi
,
N.
,
Honda
,
K.
,
Han
,
G.
,
Hayami
,
T.
,
Gheni
,
G.
et al.  (
2017
)
Essential roles of aspartate aminotransferase 1 and vesicular glutamate transporters in β-cell glutamate signaling for incretin-induced insulin secretion
.
PLoS ONE
12
,
e0187213
30
Gheni
,
G.
,
Ogura
,
M.
,
Iwasaki
,
M.
,
Yokoi
,
N.
,
Minami
,
K.
,
Nakayama
,
Y.
et al.  (
2014
)
Glutamate acts as a key signal linking glucose metabolism to incretin/cAMP action to amplify insulin secretion
.
Cell Rep.
9
,
661
673
31
Zhou
,
Y.
,
Waanders
,
L.F.
,
Holmseth
,
S.
,
Guo
,
C.
,
Berger
,
U.V.
,
Li
,
Y.
et al.  (
2014
)
Proteome analysis and conditional deletion of the EAAT2 glutamate transporter provide evidence against a role of EAAT2 in pancreatic insulin secretion in mice
.
J. Biol. Chem.
289
,
1329
1344
32
Gammelsaeter
,
R.
,
Coppola
,
T.
,
Marcaggi
,
P.
,
Storm-Mathisen
,
J.
,
Chaudhry
,
F.A.
,
Attwell
,
D.
et al.  (
2011
)
A role for glutamate transporters in the regulation of insulin secretion
.
PLoS ONE
6
,
e22960
33
Casimir
,
M.
,
Lasorsa
,
F.M.
,
Rubi
,
B.
,
Caille
,
D.
,
Palmieri
,
F.
,
Meda
,
P.
et al.  (
2009
)
Mitochondrial glutamate carrier GC1 as a newly identified player in the control of glucose-stimulated insulin secretion
.
J. Biol. Chem.
284
,
25004
25014
34
Rubi
,
B.
,
del Arco
,
A.
,
Bartley
,
C.
,
Satrustegui
,
J.
and
Maechler
,
P.
(
2004
)
The malate-aspartate NADH shuttle member Aralar1 determines glucose metabolic fate, mitochondrial activity, and insulin secretion in β cells
.
J. Biol. Chem.
279
,
55659
55666
35
Palmieri
,
L.
,
Pardo
,
B.
,
Lasorsa
,
F.M.
,
del Arco
,
A.
,
Kobayashi
,
K.
,
Iijima
,
M.
et al.  (
2001
)
Citrin and aralar1 are Ca2+-stimulated aspartate/glutamate transporters in mitochondria
.
EMBO J.
20
,
5060
5069
36
Casimir
,
M.
,
Rubi
,
B.
,
Frigerio
,
F.
,
Chaffard
,
G.
and
Maechler
,
P.
(
2009
)
Silencing of the mitochondrial NADH shuttle component aspartate-glutamate carrier AGC1/Aralar1 in INS-1E cells and rat islets
.
Biochem. J.
424
,
459
466
37
Weidenfeld
,
S.
,
Chupin
,
C.J.A.
,
Rozowsky
,
S.
and
Kuebler
,
W.M.
(
2017
)
Sodium-coupled neutral amino acid transporter SNAT2 counteracts edema formation and reduces autophagy and ER stress in acute lung injury
.
FASEB J.
31
,
725.4
https://www.fasebj.org/doi/abs/10.109/fasebj.31.1_supplement.725.4
38
Chan
,
K.
,
Busque
,
S.M.
,
Sailer
,
M.
,
Stoeger
,
C.
,
Bröer
,
S.
,
Daniel
,
H.
et al.  (
2016
)
Loss of function mutation of the Slc38a3 glutamine transporter reveals its critical role for amino acid metabolism in the liver, brain, and kidney
.
Pflugers Arch.
468
,
213
227
39
Gammelsaeter
,
R.
,
Jenstad
,
M.
,
Bredahl
,
M.K.
,
Gundersen
,
V.
and
Chaudhry
,
F.A.
(
2009
)
Complementary expression of SN1 and SAT2 in the islets of Langerhans suggests concerted action of glutamine transport in the regulation of insulin secretion
.
Biochem. Biophys. Res. Commun.
381
,
378
382
40
Hashim
,
M.
,
Yokoi
,
N.
,
Takahashi
,
H.
,
Gheni
,
G.
,
Okechi
,
O.S.
,
Hayami
,
T.
et al.  (
2018
)
Inhibition of SNAT5 induces incretin responsive state from incretin unresponsive state in pancreatic β-cells: study of β-cell spheroid clusters as a model
.
Diabetes
67
,
1795
1806
41
Kim
,
J.
,
Okamoto
,
H.
,
Huang
,
Z.
,
Anguiano
,
G.
,
Chen
,
S.
,
Liu
,
Q.
et al.  (
2017
)
Amino acid transporter Slc38a5 controls glucagon receptor inhibition-induced pancreatic α cell hyperplasia in mice
.
Cell Metab.
25
,
1348
1361.e8
42
Dean
,
E.D.
,
Li
,
M.
,
Prasad
,
N.
,
Wisniewski
,
S.N.
,
Von Deylen
,
A.
,
Spaeth
,
J.
et al.  (
2017
)
Interrupted glucagon signaling reveals hepatic α cell axis and role for l-glutamine in α cell proliferation
.
Cell Metab.
25
,
1362
1373.e5
43
Cheng
,
Q.
,
Beltran
,
V.D.
,
Chan
,
S.M.
,
Brown
,
J.R.
,
Bevington
,
A.
and
Herbert
,
T.P.
(
2016
)
System-L amino acid transporters play a key role in pancreatic β-cell signalling and function
.
J. Mol. Endocrinol.
56
,
175
187
44
Sinclair
,
L.V.
,
Rolf
,
J.
,
Emslie
,
E.
,
Shi
,
Y.B.
,
Taylor
,
P.M.
and
Cantrell
,
D.A.
(
2013
)
Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation
.
Nat. Immunol.
14
,
500
508
45
Omote
,
H.
,
Miyaji
,
T.
,
Juge
,
N.
and
Moriyama
,
Y.
(
2011
)
Vesicular neurotransmitter transporter: bioenergetics and regulation of glutamate transport
.
Biochemistry
50
,
5558
5565
46
Reimer
,
R.J.
(
2013
)
SLC17: a functionally diverse family of organic anion transporters
.
Mol. Aspects Med.
34
,
350
359
47
Amoedo
,
N.D.
,
Punzi
,
G.
,
Obre
,
E.
,
Lacombe
,
D.
,
De Grassi
,
A.
,
Pierri
,
C.L.
et al.  (
2016
)
AGC1/2, the mitochondrial aspartate-glutamate carriers
.
Biochim. Biophys. Acta
1863
,
2394
2412
48
Yoon
,
M.S.
(
2017
)
The role of mammalian target of rapamycin (mTOR) in insulin signaling
.
Nutrients
9
,
E1176
49
Pezeshki
,
A.
,
Zapata
,
R.C.
,
Singh
,
A.
,
Yee
,
N.J.
and
Chelikani
,
P.K.
(
2016
)
Low protein diets produce divergent effects on energy balance
.
Sci. Rep.
6
,
25145
50
Solon-Biet
,
S.M.
,
McMahon
,
A.C.
,
Ballard
,
J.W.
,
Ruohonen
,
K.
,
Wu
,
L.E.
,
Cogger
,
V.C.
et al.  (
2014
)
The ratio of macronutrients, not caloric intake, dictates cardiometabolic health, aging, and longevity in ad libitum-fed mice
.
Cell Metab.
19
,
418
430
51
Laeger
,
T.
,
Henagan
,
T.M.
,
Albarado
,
D.C.
,
Redman
,
L.M.
,
Bray
,
G.A.
,
Noland
,
R.C.
et al.  (
2014
)
FGF21 is an endocrine signal of protein restriction
.
J. Clin. Invest.
124
,
3913
3922
52
Rietman
,
A.
,
Schwarz
,
J.
,
Tomé
,
D.
,
Kok
,
F.J.
and
Mensink
,
M.
(
2014
)
High dietary protein intake, reducing or eliciting insulin resistance?
Eur. J. Clin. Nutr.
68
,
973
979
53
Tremblay
,
F.
,
Lavigne
,
C.
,
Jacques
,
H.
and
Marette
,
A.
(
2007
)
Role of dietary proteins and amino acids in the pathogenesis of insulin resistance
.
Annu. Rev. Nutr.
27
,
293
310
54
Maida
,
A.
,
Zota
,
A.
,
Sjøberg
,
K.A.
,
Schumacher
,
J.
,
Sijmonsma
,
T.P.
,
Pfenninger
,
A.
et al.  (
2016
)
A liver stress-endocrine nexus promotes metabolic integrity during dietary protein dilution
.
