Abstract
Since the discovery of glucagon 100 years ago, the hormone and the pancreatic islet alpha cells that produce it have remained enigmatic relative to insulin-producing beta cells. Canonically, alpha cells have been described in the context of glucagon’s role in glucose metabolism in liver, with glucose as the primary nutrient signal regulating alpha cell function. However, current data reveal a more holistic model of metabolic signalling, involving glucagon-regulated metabolism of multiple nutrients by the liver and other tissues, including amino acids and lipids, providing reciprocal feedback to regulate glucagon secretion and even alpha cell mass. Here we describe how various nutrients are sensed, transported and metabolised in alpha cells, providing an integrative model for the metabolic regulation of glucagon secretion and action. Importantly, we discuss where these nutrient-sensing pathways intersect to regulate alpha cell function and highlight key areas for future research.
Introduction
Glucagon is secreted from alpha cells located in pancreatic islets of Langerhans and is an important counter-regulatory hormone to insulin, acting to increase blood glucose. Indeed, it was this physiological hyperglycaemic effect, present in ethanol-soluble pancreatic extracts administered to dogs, that led to the identification and naming of glucagon, or glucose agonist (Kimball & Murlin 1923). In 1970, it became clear that glucagon plays an important role not only for the fasting response (Felig et al. 1969a , Marliss et al. 1970) but also in the development of metabolic diseases such as diabetes (Müller et al. 1970). Although the hormone was discovered 100 years ago, we are still debating the regulatory mechanisms that control its release from pancreatic alpha cells and the role glucagon plays in whole-body physiology. This review will focus on our current understanding of the nutrient and metabolic pathways contributing to the regulation of glucagon secretion. As part of this special collection of reviews commemorating the 100-year anniversary of the discovery of glucagon (Cantley et al. 2023), we have consciously not discussed ion channel regulation, second messenger systems or paracrine regulation in depth, as they are covered elsewhere in this series.
The physiological glucagon response
The main role of glucagon is thought to be mobilisation of glucose, via stimulation of hepatic glucose production, to maintain circulating glucose levels and prevent hypoglycaemia. It is therefore intuitive that glucagon secretion is reduced by elevations in circulating glucose levels under normal physiological conditions. This has been demonstrated several times using acute insulin-induced hypoglycaemia (De Feo et al. 1986, Malmgren & Ahren 2015) and prolonged fasting (Felig et al. 1969a , Bolli et al. 1984). It, therefore, seems reasonable that the mechanism that regulates glucagon secretion from alpha cells relies on changes in glucose metabolism. A current hypothesis is that glucose is taken up by alpha cells and oxidised to ATP. The elevated ATP levels act on pumps and channels present in the plasma membrane, causing changes in membrane potential which ultimately lead to reduced glucagon granule exocytosis (Liu et al. 2004, MacDonald et al. 2007, Vieira et al. 2007, Zhang et al. 2013, Gylfe 2016) (Fig. 1). This could suggest that alpha cells rely on glucose to maintain intracellular ATP. However, unlike beta cells, alpha cell secretory activity is high when glucose levels are low, and alpha cells appear to favour glycolysis over glucose oxidation (Schuit et al. 1997, Stamenkovic et al. 2015). In addition, several observations suggest that glucagon secretion is stimulated by long-chain fatty acids (Olofsson et al. 2004, Kristinsson et al. 2017, Bollheimer et al. 2004) and amino acids (Rocha et al. 1972). This seems logical as these substrates are released from adipose tissue, liver and skeletal muscle when glucose is sparse and glucagon secretion is elevated (Felig et al. 1969a,b, Ahlborg et al. 1974, Mourtzakis et al. 2006). In the postprandial phase, sensing of these nutrients also appears important. In general, the response to a mixed meal varies from decreased (Stern et al. 2019, Meek et al. 2021, Marliss et al. 1970, Müller et al. 1970) to elevated plasma glucagon (Marliss et al. 1970, El et al. 2021) depending on the composition and solidity. These observations may indicate the following: (i) that alpha cell metabolism may be geared toward substrates that are available during fasting, (ii) that the mechanisms of glucose-induced inhibition of glucagon secretion needs to be revised and (iii) that glucagon may play additional roles in energy homeostasis during postprandial metabolism. Here we review the literature on alpha cell metabolism and explore the relevance of glucose, lipids and amino acids for alpha cell function.