J. Clin. Invest.
126
,
3263
3278
55
Maida
,
A.
,
Zota
,
A.
,
Vegiopoulos
,
A.
,
Appak-Baskoy
,
S.
,
Augustin
,
H.G.
,
Heikenwalder
,
M.
et al.  (
2018
)
Dietary protein dilution limits dyslipidemia in obesity through FGF21-driven fatty acid clearance
.
J. Nutr. Biochem.
57
,
189
196
56
Kharitonenkov
,
A.
and
Adams
,
A.C.
(
2014
)
Inventing new medicines: the FGF21 story
.
Mol. Metab.
3
,
221
229
57
Li
,
H.
,
Wu
,
G.
,
Fang
,
Q.
,
Zhang
,
M.
,
Hui
,
X.
,
Sheng
,
B.
et al.  (
2018
)
Fibroblast growth factor 21 increases insulin sensitivity through specific expansion of subcutaneous fat
.
Nat. Commun.
9
,
272
58
Camporez
,
J.P.
,
Jornayvaz
,
F.R.
,
Petersen
,
M.C.
,
Pesta
,
D.
,
Guigni
,
B.A.
,
Serr
,
J.
et al.  (
2013
)
Cellular mechanisms by which FGF21 improves insulin sensitivity in male mice
.
Endocrinology
154
,
3099
3109
59
Fontana
,
L.
,
Cummings
,
N.E.
,
Arriola Apelo
,
S.I.
,
Neuman
,
J.C.
,
Kasza
,
I.
,
Schmidt
,
B.A.
et al.  (
2016
)
Decreased consumption of branched-chain amino acids improves metabolic health
.
Cell Rep.
16
,
520
530
60
Cummings
,
N.E.
,
Williams
,
E.M.
,
Kasza
,
I.
,
Konon
,
E.N.
,
Schaid
,
M.D.
,
Schmidt
,
B.A.
et al.  (
2018
)
Restoration of metabolic health by decreased consumption of branched-chain amino acids
.
J. Physiol.
596
,
623
645
61
Maida
,
A.
,
Chan
,
J.S.K.
,
Sjøberg
,
K.A.
,
Zota
,
A.
,
Schmoll
,
D.
,
Kiens
,
B.
et al.  (
2017
)
Repletion of branched chain amino acids reverses mTORC1 signaling but not improved metabolism during dietary protein dilution
.
Mol. Metab.
6
,
873
881
62
Yoon
,
M.S.
(
2016
)
The emerging role of branched-chain amino acids in insulin resistance and metabolism
.
Nutrients
8
,
E405
63
Yoon
,
M.S.
and
Choi
,
C.S.
(
2016
)
The role of amino acid-induced mammalian target of rapamycin complex 1(mTORC1) signaling in insulin resistance
.
Exp. Mol. Med.
48
,
e201
64
Um
,
S.H.
,
Frigerio
,
F.
,
Watanabe
,
M.
,
Picard
,
F.
,
Joaquin
,
M.
,
Sticker
,
M.
et al.  (
2004
)
Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity
.
Nature
431
,
200
205
65
De Sousa-Coelho
,
A.L.
,
Marrero
,
P.F.
and
Haro
,
D.
(
2012
)
Activating transcription factor 4-dependent induction of FGF21 during amino acid deprivation
.
Biochem. J.
443
,
165
171
66
Wanders
,
D.
,
Forney
,
L.A.
,
Stone
,
K.P.
,
Burk
,
D.H.
,
Pierse
,
A.
and
Gettys
,
T.W.
(
2017
)
FGF21 mediates the thermogenic and insulin-sensitizing effects of dietary methionine restriction but not its effects on hepatic lipid metabolism
.
Diabetes
66
,
858
867
67
Wanders
,
D.
,
Stone
,
K.P.
,
Dille
,
K.
,
Simon
,
J.
,
Pierse
,
A.
and
Gettys
,
T.W.
(
2015
)
Metabolic responses to dietary leucine restriction involve remodeling of adipose tissue and enhanced hepatic insulin signaling
.
Biofactors
41
,
391
402
68
Bröer
,
S.
and
Fairweather
,
S.J.
(
2018
)
Amino acid transport across the mammalian intestine
.
Compr. Physiol.
9
,
343
373
69
Kowalczuk
,
S.
,
Bröer
,
A.
,
Tietze
,
N.
,
Vanslambrouck
,
J.M.
,
Rasko
,
J.E.
and
Bröer
,
S.
(
2008
)
A protein complex in the brush-border membrane explains a Hartnup disorder allele
.
FASEB J.
22
,
2880
2887
70
Bröer
,
S.
(
2008
)
Amino acid transport across mammalian intestinal and renal epithelia
.
Physiol. Rev.
88
,
249
286
71
Bohmer
,
C.
,
Bröer
,
A.
,
Munzinger
,
M.
,
Kowalczuk
,
S.
,
Rasko
,
J.E.
,
Lang
,
F.
et al.  (
2005
)
Characterization of mouse amino acid transporter B0AT1 (slc6a19)
.
Biochem. J.
389
,
745
751
72
Camargo
,
S.M.
,
Makrides
,
V.
,
Virkki
,
L.V.
,
Forster
,
I.C.
and
Verrey
,
F.
(
2005
)
Steady-state kinetic characterization of the mouse B(0)AT1 sodium-dependent neutral amino acid transporter
.
Pflugers Arch.
451
,
338
348
73
Bröer
,
S.
(
2009
)
The role of the neutral amino acid transporter B0AT1 (SLC6A19) in Hartnup disorder and protein nutrition
.
IUBMB Life
61
,
591
599
74
Bröer
,
A.
,
Klingel
,
K.
,
Kowalczuk
,
S.
,
Rasko
,
J.E.
,
Cavanaugh
,
J.
and
Bröer
,
S.
(
2004
)
Molecular cloning of mouse amino acid transport system B0, a neutral amino acid transporter related to Hartnup disorder
.
J. Biol. Chem.
279
,
24467
24476
75
Fairweather
,
S.J.
,
Bröer
,
A.
,
O'Mara
,
M.L.
and
Bröer
,
S.
(
2012
)
Intestinal peptidases form functional complexes with the neutral amino acid transporter B(0)AT1
.
Biochem. J.
446
,
135
148
76
Singer
,
D.
,
Camargo
,
S.M.
,
Ramadan
,
T.
,
Schäfer
,
M.
,
Mariotta
,
L.
,
Herzog
,
B.
et al.  (
2012
)
Defective intestinal amino acid absorption in Ace2 null mice
.
Am. J. Physiol. Gastrointest. Liver Physiol.
303
,
G686
G695
77
Malakauskas
,
S.M.
,
Quan
,
H.
,
Fields
,
T.A.
,
McCall
,
S.J.
,
Yu
,
M.J.
,
Kourany
,
W.M.
et al.  (
2007
)
Aminoaciduria and altered renal expression of luminal amino acid transporters in mice lacking novel gene collectrin
.
Am. J. Physiol. Renal Physiol.
292
,
F533
F544
78
Danilczyk
,
U.
,
Sarao
,
R.
,
Remy
,
C.
,
Benabbas
,
C.
,
Stange
,
G.
,
Richter
,
A.
et al.  (
2006
)
Essential role for collectrin in renal amino acid transport
.
Nature
444
,
1088
1091
79
Fairweather
,
S.J.
,
Bröer
,
A.
,
Subramanian
,
N.
,
Tumer
,
E.
,
Cheng
,
Q.
,
Schmoll
,
D.
et al.  (
2015
)
Molecular basis for the interaction of the mammalian amino acid transporters B0AT1 and B0AT3 with their ancillary protein collectrin
.
J. Biol. Chem.
290
,
24308
24325
80
Bröer
,
S.
,
Cavanaugh
,
J.A.
and
Rasko
,
J.E.
(
2005
)
Neutral amino acid transport in epithelial cells and its malfunction in Hartnup disorder
.
Biochem. Soc Trans.
33
,
233
236
81
Seow
,
H.F.
,
Bröer
,
S.
,
Bröer
,
A.
,
Bailey
,
C.G.
,
Potter
,
S.J.
,
Cavanaugh
,
J.A.
et al.  (
2004
)
Hartnup disorder is caused by mutations in the gene encoding the neutral amino acid transporter SLC6A19
.
Nat. Genet.
36
,
1003
1007
82
Kleta
,
R.
,
Romeo
,
E.
,
Ristic
,
Z.
,
Ohura
,
T.
,
Stuart
,
C.
,
Arcos-Burgos
,
M.
et al.  (
2004
)
Mutations in SLC6A19, encoding B0AT1, cause Hartnup disorder
.
Nat. Genet.
36
,
999
1002
83
Stone
,
K.P.
,
Wanders
,
D.
,
Orgeron
,
M.
,
Cortez
,
C.C.
and
Gettys
,
T.W.