Glucose-regulated glucagon secretion. Glucose is currently suggested to regulate glucagon secretion through glucose oxidation and increased ATP production. Glucose is taken up through sodium glucose transporter 1 (SGLT1) and glucose transporter 1 (GLUT1), before phosphorylation by glucokinase acts as an entry point to glycolysis. The glycolytic end product, pyruvate, is then converted to acetyl-CoA by pyruvate dehydrogenase (PDH) in the mitochondria. PDH is regulated through phosphorylation by PDH kinases 1-4. The following tricarboxylic acid (TCA) cycle reactions lead to the production of NADH and FADH2, which are used for ATP synthesis in the electron transport chain. At low glucose (<4 mmol/L), ATP levels are modest, the KATP channel is partially closed allowing voltage-gated sodium channels to remain active, action potentials to form, promoting calcium influx and glucagon secretion. At high glucose (>5.5 mmol/L) increased ATP levels are thought to lead to full closure of the ATP-sensitive potassium channels (KATP), depolarising the membrane and inhibiting voltage-gated sodium channels, lowering calcium influx and reducing glucagon secretion. (A) Alpha cell at low glucose (<4 mmol/L glucose). (B) Alpha cell at high glucose (>5.5 mmol/L). Created with BioRender.com.
Citation: Journal of Endocrinology 259, 1; 10.1530/JOE-23-0081
Metabolic fate of glucose
Oxidation of glucose
Glucagon secretion is already inhibited at low glucose (<5 mM), and at these concentrations, the effect of glucose on glucagon secretion is suggested to be intrinsic. Alpha cells are equipped with glucose transporter 1 (GLUT1) and sodium glucose transporter (SGLT) 1 (Heimberg et al. 1995, Suga et al. 2019) which have a low Km for glucose (1–2 mM and 0.5 mM, respectively) (Gorovits & Charron 2003, Koepsell 2020) (Fig. 1). Thus, while alpha cell glucose uptake is limited at higher concentrations of glucose, intracellular glucose metabolism is continuous and essentially independent of physiological extracellular glucose concentrations. Once inside the alpha cell, glucose is initially phosphorylated by hexokinases to yield glucose-6-phosphate (Wilson 2003). In islet cells, glucose sensing and metabolism are mainly thought to be carried out by glucokinase (hexokinase IV) (Printz et al. 1993, Iynedjian et al. 1989, Basco et al. 2018) (Fig. 1). Unlike hexokinase isoforms I–III that have a high affinity for glucose (Shinohara et al. 1998, Wilson 2003), glucokinase has a high Km and is not inhibited by the product of its reaction (Purich et al. 1973). This allows the enzyme to be continuously active even at high glucose concentrations. In alpha cells, glucokinase has been suggested to account for more than 90% of the glucose utilisation (Heimberg et al. 1995), with knockdown of alpha cell glucokinase leading to a loss of glucose-regulated glucagon secretion in both intact islets (Basco et al. 2018) and FACS-sorted alpha cells (Moede et al. 2020). The activation of glucokinase improves glucose repression of glucagon secretion and prevents high-fat-diet-induced changes in glucose tolerance and glucagon secretion (Bahl et al. 2021). Although glycolytic activity in alpha cells is of similar magnitude to that in beta cells, it is unclear what proportion of glucose is fully oxidised. Some studies suggest that glucose oxidation is much lower (Schuit et al. 1997, Stamenkovic et al. 2015) and that ATP (Detimary et al. 1998), FADH2 (Quesada et al. 2006) and NADH (Quoix et al. 2009) do not change in response to elevations in glucose. However, others suggest that elevations in glucose lead to elevated glucose oxidation (Östenson 1979, 1980), increased ATP production (Basco et al. 2018, Knudsen et al. 2019, Zhang et al. 2013, Briant et al. 2018, Li et al. 2015) and small changes in mitochondrial membrane potential (Diao et al. 2008). It is impossible from these observations to determine the fate of glucose in alpha cells as the methodology varies greatly and experiments were conducted with glucose as the only available substrate. For glucose to drive oxidative phosphorylation, pyruvate, the end-product of