(
2014
)
Mechanisms of increased in vivo insulin sensitivity by dietary methionine restriction in mice
.
Diabetes
63
,
3721
3733
84
Wanders
,
D.
,
Stone
,
K.P.
,
Forney
,
L.A.
,
Cortez
,
C.C.
,
Dille
,
K.N.
,
Simon
,
J.
et al.  (
2016
)
Role of GCN2-independent signaling through a noncanonical PERK/NRF2 pathway in the physiological responses to dietary methionine restriction
.
Diabetes
65
,
1499
1510
85
Lees
,
E.K.
,
Banks
,
R.
,
Cook
,
C.
,
Hill
,
S.
,
Morrice
,
N.
,
Grant
,
L.
et al.  (
2017
)
Direct comparison of methionine restriction with leucine restriction on the metabolic health of C57BL/6J mice
.
Sci. Rep.
7
,
9977
86
Yu
,
D.
,
Yang
,
S.E.
,
Miller
,
B.R.
,
Wisinski
,
J.A.
,
Sherman
,
D.S.
,
Brinkman
,
J.A.
et al.  (
2018
)
Short-term methionine deprivation improves metabolic health via sexually dimorphic, mTORC1-independent mechanisms
.
FASEB J.
32
,
3471
3482
87
Forney
,
L.A.
,
Stone
,
K.P.
,
Wanders
,
D.
and
Gettys
,
T.W.
(
2018
)
Sensing and signaling mechanisms linking dietary methionine restriction to the behavioral and physiological components of the response
.
Front. Neuroendocrinol.
51
,
36
45
88
Hill
,
C.M.
,
Berthoud
,
H.R.
,
Münzberg
,
H.
and
Morrison
,
C.D.
(
2018
)
Homeostatic sensing of dietary protein restriction: a case for FGF21
.
Front. Neuroendocrinol.
51
,
125
131
89
Hill
,
C.M.
and
Morrison
,
C.D.
(
2018
)
Dietary branched chain amino acids and metabolic health: when less is more
.
J. Physiol.
596
,
555
556
90
Javed
,
K.
,
Cheng
,
Q.
,
Carroll
,
A.J.
,
Truong
,
T.T.
and
Bröer
,
S.
(
2018
)
Development of biomarkers for inhibition of SLC6A19 (B(0)AT1) – a potential target to treat metabolic disorders
.
Int. J. Mol. Sci.
19
,
E3597
91
Emanuelli
,
B.
,
Vienberg
,
S.G.
,
Smyth
,
G.
,
Cheng
,
C.
,
Stanford
,
K.I.
,
Arumugam
,
M.
et al.  (
2014
)
Interplay between FGF21 and insulin action in the liver regulates metabolism
.
J. Clin. Invest.
124
,
515
527
92
Coskun
,
T.
,
Bina
,
H.A.
,
Schneider
,
M.A.
,
Dunbar
,
J.D.
,
Hu
,
C.C.
,
Chen
,
Y.
et al.  (
2008
)
Fibroblast growth factor 21 corrects obesity in mice
.
Endocrinology
149
,
6018
6027
93
Xu
,
J.
,
Lloyd
,
D.J.
,
Hale
,
C.
,
Stanislaus
,
S.
,
Chen
,
M.
,
Sivits
,
G.
et al.  (
2009
)
Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice
.
Diabetes
58
,
250
259
94
Sarruf
,
D.A.
,
Thaler
,
J.P.
,
Morton
,
G.J.
,
German
,
J.
,
Fischer
,
J.D.
,
Ogimoto
,
K.
et al.  (
2010
)
Fibroblast growth factor 21 action in the brain increases energy expenditure and insulin sensitivity in obese rats
.
Diabetes
59
,
1817
1824
95
Potthoff
,
M.J.
(
2017
)
FGF21 and metabolic disease in 2016: a new frontier in FGF21 biology
.
Nat. Rev. Endocrinol.
13
,
74
76
96
Staiger
,
H.
,
Keuper
,
M.
,
Berti
,
L.
,
de Angelis M
,
H.
and
Häring
,
H.U.
(
2017
)
Fibroblast growth factor 21-metabolic role in mice and men
.
Endocr. Rev.
38
,
468
488
97
Reimann
,
F.
,
Ward
,
P.S.
and
Gribble
,
F.M.
(
2006
)
Signaling mechanisms underlying the release of glucagon-like peptide 1
.
Diabetes
55
,
S78
S85
98
Cheng
,
Q.
,
Shah
,
N.
,
Bröer
,
A.
,
Fairweather
,
S.
,
Jiang
,
Y.
,
Schmoll
,
D.
et al.  (
2017
)
Identification of novel inhibitors of the amino acid transporter B(0) AT1 (SLC6A19), a potential target to induce protein restriction and to treat type 2 diabetes
.
Br. J. Pharmacol.
174
,
468
482
99
Belanger
,
A.M.
,
Przybylska
,
M.
,
Gefteas
,
E.
,
Furgerson
,
M.
,
Geller
,
S.
,
Kloss
,
A.
et al.  (
2018
)
Inhibiting neutral amino acid transport for the treatment of phenylketonuria
.
JCI Insight
3
,
121762
100
Pochini
,
L.
,
Seidita
,
A.
,
Sensi
,
C.
,
Scalise
,
M.
,
Eberini
,
I.
and
Indiveri
,
C.
(
2014
)
Nimesulide binding site in the B0AT1 (SLC6A19) amino acid transporter. Mechanism of inhibition revealed by proteoliposome transport assay and molecular modelling
.
Biochem. Pharmacol.
89
,
422
430
101
Danthi
,
S.J.
,
Liang
,
B.
,
Smicker
,
O.
,
Coupland
,
B.
,
Gregory
,
J.
,
Gefteas
,
E.
et al.  (
2019
)
Identification and characterization of inhibitors of a neutral amino acid transporter, SLC6A19, using two functional cell-based assays
.
SLAS Discov.
24
,
114
120
102
Scriver
,
C.R.
,
Mahon
,
B.
,
Levy
,
H.L.
,
Clow
,
C.L.
,
Reade
,
T.M.
,
Kronick
,
J.
et al.  (
1987
)
The Hartnup phenotype: Mendelian transport disorder, multifactorial disease
.
Am. J. Hum. Genet.
40
,
401
412
PMID:
[PubMed]
103
Matthews
,
D.
(
1991
)
Protein Absorption: Development and Present State of the Subject
,
Wiley-Liss
,
New York
, p.
414
104
Liang
,
R.
,
Fei
,
Y.J.
,
Prasad
,
P.D.
,
Ramamoorthy
,
S.
,
Han
,
H.
,
Yang-Feng
,
T.L.
et al.  (
1995
)
Human intestinal H+/peptide cotransporter: cloning, functional expression, and chromosomal localization
.
J. Biol. Chem.
270
,
6456
6463
105
Knütter
,
I.
,
Rubio-Aliaga
,
I.
,
Boll
,
M.
,
Hause
,
G.
,
Daniel
,
H.
,
Neubert
,
K.
et al.  (
2002
)
H+-peptide cotransport in the human bile duct epithelium cell line SK-ChA-1
.
Am. J. Physiol. Gastrointest. Liver Physiol.
283
,
G222
G229
106
Bockman
,
D.E.
,
Ganapathy
,
V.
,
Oblak
,
T.G.
and
Leibach
,
F.H.
(
1997
)
Localization of peptide transporter in nuclei and lysosomes of the pancreas
.
Int. J. Pancreatol.
22
,
221
225
107
Groneberg
,
D.A.
,
Döring
,
F.
,
Eynott
,
P.R.
,
Fischer
,
A.
and
Daniel
,
H.
(
2001
)
Intestinal peptide transport: ex vivo uptake studies and localization of peptide carrier PEPT1
.
Am. J. Physiol. Gastrointest. Liver Physiol.
281
,
G697
G704
108
Ogihara
,
H.
,
Saito
,
H.
,
Shin
,
B.C.
,
Terada
,
T.
,
Takenoshita
,
S.
,
Nagamachi
,
Y.
et al.  (
1996
)
Immuno-localization of H+/peptide cotransporter in rat digestive tract
.
Biochem. Biophys. Res. Commun.
220
,
848
852
109
Ganapathy
,
V.
and
Leibach
,
F.H.
(
1985
)
Is intestinal peptide transport energized by a proton gradient?
Am. J. Physiol.
249
,
G153
G160
110
Zietek
,
T.
,
Rath
,
E.
,
Haller
,
D.
and
Daniel
,
H.
(
2015
)
Intestinal organoids for assessing nutrient transport, sensing and incretin secretion
.
Sci. Rep.
5
,
16831
111
Dranse
,
H.J.
,
Waise
,
T.M.Z.
,
Hamr
,
S.C.
,
Bauer
,
P.V.
,
Abraham
,
M.A.