glycolysis, must enter the tricarboxylic acid (TCA) cycle where it is converted to acetyl-CoA by pyruvate dehydrogenase (PDH) (Fig. 1). The amount of pyruvate that enters the TCA cycle as acetyl-CoA is to some extent regulated by changes in PDH activity, partly through inhibitory phosphorylation by PDH kinases (PDK1-4) and de-phosphorylation by PDH phosphatases (PDP1 and 2) (Jelinek & Moxley 2021) (Fig. 1). It is therefore interesting that alpha cells express high levels of PDK4 compared to other islet cell types (Mawla & Huising 2019). PDK4 is upregulated during fasting in islets (Sugden et al. 2001) as well as other tissues (Pilegaard et al. 2003, Wu et al. 1998) and plays a crucial role in the switch between glucose and fatty acid oxidation (Hue & Taegtmeyer 2009). The high expression of PDK4 suggests that a limited amount of pyruvate enters the TCA cycle in alpha cells. This is in line with findings suggesting that alpha cells favour glycolytic metabolism (Schuit et al. 1997) and have high expression of lactate dehydrogenase (LDHA) (Mawla & Huising 2019, Rutter et al. 2020, Sanchez et al. 2021) and monocarboxylate transporters (MCT) 1 and 4 (Mawla & Huising 2019). However, it should be noted that one study does suggest that the addition of pyruvate circumvents glycolysis and therefore leads to ATP production in alpha cells (Ishihara et al. 2003). Increased lactate production from elevations in glucose has also been suggested to regulate glucagon secretion in rodent and human alpha cells through activation of ATP-sensitive potassium channels (KATP) (Zaborska et al. 2020). The high expression of MCT4 could also indicate a need for high levels of lactate efflux as seen in cancer cells (Baenke et al. 2015) and glycolytic muscles (Bonen 2001). In addition, rodent alpha cells do not seem to be as dependent on anaplerotic pyruvate metabolism as beta cells, as pyruvate carboxylase expression is seven-fold lower (Schuit et al. 1997, Benner et al. 2014). However, equivalent expression of pyruvate carboxylase is observed in human alpha and beta cells (Benner et al. 2014, Ackermann et al. 2016) suggesting that human alpha cells utilise glucose-driven anaplerosis via pyruvate carboxylase more readily than rodent alpha cells. In addition, phosphoenolpyruvate carboxykinase 2 (PCK2) shows strong expression in both rodent and human alpha cells, along with some malic enzyme isoforms (Me1 rodent; ME2, ME3 human) (Benner et al. 2014, Ackermann et al. 2016) suggesting that alternative anaplerotic reactions may exist in alpha cells. In beta cells, the high pyruvate-derived flux through the TCA cycle (Schuit et al. 1997) is required to replenish TCA cycle intermediates. This does not seem to be required to the same extent in alpha cells. Together these observations suggest that alpha cells do not have a very high flux of glucose-derived metabolites through the TCA cycle.
Alternatively, to glycolysis and oxidative phosphorylation, glucose could be metabolised in the pentose phosphate pathway (PPP). Branching off after the first step in glycolysis, the pathway leads to the synthesis of ribose 5-phosphate and NADPH, the latter of which plays a critical role as a reducing reagent in many cellular pathways and is important for the synthesis of fatty acids (Patra & Hay 2014), a pathway required for the correct regulation of glucagon secretion (Veprik et al. 2022). In addition, NADPH also plays a vital role in the cellular redox potential (Kerksick & Willoughby 2005, Wamelink et al. 2008). Alpha cells express high levels of antioxidant genes compared to beta cells (Miki et al. 2018), suggesting that maintaining tight control of reactive oxygen levels is important. Despite the evidence for similar glucose utilisation between the pancreatic beta and alpha cells, there seem to be important differences in glucose metabolism. Beta cells have a high capacity for glucose oxidation, while alpha cells rely on glycolysis and lactate production; it is, therefore, likely that alpha cells preferentially utilise other substrates to maintain the energy production needed for glucagon secretion.