,
Rasmussen
,
B.A.
et al.  (
2018
)
Physiological and therapeutic regulation of glucose homeostasis by upper small intestinal PepT1-mediated protein sensing
.
Nat. Commun.
9
,
1118
112
Diakogiannaki
,
E.
,
Pais
,
R.
,
Tolhurst
,
G.
,
Parker
,
H.E.
,
Horscroft
,
J.
,
Rauscher
,
B.
et al.  (
2013
)
Oligopeptides stimulate glucagon-like peptide-1 secretion in mice through proton-coupled uptake and the calcium-sensing receptor
.
Diabetologia
56
,
2688
2696
113
Gutierrez-Aguilar
,
R.
and
Woods
,
S.C.
(
2011
)
Nutrition and L and K-enteroendocrine cells
.
Curr. Opin. Endocrinol. Diabetes Obes.
18
,
35
41
114
Milner
,
R.D.
(
1969
)
The mechanism by which leucine and arginine stimulate insulin release in vitro
.
Biochim. Biophys. Acta
192
,
154
156
115
Milner
,
R.D.
(
1969
)
Stimulation of insulin secretion in vitro by essential amino acids
.
Lancet
1
,
1075
1076
116
Gylfe
,
E.
(
1976
)
Comparison of the effects of leucines, non-metabolizable leucine analogues and other insulin secretagogues on the activity of glutamate dehydrogenase
.
Acta Diabetol. Lat.
13
,
20
24
117
Sener
,
A.
,
Conget
,
I.
,
Rasschaert
,
J.
,
Leclercq-Meyer
,
V.
,
Villanueva-Peñacarrillo
,
M.L.
,
Valverde
,
I.
et al.  (
1994
)
Insulinotropic action of glutamic acid dimethyl ester
.
Am. J. Physiol.
267
,
E573
E584
118
Høy
,
M.
,
Maechler
,
P.
,
Efanov
,
A.M.
,
Wollheim
,
C.B.
,
Berggren
,
P.O.
and
Gromada
,
J.
(
2002
)
Increase in cellular glutamate levels stimulates exocytosis in pancreatic β-cells
.
FEBS Lett.
531
,
199
203
119
Maechler
,
P.
and
Wollheim
,
C.B.
(
1999
)
Mitochondrial glutamate acts as a messenger in glucose-induced insulin exocytosis
.
Nature
402
,
685
689
120
Maechler
,
P.
,
Kennedy
,
E.D.
,
Wang
,
H.
and
Wollheim
,
C.B.
(
1998
)
Desensitization of mitochondrial Ca2+ and insulin secretion responses in the β cell
.
J. Biol. Chem.
273
,
20770
20778
121
Li
,
C.
,
Buettger
,
C.
,
Kwagh
,
J.
,
Matter
,
A.
,
Daikhin
,
Y.
,
Nissim
,
I.B.
et al.  (
2004
)
A signaling role of glutamine in insulin secretion
.
J. Biol. Chem.
279
,
13393
13401
122
Fahien
,
L.A.
and
MacDonald
,
M.J.
(
2011
)
The complex mechanism of glutamate dehydrogenase in insulin secretion
.
Diabetes
60
,
2450
2454
123
MacDonald
,
M.J.
and
Fahien
,
L.A.
(
2000
)
Glutamate is not a messenger in insulin secretion
.
J. Biol. Chem.
275
,
34025
34027
124
Yamada
,
S.
,
Komatsu
,
M.
,
Sato
,
Y.
,
Yamauchi
,
K.
,
Aizawa
,
T.
and
Hashizume
,
K.
(
2001
)
Glutamate is not a major conveyer of ATP-sensitive K+ channel-independent glucose action in pancreatic islet β cell
.
Endocr. J.
48
,
391
395
125
Uno
,
K.
,
Yamada
,
T.
,
Ishigaki
,
Y.
,
Imai
,
J.
,
Hasegawa
,
Y.
,
Sawada
,
S.
et al.  (
2015
)
A hepatic amino acid/mTOR/S6K-dependent signalling pathway modulates systemic lipid metabolism via neuronal signals
.
Nat. Commun.
6
,
7940
126
Jitrapakdee
,
S.
,
Wutthisathapornchai
,
A.
,
Wallace
,
J.C.
and
MacDonald
,
M.J.
(
2010
)
Regulation of insulin secretion: role of mitochondrial signalling
.
Diabetologia
53
,
1019
1032
127
Naito
,
S.
and
Ueda
,
T.
(
1985
)
Characterization of glutamate uptake into synaptic vesicles
.
J. Neurochem.
44
,
99
109
128
Moriyama
,
Y.
and
Yamamoto
,
A.
(
1995
)
Vesicular l-glutamate transporter in microvesicles from bovine pineal glands. Driving force, mechanism of chloride anion activation, and substrate specificity
.
J. Biol. Chem.
270
,
22314
22320
129
Juge
,
N.
,
Gray
,
J.A.
,
Omote
,
H.
,
Miyaji
,
T.
,
Inoue
,
T.
,
Hara
,
C.
et al.  (
2010
)
Metabolic control of vesicular glutamate transport and release
.
Neuron
68
,
99
112
130
Juge
,
N.
,
Yoshida
,
Y.
,
Yatsushiro
,
S.
,
Omote
,
H.
and
Moriyama
,
Y.
(
2006
)
Vesicular glutamate transporter contains two independent transport machineries
.
J. Biol. Chem.
281
,
39499
39506
131
Carlson
,
M.D.
,
Kish
,
P.E.
and
Ueda
,
T.
(
1989
)
Characterization of the solubilized and reconstituted ATP-dependent vesicular glutamate uptake system
.
J. Biol. Chem.
264
,
7369
7376
PMID:
[PubMed]
132
Schäfer
,
M.K.
,
Varoqui
,
H.
,
Defamie
,
N.
,
Weihe
,
E.
and
Erickson
,
J.D.
(
2002
)
Molecular cloning and functional identification of mouse vesicular glutamate transporter 3 and its expression in subsets of novel excitatory neurons
.
J. Biol. Chem.
277
,
50734
50748
133
Gras
,
C.
,
Herzog
,
E.
,
Bellenchi
,
G.C.
,
Bernard
,
V.
,
Ravassard
,
P.
,
Pohl
,
M.
et al.  (
2002
)
A third vesicular glutamate transporter expressed by cholinergic and serotoninergic neurons
.
J. Neurosci.
22
,
5442
5451
134
Fremeau
,
R.T.,
Jr
,
Troyer
,
M.D.
,
Pahner
,
I.
,
Nygaard
,
G.O.
,
Tran
,
C.H.
,
Reimer
,
R.J.
et al.  (
2001
)
The expression of vesicular glutamate transporters defines two classes of excitatory synapse
.
Neuron
31
,
247
260
135
Herzog
,
E.
,
Bellenchi
,
G.C.
,
Gras
,
C.
,
Bernard
,
V.
,
Ravassard
,
P.
,
Bedet
,
C.
et al.  (
2001
)
The existence of a second vesicular glutamate transporter specifies subpopulations of glutamatergic neurons
.
J. Neurosci.
21
,
RC181
136
Varoqui
,
H.
,
Schäfer
,
M.K.
,
Zhu
,
H.
,
Weihe
,
E.
and
Erickson
,
J.D.
(
2002
)
Identification of the differentiation-associated Na+/PI transporter as a novel vesicular glutamate transporter expressed in a distinct set of glutamatergic synapses
.
J. Neurosci.
22
,
142
155
137
Bai
,
L.
,
Xu
,
H.
,
Collins
,
J.F.
and
Ghishan
,
F.K.
(
2001
)
Molecular and functional analysis of a novel neuronal vesicular glutamate transporter
.
J. Biol. Chem.
276
,
36764
36769
138
Bellocchio
,
E.E.
,
Reimer
,
R.J.
,
Jr
,
F.R.
and
Edwards
,
R.H.
(
2000
)
Uptake of glutamate into synaptic vesicles by an inorganic phosphate transporter
.
Science
289
,
957
960
139
Schenck
,
S.
,
Wojcik
,
S.M.
,
Brose
,
N.
and
Takamori
,
S.
(
2009
)
A chloride conductance in VGLUT1 underlies maximal glutamate loading into synaptic vesicles
.
Nat. Neurosci.
12
,
156
162
140
Wolosker
,
H.
,
de Souza
,
D.O.
and
de Meis
,
L.
(
1996
)
Regulation of glutamate transport into synaptic vesicles by chloride and proton gradient
.
J. Biol. Chem.
271
,
11726
11731
141
Manfras
,
B.J.
and
Boehm
,
B.O.
(
1995
)
Expression of a glutamate transporter cDNA in human pancreatic islets
.
Exp. Clin. Endocrinol. Diabetes
103
,
95
98
142
Kim
,
S.Y.