Fatty acid metabolism and the regulation of glucagon secretion
Oxidation of fatty acids
Metabolic flexibility allows most cells to utilise glucose under normoglycaemic conditions and switch to other substrates, such as lipids, amino acids and/or ketones, when glucose availability is limited (Laffel 1999, Browning et al. 2012, Goodpaster & Sparks 2017). Unlike other endocrine cell types, alpha cell secretory activity is highest when glucose is limited, and the apparent low capacity for glucose oxidation (Schuit et al. 1997, Detimary et al. 1998) would suggest that alpha cells may depend on other substrates for ATP production. Glucagon secretion and circulating concentrations of NEFA share similar kinetics during fasting (Marliss et al. 1970) and exercise (Mourtzakis et al. 2006). Fatty acids have previously been shown to have both stimulatory (Flodgren et al. 2007, Hong et al. 2007, Hong et al. 2005) and inhibitory (Madison et al. 1968, Edwards & Taylor 1970, Luyckx & Lefebvre 1970) effects on glucagon secretion. However, recent data show that longer chain fatty acids, such as laurate (C12:0), myristate (C14:0), palmitate (C16:0) and stearate (C18:0) (Olofsson et al. 2004, Fujiwara et al. 2007, Hong et al. 2005, Wang et al. 2011), stimulate glucagon secretion through effects on cytoplasmic Ca2+ levels (Wang et al. 2011, Olofsson et al. 2004, Fujiwara et al. 2007) or fatty acid oxidation (Kristinsson et al. 2017, Hong et al. 2007). In agreement, loss of fatty acid uptake into the mitochondria through knockdown of Carnitine Palmitoyl Transferase 1a (CPT1a) (Fig. 2) leads to lower fat oxidation and glucagon secretion at low glucose concentrations (Briant et al. 2018). This suggests that alpha cells use fatty acid oxidation to produce ATP, promoting glucagon secretion at low glucose, which may also explain the stimulatory effect of fatty acids on intracellular calcium in alpha cells (Olofsson et al. 2004). Despite this, we do not know how fatty acid oxidation in alpha cells is regulated. Cytosolic acetyl-CoA, produced by glucose or glutamine metabolism, can be utilised by acetyl-CoA carboxylase 2 (ACC2/ACACB), an ACC isoform localised to the mitochondria (Abu-Elheiga et al. 2000) that regulates fatty acid oxidation via malonyl-CoA-mediated suppression of CPT1. This facilitates the switch between the mitochondrial fuel sources in tissues such as muscle and liver. Although ACC1 (discussed below) is the dominant ACC isoform expressed in alpha cells (Benner et al. 2014, Ackermann et al. 2016), a role for ACC2 in regulating glucagon secretion cannot be ruled out, as experiments demonstrating suppression of glucagon release using the small molecule TOFA (Veprik et al. 2022) targets both ACC1 and ACC2 isoforms. This suggests that elevations in glucose may be able to inhibit fatty acid oxidation in alpha cells (Hue & Taegtmeyer 2009). In addition, AMP-activated protein kinase (AMPK) is required for glucagon release when glucose is limited (Sun et al. 2015), which could suggest that alpha cells rely on AMPK to inhibit ACC2 and maintain fatty acid oxidation at low glucose (Fig. 2). Together, this suggests that fatty acid oxidation may be regulated to control glucagon secretion and that glucose metabolism in alpha cells is directed towards fatty acid synthesis.
Fatty acid metabolism and the regulation of glucagon secretion. Several pathways involving fatty acid metabolism and lipid signalling have been implicated in the regulation of glucagon secretion. Glucose metabolism is proposed to drive anaplerotic entry of substrate to the mitochondria, leading to cataplerotic export of citrate from mitochondria, supporting generation of acetyl-CoA in the cytosol by ATP-citrate lyase (ACLY). Acetyl-CoA carboxylase 1 (ACC1/ACACA) generates malonyl-CoA, the first committed step in de novo lipogenesis: ACC1 activity is critical for regulated glucagon secretion and alpha cell growth. Malonyl-CoA is utilised by fatty acid synthase (FASN) to generate free fatty acids, which can be converted to fatty acyl-CoA esters via acyl-CoA synthetase (ACSL). Exogenous long-chain fatty acids have been reported to promote glucagon secretion via the GPR40/FFAR1 receptor, whilst also contributing to the intracellular lipid pool, possibly via the fatty acid scavenger receptor CD36. Intracellular fatty acids can undergo beta-oxidation to generate ATP in alpha cells, a process regulated by carnitine palmitoyl transferase 1 (CPT1a) which plays an important role in glucagon secretion, potentially contributing to the partial KATP channel closure required for action potential formation and glucagon secretion at low glucose levels. When glucose is elevated in hepatocytes, cataplerotic flux can also lead to conversion of acetyl-CoA to malonyl-CoA at the mitochondrial membrane via acetyl-CoA carboxylase 2 (ACC2/ACACB), acting to inhibit CPT1 and therefore beta-oxidation, thus preventing a futile cycle (synthesis and oxidation of fatty acids) from forming: this mechanism is currently untested in alpha cells. Fatty acyl-CoA can also contribute to the post-translational S-acylation of proteins, such as the KATP channel subunit Kir6.2. Global S-acylation has a net restraining effect on glucagon secretion. Created with BioRender.com.