,
Chao
,
W.
,
Choi
,
S.Y.
and
Volsky
,
D.J.
(
2003
)
Cloning and characterization of the 3′-untranslated region of the human excitatory amino acid transporter 2 transcript
.
J. Neurochem.
86
,
1458
1467
143
Bai
,
L.
,
Zhang
,
X.
and
Ghishan
,
F.K.
(
2003
)
Characterization of vesicular glutamate transporter in pancreatic α- and β-cells and its regulation by glucose
.
Am. J. Physiol. Gastrointest. Liver Physiol.
284
,
G808
G814
144
Cataland
,
S.
,
Crockett
,
S.E.
,
Brown
,
J.C.
and
Mazzaferri
,
E.L.
(
1974
)
Gastric inhibitory polypeptide (GIP) stimulation by oral glucose in man
.
J. Clin. Endocrinol. Metab.
39
,
223
228
145
Kreymann
,
B.
,
Williams
,
G.
,
Ghatei
,
M.A.
and
Bloom
,
S.R.
(
1987
)
Glucagon-like peptide-1 7-36: a physiological incretin in man
.
Lancet
2
,
1300
1304
146
Mojsov
,
S.
,
Kopczynski
,
M.G.
and
Habener
,
J.F.
(
1990
)
Both amidated and nonamidated forms of glucagon-like peptide I are synthesized in the rat intestine and the pancreas
.
J. Biol. Chem.
265
,
8001
8008
PMID:
[PubMed]
147
Weir
,
G.C.
,
Mojsov
,
S.
,
Hendrick
,
G.K.
and
Habener
,
J.F.
(
1989
)
Glucagonlike peptide I (7-37) actions on endocrine pancreas
.
Diabetes
38
,
338
342
148
Siegel
,
E.G.
and
Creutzfeldt
,
W.
(
1985
)
Stimulation of insulin release in isolated rat islets by GIP in physiological concentrations and its relation to islet cyclic AMP content
.
Diabetologia
28
,
857
861
149
Shibasaki
,
T.
,
Takahashi
,
H.
,
Miki
,
T.
,
Sunaga
,
Y.
,
Matsumura
,
K.
,
Yamanaka
,
M.
et al.  (
2007
)
Essential role of Epac2/Rap1 signaling in regulation of insulin granule dynamics by cAMP
.
Proc. Natl Acad. Sci. U.S.A.
104
,
19333
19338
150
Seino
,
S.
and
Shibasaki
,
T.
(
2005
)
PKA-dependent and PKA-independent pathways for cAMP-regulated exocytosis
.
Physiol. Rev.
85
,
1303
1342
151
Yokoi
,
N.
,
Gheni
,
G.
,
Takahashi
,
H.
and
Seino
,
S.
(
2016
)
β-Cell glutamate signaling: its role in incretin-induced insulin secretion
.
J. Diabetes Invest.
7
,
38
43
152
Muscelli
,
E.
,
Mari
,
A.
,
Casolaro
,
A.
,
Camastra
,
S.
,
Seghieri
,
G.
,
Gastaldelli
,
A.
et al.  (
2008
)
Separate impact of obesity and glucose tolerance on the incretin effect in normal subjects and type 2 diabetic patients
.
Diabetes
57
,
1340
1348
153
Muscelli
,
E.
,
Mari
,
A.
,
Natali
,
A.
,
Astiarraga
,
B.D.
,
Camastra
,
S.
,
Frascerra
,
S.
et al.  (
2006
)
Impact of incretin hormones on β-cell function in subjects with normal or impaired glucose tolerance
.
Am. J. Physiol. Endocrinol. Metab.
291
,
E1144
E11450
154
Ostenson
,
C.G.
,
Khan
,
A.
,
Abdel-Halim
,
S.M.
,
Guenifi
,
A.
,
Suzuki
,
K.
,
Goto
,
Y.
et al.  (
1993
)
Abnormal insulin secretion and glucose metabolism in pancreatic islets from the spontaneously diabetic GK rat
.
Diabetologia
36
,
3
8
155
Holst
,
J.J.
,
Knop
,
F.K.
,
Vilsbøll
,
T.
,
Krarup
,
T.
and
Madsbad
,
S.
(
2011
)
Loss of incretin effect is a specific, important, and early characteristic of type 2 diabetes
.
Diabetes Care
34
,
S251
S257
156
Nauck
,
M.A.
,
Heimesaat
,
M.M.
,
Orskov
,
C.
,
Holst
,
J.J.
,
Ebert
,
R.
and
Creutzfeldt
,
W.
(
1993
)
Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus
.
J. Clin. Invest.
91
,
301
307
157
Tabb
,
J.S.
,
Kish
,
P.E.
,
Van Dyke
,
R.
and
Ueda
,
T.
(
1992
)
Glutamate transport into synaptic vesicles. Roles of membrane potential, pH gradient, and intravesicular pH
.
J. Biol. Chem.
267
,
15412
15418
PMID:
[PubMed]
158
Weaver
,
C.D.
,
Gundersen
,
V.
and
Verdoorn
,
T.A.
(
1998
)
A high affinity glutamate/aspartate transport system in pancreatic islets of Langerhans modulates glucose-stimulated insulin secretion
.
J. Biol. Chem.
273
,
1647
1653
159
Chevassus
,
H.
,
Renard
,
E.
,
Bertrand
,
G.
,
Mourand
,
I.
,
Puech
,
R.
,
Molinier
,
N.
et al.  (
2002
)
Effects of oral monosodium (l)-glutamate on insulin secretion and glucose tolerance in healthy volunteers
.
Br. J. Clin. Pharmacol.
53
,
641
643
160
Sehlin
,
J.
(
1972
)
Uptake and oxidation of glutamic acid in mammalian pancreatic islets
.
Hormones
3
,
156
166
PMID:
[PubMed]
161
Otter
,
S.
and
Lammert
,
E.
(
2016
)
Exciting times for pancreatic islets: glutamate signaling in endocrine cells
.
Trends Endocrinol. Metab.
27
,
177
188
162
Feldmann
,
N.
,
del Rio
,
R.M.
,
Gjinovci
,
A.
,
Tamarit-Rodriguez
,
J.
,
Wollheim
,
C.B.
and
Wiederkehr
,
A.
(
2011
)
Reduction of plasma membrane glutamate transport potentiates insulin but not glucagon secretion in pancreatic islet cells
.
Mol. Cell. Endocrinol.
338
,
46
57
163
MacDonald
,
M.J.
,
Longacre
,
M.J.
,
Stoker
,
S.W.
,
Kendrick
,
M.
,
Thonpho
,
A.
,
Brown
,
L.J.
et al.  (
2011
)
Differences between human and rodent pancreatic islets: low pyruvate carboxylase, ATP citrate lyase, and pyruvate carboxylation and high glucose-stimulated acetoacetate in human pancreatic islets
.
J. Biol. Chem.
286
,
18383
18396
164
Marquard
,
J.
,
Otter
,
S.
,
Welters
,
A.
,
Stirban
,
A.
,
Fischer
,
A.
,
Eglinger
,
J.
et al.  (
2015
)
Characterization of pancreatic NMDA receptors as possible drug targets for diabetes treatment
.
Nat. Med.
21
,
363
372
165
Vetterli
,
L.
,
Carobbio
,
S.
,
Pournourmohammadi
,
S.
,
Martin-Del-Rio
,
R.
,
Skytt
,
D.M.
,
Waagepetersen
,
H.S.
et al.  (
2012
)
Delineation of glutamate pathways and secretory responses in pancreatic islets with β-cell-specific abrogation of the glutamate dehydrogenase
.
Mol. Biol. Cell
23
,
3851
3862
166
Anno
,
T.
,
Uehara
,
S.
,
Katagiri
,
H.
,
Ohta
,
Y.
,
Ueda
,
K.
,
Mizuguchi
,
H.
et al.  (
2004
)
Overexpression of constitutively activated glutamate dehydrogenase induces insulin secretion through enhanced glutamate oxidation
.
Am. J. Physiol. Endocrinol. Metab.
286
,
E280
E285
167
Fiermonte
,
G.
,
Palmieri
,
L.
,
Todisco
,
S.
,
Agrimi
,
G.
,
Palmieri
,
F.
and
Walker
,
J.E.
(
2002
)
Identification of the mitochondrial glutamate transporter. Bacterial expression, reconstitution, functional characterization, and tissue distribution of two human isoforms
.
J. Biol. Chem.
277
,
19289
19294
168
Palmieri
,
F.
(
2004
)
The mitochondrial transporter family (SLC25): physiological and pathological implications
.
Pflugers Arch.
447
,
689
709
169
Eto
,
K.
,
Tsubamoto
,
Y.
,
Terauchi
,
Y.
,
Sugiyama
,
T.
,
Kishimoto
,
T.