Citation: Journal of Endocrinology 259, 1; 10.1530/JOE-23-0081
Alpha cells also express several transcriptional regulators such as peroxisome proliferator-activated receptor alpha (PPARα), PPAR gamma coactivator 1a (PGC-1A) and estrogen-related receptor alpha (ERRa) (Benner et al. 2014, Mawla & Huising 2019), which regulate the transcription of genes involved in fatty acid oxidation such as CPT1a, PDK4 and CD36 (a fatty acid scavenger that is important for fatty acid uptake) (Fig. 2) (Rakhshandehroo et al. 2009, Araki et al. 2007, Leone et al. 1999). In line with this, fasting leads to increased expression of PGC-1α (Zhang et al. 2005) and PDK4 (Sugden et al. 2001) in intact rat islets. This suggests that these transcriptional regulators are important for the metabolic programme in alpha cells and the regulation of glucagon secretion.
De novo lipogenesis
De novo lipogenesis (DNL) involves the production of lipids from carbon sources including carbohydrates and fatty acids. This process is active in classical lipogenic tissues, principally hepatocytes and adipocytes, as a process for energy storage. Glucose-driven DNL requires anaplerotic flux via pyruvate carboxylase, phosphoenolpyruvate carboxykinase or malic enzyme, leading to cataplerotic export of citrate from mitochondria, which is subsequently converted to acetyl-CoA via ATP-citrate lyase (ACLY) in the cytosol. ACC1 converts acetyl-CoA to malonyl-CoA, in the first committed step of DNL: malonyl-CoA is the rate-limiting substrate for fatty acid synthase (FASN) which produces the saturated fatty acid palmitate.
Several studies have investigated the role of the ACC1-coupled lipogenic pathway in beta cells, via genetic or pharmacological approaches, revealing a key role in insulin secretion and beta cell growth (Zhang & Kim 1998, Roduit et al. 2004, MacDonald et al. 2008, Ronnebaum et al. 2008, Cantley et al. 2019). Key nodes supporting the DNL pathway are expressed in both rodent and human pancreatic alpha cells including pyruvate carboxylase, ACLY, ACC1 and FASN (Benner et al. 2014, Ackermann et al. 2016) (Fig. 2). Conditional deletion of ACC1 in pro-glucagon expressing cells, or pharmacological ACC inhibition, has revealed that the loss of ACC1 activity impairs glucagon secretion at hypoglycaemic glucose concentrations, underpinned by a failure of the KATP channel to open at low glucose (Veprik et al. 2022). It remains to be fully elucidated how ACC1 activity influences alpha cell function, but one putative mechanism is the regulation of protein S-acylation (palmitoylation), a common post-translational modification of cell surface proteins requiring fatty acyl-CoA as a substrate. Pharmacological disruption of global S-acylation in alpha cells markedly enhanced glucagon secretion (Veprik et al. 2022) indicating a net-restraining effect of S-acylation on alpha cell function. Moreover, S-acylation of the KATP channel subunit Kir6.2 is dynamically regulated by glucose and ACC activity in alpha cells, suggesting a link between ACC1 activity and the control of cell surface channels involved in glucose sensing. Further studies into S-acylation, including the role of specific cysteine residues, will deepen our mechanistic understanding of the link between metabolism, DNL and secretory tone.