,
Takahashi
,
N.
et al.  (
1999
)
Role of NADH shuttle system in glucose-induced activation of mitochondrial metabolism and insulin secretion
.
Science
283
,
981
985
170
Eto
,
K.
,
Suga
,
S.
,
Wakui
,
M.
,
Tsubamoto
,
Y.
,
Terauchi
,
Y.
,
Taka
,
J.
et al.  (
1999
)
NADH shuttle system regulates K(ATP) channel-dependent pathway and steps distal to cytosolic Ca2+ concentration elevation in glucose-induced insulin secretion
.
J. Biol. Chem.
274
,
25386
25392
171
Maechler
,
P.
,
Antinozzi
,
P.A.
and
Wollheim
,
C.B.
(
2000
)
Modulation of glutamate generation in mitochondria affects hormone secretion in INS-1E β cells
.
IUBMB Life
50
,
27
31
172
Bertrand
,
G.
,
Ishiyama
,
N.
,
Nenquin
,
M.
,
Ravier
,
M.A.
and
Henquin
,
J.C.
(
2002
)
The elevation of glutamate content and the amplification of insulin secretion in glucose-stimulated pancreatic islets are not causally related
.
J. Biol. Chem.
277
,
32883
32891
173
MacDonald
,
M.J.
(
1982
)
Evidence for the malate aspartate shuttle in pancreatic islets
.
Arch. Biochem. Biophys.
213
,
643
649
174
Marmol
,
P.
,
Pardo
,
B.
,
Wiederkehr
,
A.
,
del Arco
,
A.
,
Wollheim
,
C.B.
and
Satrústegui
,
J.
(
2009
)
Requirement for aralar and its Ca2+-binding sites in Ca2+ signal transduction in mitochondria from INS-1 clonal β-cells
.
J. Biol. Chem.
284
,
515
524
175
Carobbio
,
S.
,
Frigerio
,
F.
,
Rubi
,
B.
,
Vetterli
,
L.
,
Bloksgaard
,
M.
,
Gjinovci
,
A.
et al.  (
2009
)
Deletion of glutamate dehydrogenase in β-cells abolishes part of the insulin secretory response not required for glucose homeostasis
.
J. Biol. Chem.
284
,
921
929
176
Stanley
,
C.A.
,
Lieu
,
Y.K.
,
Hsu
,
B.Y.
,
Burlina
,
A.B.
,
Greenberg
,
C.R.
,
Hopwood
,
N.J.
et al.  (
1998
)
Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene
.
N. Engl. J. Med.
338
,
1352
1357
177
Li
,
C.
,
Matter
,
A.
,
Kelly
,
A.
,
Petty
,
T.J.
,
Najafi
,
H.
,
MacMullen
,
C.
et al.  (
2006
)
Effects of a GTP-insensitive mutation of glutamate dehydrogenase on insulin secretion in transgenic mice
.
J. Biol. Chem.
281
,
15064
15072
178
Cline
,
G.W.
,
Lepine
,
R.L.
,
Papas
,
K.K.
,
Kibbey
,
R.G.
and
Shulman
,
G.I.
(
2004
)
13C NMR isotopomer analysis of anaplerotic pathways in INS-1 cells
.
J. Biol. Chem.
279
,
44370
44375
179
Sener
,
A.
,
Owen
,
A.
,
Malaisse-Lagae
,
F.
and
Malaisse
,
W.J.
(
1982
)
The stimulus-secretion coupling of amino acid-induced insulin release. XI. Kinetics of deamination and transamination reactions
.
Horm. Metab. Res.
14
,
405
409
180
Di Cairano
,
E.S.
,
Davalli
,
A.M.
,
Perego
,
L.
,
Sala
,
S.
,
Sacchi
,
V.F.
,
La Rosa
,
S.
et al.  (
2011
)
The glial glutamate transporter 1 (GLT1) is expressed by pancreatic β-cells and prevents glutamate-induced β-cell death
.
J. Biol. Chem.
286
,
14007
14018
181
Grewer
,
C.
,
Gameiro
,
A.
and
Rauen
,
T.
(
2014
)
SLC1 glutamate transporters
.
Pflugers Arch.
466
,
3
24
182
Jensen
,
A.A.
,
Fahlke
,
C.
,
Bjørn-Yoshimoto
,
W.E.
and
Bunch
,
L.
(
2015
)
Excitatory amino acid transporters: recent insights into molecular mechanisms, novel modes of modulation and new therapeutic possibilities
.
Curr. Opin. Pharmacol.
20
,
116
123
183
Billups
,
B.
,
Rossi
,
D.
and
Attwell
,
D.
(
1996
)
Anion conductance behavior of the glutamate uptake carrier in salamander retinal glial cells
.
J. Neurosci.
16
,
6722
6731
184
Eliasof
,
S.
and
Jahr
,
C.E.
(
1996
)
Retinal glial cell glutamate transporter is coupled to an anionic conductance
.
Proc. Natl Acad. Sci. U.S.A.
93
,
4153
4158
185
Grewer
,
C.
,
Watzke
,
N.
,
Wiessner
,
M.
and
Rauen
,
T.
(
2000
)
Glutamate translocation of the neuronal glutamate transporter EAAC1 occurs within milliseconds
.
Proc. Natl Acad. Sci. U.S.A.
97
,
9706
9711
186
Otis
,
T.S.
and
Jahr
,
C.E.
(
1998
)
Anion currents and predicted glutamate flux through a neuronal glutamate transporter
.
J. Neurosci.
18
,
7099
7110
187
Wadiche
,
J.I.
,
Amara
,
S.G.
and
Kavanaugh
,
M.P.
(
1995
)
Ion fluxes associated with excitatory amino acid transport
.
Neuron
15
,
721
728
188
Jenstad
,
M.
and
Chaudhry
,
F.A.
(
2013
)
The amino acid transporters of the glutamate/GABA-glutamine cycle and their impact on insulin and glucagon secretion
.
Front. Endocrinol.
4
,
199
189
Eto
,
K.
,
Yamashita
,
T.
,
Hirose
,
K.
,
Tsubamoto
,
Y.
,
Ainscow
,
E.K.
,
Rutter
,
G.A.
et al.  (
2003
)
Glucose metabolism and glutamate analog acutely alkalinize pH of insulin secretory vesicles of pancreatic β-cells
.
Am. J. Physiol. Endocrinol. Metab.
285
,
E262
E271
190
Bröer
,
S.
(
2014
)
The SLC38 family of sodium–amino acid co-transporters
.
Pflugers Arch.
466
,
155
172
191
Hatanaka
,
T.
,
Huang
,
W.
,
Wang
,
H.
,
Sugawara
,
M.
,
Prasad
,
P.D.
,
Leibach
,
F.H.
et al.  (
2000
)
Primary structure, functional characteristics and tissue expression pattern of human ATA2, a subtype of amino acid transport system A
.
Biochim. Biophys. Acta
1467
,
1
6
192
Tadros
,
L.B.
,
Taylor
,
P.M.
and
Rennie
,
M.J.
(
1993
)
Characteristics of glutamine transport in primary tissue culture of rat skeletal muscle
.
Am. J. Physiol.
265
,
E135
E144
193
Hyde
,
R.
,
Peyrollier
,
K.
and
Hundal
,
H.S.
(
2002
)
Insulin promotes the cell surface recruitment of the SAT2/ATA2 system A amino acid transporter from an endosomal compartment in skeletal muscle cells
.
J. Biol. Chem.
277
,
13628
13634
194
Gaccioli
,
F.
,
Huang
,
C.C.
,
Wang
,
C.
,
Bevilacqua
,
E.
,
Franchi-Gazzola
,
R.
,
Gazzola
,
G.C.
et al.  (
2006
)
Amino acid starvation induces the SNAT2 neutral amino acid transporter by a mechanism that involves eukaryotic initiation factor 2α phosphorylation and cap-independent translation
.
J. Biol. Chem.
281
,
17929
17940
195
Hyde
,
R.
,
Hajduch
,
E.
,
Powell
,
D.J.
,
Taylor
,
P.M.
and
Hundal
,
H.S.
(
2005
)
Ceramide down-regulates system A amino acid transport and protein synthesis in rat skeletal muscle cells
.
FASEB J.
19
,
461
463
196
Bröer
,
A.
,
Gauthier-Coles
,
G.
,
Rahimi
,
F.
,
van Geldermalsen
,
M.
,
Dorsch
,
D.
,
Wegener
,
A.
et al.  (
2019
)
Ablation of the ASCT2 (SLC1A5) gene encoding a neutral amino acid transporter reveals transporter plasticity and redundancy in cancer cells
.
J. Biol. Chem.
jbc.RA118.006378
197
Velázquez-Villegas
,
L.A.
,
Ortíz
,
V.
,
Ström
,
A.
,
Torres
,
N.
,
Engler
,
D.A.
,
Matsunami
,
R.
et al.  (
2014
)
Transcriptional regulation of the sodium-coupled neutral amino acid transporter (SNAT2) by 17β-estradiol
.
Proc. Natl Acad. Sci. U.S.A.
111
,
11443
11448
198
Kipnis
,
D.M.
and
Noall
,
M.W.
(
1958
)
Stimulation of amino acid transport by insulin in the isolated rat diaphragm
.
Biochim. Biophys. Acta
28
,
226
227
199
Bonadonna
,
R.C.
,
Saccomani
,
M.P.
,
Cobelli
,
C.
and
DeFronzo
,
R.A.
(
1993
)
Effect of insulin on system A amino acid transport in human skeletal muscle
.
J. Clin. Invest.
91
,
514
521
200
Drummond
,
M.J.
,
Glynn
,
E.L.
,
Fry
,
C.S.
,
Timmerman
,
K.L.
,
Volpi
,
E.
and
Rasmussen
,
B.B.
(
2010
)
An increase in essential amino acid availability upregulates amino acid transporter expression in human skeletal muscle
.
Am. J. Physiol. Endocrinol. Metab.
298
,
E1011
E1018
201
Taylor
,
P.M.
(
2014
)
Role of amino acid transporters in amino acid sensing
.
Am. J. Clin. Nutr.
99
,
223s
230s
202
Dickinson
,
J.M.
and
Rasmussen
,
B.B.
(
2013
)
Amino acid transporters in the regulation of human skeletal muscle protein metabolism
.
Curr. Opin. Clin. Nutr. Metab. Care
16
,
638
644
203
Krokowski
,
D.
,
Han
,
J.
,
Saikia
,
M.
,
Majumder
,
M.
,
Yuan
,
C.L.
,
Guan
,
B.J.
et al.  (
2013
)
A self-defeating anabolic program leads to β-cell apoptosis in endoplasmic reticulum stress-induced diabetes via regulation of amino acid flux
.
J. Biol. Chem.
288
,
17202
17213
204
Back
,
S.H.
,
Scheuner
,
D.
,
Han
,
J.
,
Song
,
B.
,
Ribick
,
M.
,
Wang
,
J.
et al.  (
2009
)
Translation attenuation through eIF2α phosphorylation prevents oxidative stress and maintains the differentiated state in β cells
.
Cell Metab.
10
,
13
26
205
Chaudhry
,
F.A.
,
Reimer
,
R.J.
,
Krizaj
,
D.
,
Barber
,
D.
,
Storm-Mathisen
,
J.
,
Copenhagen
,
D.R.
et al.  (
1999
)
Molecular analysis of system N suggests novel physiological roles in nitrogen metabolism and synaptic transmission
.
Cell
99
,
769
780
206
Gu
,
S.
,
Roderick
,
H.L.
,
Camacho
,
P.
and
Jiang
,
J.X.
(
2000
)
Identification and characterization of an amino acid transporter expressed differentially in liver
.
Proc. Natl Acad. Sci. U.S.A.
97
,
3230
3235
207
DeBerardinis
,
R.J.
and
Cheng
,
T.
(
2009
)
Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer
.
Oncogene
29
,
313
324
208
Rubio-Aliaga
,
I.
and
Wagner
,
C.A.
(
2016
)
Regulation and function of the SLC38A3/SNAT3 glutamine transporter
.
Channels
10
,
440
452
209
Gu
,
S.
,
Villegas
,
C.J.
and
Jiang
,
J.X.
(
2005
)
Differential regulation of amino acid transporter SNAT3 by insulin in hepatocytes
.
J. Biol. Chem.
280
,
26055
26062
210
Suryawan
,
A.
,
Nguyen
,
H.V.
,
Almonaci
,
R.D.
and
Davis
,
T.A.
(
2013
)
Abundance of amino acid transporters involved in mTORC1 activation in skeletal muscle of neonatal pigs is developmentally regulated
.
Amino Acids
45
,
523
530
211
Zawalich
,
W.S.
,
Yamazaki
,
H.
,
Zawalich
,
K.C.
and
Cline
,
G.
(
2004
)
Comparative effects of amino acids and glucose on insulin secretion from isolated rat or mouse islets
.
J. Endocrinol.
183
,
309
319
212
Gao
,
Z.Y.
,
Li
,
G.
,
Najafi
,
H.
,
Wolf
,
B.A.
and
Matschinsky
,
F.M.
(
1999
)
Glucose regulation of glutaminolysis and its role in insulin secretion
.
Diabetes
48
,
1535
1542
213
Nakanishi
,
T.
,
Kekuda
,
R.
,
Fei
,
Y.J.
,
Hatanaka
,
T.
,
Sugawara
,
M.
,
Martindale
,
R.G.
et al.  (
2001
)
Cloning and functional characterization of a new subtype of the amino acid transport system N
.
Am. J. Physiol. Cell Physiol.
281
,
C1757
C1768
214
Nakanishi
,
T.
,
Sugawara
,
M.
,
Huang
,
W.
,
Martindale
,
R.G.
,
Leibach
,
F.H.
,
Ganapathy
,
M.E.
et al.  (
2001
)
Structure, function, and tissue expression pattern of human SN2, a subtype of the amino acid transport system N
.
Biochem. Biophys. Res. Commun.
281
,
1343
1348
215
D'Alessio
,
D.
(
2011
)
The role of dysregulated glucagon secretion in type 2 diabetes
.
Diabetes Obes. Metab.
13
,
126
132
216
Reaven
,
G.M.
,
Chen
,
Y.D.
,
Golay
,
A.
,
Swislocki
,
A.L.
and
Jaspan
,
J.B.
(
1987
)
Documentation of hyperglucagonemia throughout the day in nonobese and obese patients with noninsulin-dependent diabetes mellitus
.
J. Clin. Endocrinol. Metab.
64
,
106
110
217
Bozadjieva
,
N.
,
Blandino-Rosano
,
M.
,
Chase
,
J.
,
Dai
,
X.Q.
,
Cummings
,
K.
,
Gimeno
,
J.
et al.  (
2017
)
Loss of mTORC1 signaling alters pancreatic alpha cell mass and impairs glucagon secretion
.
J. Clin. Invest.
127
,
4379
4393
218
Solloway
,
M.J.
,
Madjidi
,
A.
,
Gu
,
C.
,
Eastham-Anderson
,
J.
,
Clarke
,
H.J.
,
Kljavin
,
N.
et al.  (
2015
)
Glucagon couples hepatic amino acid catabolism to mTOR-dependent regulation of α-cell mass
.
Cell Rep.
12
,
495
510
219
Hayashi
,
Y.
and
Seino
,
Y.
(
2018
)
Regulation of amino acid metabolism and α-cell proliferation by glucagon
.
J. Diabetes Invest.
220
Fotiadis
,
D.
,
Kanai
,
Y.
and
Palacin
,
M.
(
2013
)
The SLC3 and SLC7 families of amino acid transporters
.
Mol. Aspects Med.
34
,
139
158
221
Bröer
,
S.
(
2018
)
Amino acid transporters as disease modifiers and drug targets
.
SLAS Discov.
23
,
303
320
222
Meier
,
C.
,
Ristic
,
Z.
,
Klauser
,
S.
and
Verrey
,
F.
(
2002
)
Activation of system L heterodimeric amino acid exchangers by intracellular substrates
.
EMBO J.
21
,
580
589
223
Hodson
,
N.
,
Brown
,
T.
,
Joanisse
,
S.
,
Aguirre
,
N.
,
West
,
W.D.
,
Moore
,
R.D.
et al.  (
2018
)
Characterisation of l-type amino acid transporter 1 (LAT1) expression in human skeletal muscle by immunofluorescent microscopy
.
Nutrients
10
,
E23
224
Ritchie
,
J.W.
,
Baird
,
F.E.
,
Christie
,
G.R.
,
Stewart
,
A.
,
Low
,
S.Y.
,
Hundal
,
H.S.
et al.  (
2001
)
Mechanisms of glutamine transport in rat adipocytes and acute regulation by cell swelling
.
Cell. Physiol. Biochem.
11
,
259
270
225
Kanai
,
Y.
,
Segawa
,
H.
,
Miyamoto
,
K.I.
,
Uchino
,
H.
,
Takeda
,
E.
and
Endou
,
H.
(
1998
)
Expression cloning and characterization of a transporter for large neutral amino acids activated by the heavy chain of 4F2 antigen (CD98)
.
J. Biol. Chem.
273
,
23629
23632
226
Newgard
,
C.B.
(
2017
)
Metabolomics and metabolic diseases: where do we stand?
Cell Metab.
25
,
43
56
227
Lackey
,
D.E.
,
Lynch
,
C.J.
,
Olson
,
K.C.
,
Mostaedi
,
R.
,
Ali
,
M.
,
Smith
,
W.H.
et al.  (
2013
)
Regulation of adipose branched-chain amino acid catabolism enzyme expression and cross-adipose amino acid flux in human obesity
.
Am. J. Physiol. Endocrinol. Metab.
304
,
E1175
E1187
228
Gancheva
,
S.
,
Jelenik
,
T.
,
Álvarez-Hernández
,
E.
and
Roden
,
M.
(
2018
)
Interorgan metabolic crosstalk in human insulin resistance
.
Physiol. Rev.
98
,
1371
1415
229
Newgard
,
C.B.
(
2012
)
Interplay between lipids and branched-chain amino acids in development of insulin resistance
.
Cell Metab.
15
,
606
614
230
Yamamoto
,
Y.
,
Sawa
,
R.
,
Wake
,
I.
,
Morimoto
,
A.
and
Okimura
,
Y.
(
2017
)
Glucose-mediated inactivation of AMP-activated protein kinase reduces the levels of l-type amino acid transporter 1 mRNA in C2C12 cells
.
Nutr. Res.
47
,
13
20
231
Sener
,
A.
and
Malaisse
,
W.J.
(
1980
)
l-Leucine and a nonmetabolized analogue activate pancreatic islet glutamate dehydrogenase
.
Nature
288
,
187
189
232
Yielding
,
K.L.
and
Tomkins
,
G.M.
(
1961
)
An effect of l-leucine and other essential amino acids on the structure and activity of glutamic dehydrogenase
.
Proc. Natl Acad. Sci. U.S.A.
47
,
983
989
233
Mourao
,
J.M.
,
McGivan
,
J.D.
and
Chappell
,
J.B.
(
1975
)
The effects l-leucine on the synthesis of urea, glutamate and glutamine by isolated rat liver cells
.
Biochem. J.
146
,
457
464
234
Sener
,
A.
,
Malaisse-Lagae
,
F.
and
Malaisse
,
W.J.
(
1981
)
Stimulation of pancreatic islet metabolism and insulin release by a nonmetabolizable amino acid
.
Proc. Natl Acad. Sci. U.S.A.
78
,
5460
5464
235
Malaisse-Lagae
,
F.
,
Sener
,
A.
,
Garcia-Morales
,
P.
,
Valverde
,
I.
and
Malaisse
,
W.J.
(
1982
)
The stimulus-secretion coupling of amino acid-induced insulin release. Influence of a nonmetabolized analog of leucine on the metabolism of glutamine in pancreatic islets
.
J. Biol. Chem.
257
,
3754
3758
PMID:
[PubMed]
236
Malaisse
,
W.J.
,
Sener
,
A.
,
Malaisse-Lagae
,
F.
,
Welsh
,
M.
,
Matthews
,
D.E.
,
Bier
,
D.M.
et al.  (
1982
)
The stimulus-secretion coupling of amino acid-induced insulin release. Metabolic response of pancreatic islets of l-glutamine and l-leucine
.
J. Biol. Chem.
257
,
8731
8737
PMID:
[PubMed]
237
Panten
,
U.
,
Zielmann
,
S.
,
Langer
,
J.
,
Zunkler
,
B.J.
and
Lenzen
,
S.
(
1984
)
Regulation of insulin secretion by energy metabolism in pancreatic B-cell mitochondria. Studies with a non-metabolizable leucine analogue
.
Biochem. J.
219
,
189
196
238
Hsu
,
B.Y.
,
Kelly
,
A.
,
Thornton
,
P.S.
,
Greenberg
,
C.R.
,
Dilling
,
L.A.
and
Stanley
,
C.A.
(
2001
)
Protein-sensitive and fasting hypoglycemia in children with the hyperinsulinism/hyperammonemia syndrome
.
J. Pediatr.
138
,
383
389
239
Stanley
,
C.A.
,
Fang
,
J.
,
Kutyna
,
K.
,
Hsu
,
B.Y.
,
Ming
,
J.E.
,
Glaser
,
B.
et al.  (
2000
)
Molecular basis and characterization of the hyperinsulinism/hyperammonemia syndrome: predominance of mutations in exons 11 and 12 of the glutamate dehydrogenase gene. HI/HA Contributing Investigators
.
Diabetes
49
,
667
673
240
Khunweeraphong
,
N.
,
Nagamori
,
S.
,
Wiriyasermkul
,
P.
,
Nishinaka
,
Y.
,
Wongthai
,
P.
,
Ohgaki
,
R.
et al.  (
2012
)
Establishment of stable cell lines with high expression of heterodimers of human 4F2hc and human amino acid transporter LAT1 or LAT2 and delineation of their differential interaction with α-alkyl moieties
.
J. Pharmacol. Sci.
119
,
368
380
241
Milkereit
,
R.
,
Persaud
,
A.
,
Vanoaica
,
L.
,
Guetg
,
A.
,
Verrey
,
F.
and
Rotin
,
D.
(
2015
)
LAPTM4b recruits the LAT1-4F2hc Leu transporter to lysosomes and promotes mTORC1 activation
.
Nat. Commun.
6
,
7250
242
Weng
,
L.
,
Han
,
Y.P.
,
Enomoto
,
A.
,
Kitaura
,
Y.
,
Nagamori
,
S.
,
Kanai
,
Y.
et al.  (
2018
)
Negative regulation of amino acid signaling by MAPK-regulated 4F2hc/Girdin complex
.
PLoS Biol.
16
,
e2005090
243
Fahien
,
L.A.
,
MacDonald
,
M.J.
,
Kmiotek
,
E.H.
,
Mertz
,
R.J.
and
Fahien
,
C.M.
(
1988
)
Regulation of insulin release by factors that also modify glutamate dehydrogenase
.
J. Biol. Chem.
263
,
13610
13614
PMID:
[PubMed]
244
Wente
,
W.
,
Efanov
,
A.M.
,
Brenner
,
M.
,
Kharitonenkov
,
A.
,
Köster
,
A.
,
Sandusky
,
G.E.
et al.  (
2006
)
Fibroblast growth factor-21 improves pancreatic β-cell function and survival by activation of extracellular signal-regulated kinase 1/2 and Akt signaling pathways
.
Diabetes
55
,
2470
2478
245
Morrison
,
C.D.
and
Laeger
,
T.
(
2015
)
Protein-dependent regulation of feeding and metabolism
.
Trends Endocrinol. Metab.
26
,
256
262
246
Morrison
,
C.D.
,
Reed
,
S.D.
and
Henagan
,
T.M.
(
2012
)
Homeostatic regulation of protein intake: in search of a mechanism
.
Am. J. Physiol. Regul. Integr. Comp. Physiol.
302
,
R917
R928
247
Stemmer
,
K.
,
Zani
,
F.
,
Habegger
,
K.M.
,
Neff
,
C.
,
Kotzbeck
,
P.
,
Bauer
,
M.
et al.  (
2015
)
FGF21 is not required for glucose homeostasis, ketosis or tumour suppression associated with ketogenic diets in mice
.
Diabetologia
58
,
2414
2423
248
Wilson
,
G.J.
,
Lennox
,
B.A.
,
She
,
P.
,
Mirek
,
E.T.
,
Al Baghdadi
,
R.J.
,
Fusakio
,
M.E.
et al.  (
2015
)
GCN2 is required to increase fibroblast growth factor 21 and maintain hepatic triglyceride homeostasis during asparaginase treatment
.
Am. J. Physiol. Endocrinol. Metab.
308
,
E283
E293
249
Lundsgaard
,
A.M.
,
Fritzen
,
A.M.
,
Sjøberg
,
K.A.
,
Myrmel
,
L.S.
,
Madsen
,
L.
,
Wojtaszewski
,
J.F.P.
et al.  (
2017
)
Circulating FGF21 in humans is potently induced by short term overfeeding of carbohydrates
.
Mol. Metab.
6
,
22
29
250
Lundsgaard
,
A.M.
,
Sjøberg
,
K.A.
,
Høeg
,
L.D.
,
Jeppesen
,
J.
,
Jordy
,
A.B.
,
Serup
,
A.K.
et al.  (
2017
)
Opposite regulation of insulin sensitivity by dietary lipid versus carbohydrate excess
.
Diabetes
66
,
2583
2595
251
Solon-Biet
,
S.M.
,
Cogger
,
V.C.
,
Pulpitel
,
T.
,
Heblinski
,
M.
,
Wahl
,
D.
,
McMahon
,
A.C.
et al.  (
2016
)
Defining the nutritional and metabolic context of FGF21 using the geometric framework
.
Cell Metab.
24
,
555
565
252
Kurosu
,
H.
,
Choi
,
M.
,
Ogawa
,
Y.
,
Dickson
,
A.S.
,
Goetz
,
R.
,
Eliseenkova
,
A.V.
et al.  (
2007
)
Tissue-specific expression of β-Klotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21
.
J. Biol. Chem.
282
,
26687
26695