In addition to influencing glucagon secretion, the ACC1-coupled pathway is involved in the regulation of alpha cell mass. Deletion of ACC1 reduced alpha cell size, total alpha cell mass and pancreatic glucagon content but without significantly altering proliferation rates, highlighting a multi-faceted role for ACC1 in maintaining a functional alpha cell mass (Veprik et al. 2022). The mechanisms underpinning this ACC1-dependent alpha cell size phenotype have yet to be determined, although in beta cells, the loss of ACC1 results in reduced levels of total P70S6Kinase (Cantley et al. 2019), a key regulatory node controlling protein synthesis and cell growth and mTOR substrate.
Alongside anaplerotic glucose metabolism, the amino acid l-glutamine can also act as a carbon source for DNL (Fig. 3 red arrows). For example, protein-rich diets enhance DNL in hepatocytes (Charidemou et al. 2019), and rapidly growing cancer cells and cell lines utilise reductive mitochondrial metabolism of glutamine-derived alpha-ketoglutarate (aKG) to produce citrate for DNL, supporting cell growth (Metallo et al. 2011). Reductive flux from aKG has recently been demonstrated to play a role in insulin secretion in pancreatic beta cells (Zhang et al. 2021). l-glutamine released from the liver can drive alpha cell proliferation, acting as a critical intermediate in a liver–alpha cell axis (Dean et al. 2017), as well as enhancing glucagon secretion (Dean 2020). Given that ACC1 is necessary for the normal growth and function of alpha cells (Veprik et al. 2022), it is likely, although as yet untested, that ACC1 underpins glutamine action in the alpha cell during health and metabolic disease. This suggests that the ACC1-coupled pathway plays a key role in nutrient sensing in endocrine cells to maintain secretory potential, rather than as an energy storage mechanism seen in the liver or adipose tissue: future insights into the tissue-specific regulation of ACC1 activity will help to uncover how this pathway fulfils these distinct cellular roles.
Amino acid regulation of glucagon secretion. Various amino acids regulate glucagon secretion by multiple convergent mechanisms. Sodium cotransport via SLC38A4 of amino acids (e.g. alanine or glutamine) may promote glucagon secretion via activation of voltage-gated sodium channels which then stimulate voltage-gated P/Q calcium channels. The influx of calcium leads to the activation of exocytotic machinery and glucagon secretion. Red arrows indicate reductive metabolic pathway for glutamine/glutamate that may link glutamine oxidation to pathways for de novo lipogenesis. Arginine acts as a cation leading to depolarization and subsequent glucagon secretion. Arginine may also be metabolized to nitric oxide or ornithine in alpha cells although the mechanisms leading to secretion are less clear. Arginine metabolism via the urea cycle may occur and interact with the TCA cycle. ASA, arginosuccinate; α-KG, alpha-ketoglutarate; cGLS, cytosolic glutaminase; mGLS, mitochondrial glutaminase; NO, nitric oxide; NOS, nitric oxide synthase; VG, voltage gated. Created with BioRender.com.
Citation: Journal of Endocrinology 259, 1; 10.1530/JOE-23-0081
Signalling by fatty acids to regulate glucagon secretion
The metabolic phenotype of alpha cells is a clear indicator that fatty acid metabolism is important for maintaining intracellular ATP and the regulation of glucagon secretion by glucose. However, whether exogenous fatty acids regulate glucagon secretion is not so clear. Besides the metabolic effects described above, fatty acids have also been suggested to regulate glucagon secretion through signalling or indirect paracrine action. Alpha cells express the long-chain free fatty acid receptor FFAR1/GPR40, although at a lower expression level than neighbouring beta cells (Flodgren et al. 2007, Wang et al. 2011, Benner et al. 2014, Ackermann et al. 2016) in which FFAR1 activation potentiates the second phase of insulin secretion via Protein Kinase D1 (Ferdaoussi et al. 2012). Disruption of FFAR1 signalling in islets blunts the potentiation of glucagon release by linoleic acid (Flodgren et al. 2007, Wang et al. 2011) and palmitate (Kristinsson et al. 2017). However, the FFAR1 activating compound TAK-875 did not alter glucagon secretion from human islets (Yashiro et al. 2012), suggesting more work is needed to elucidate the role of FFAR1 in alpha cell function. In line with this, another study suggested that it is FFAR4 signalling and not FFAR1 signalling which stimulates glucagon secretion (Wu et al. 2021). Other studies have implicated the exogenous fatty acid palmitate in the proliferation of islet alpha cells in vitro (Ben-Zvi et al. 2015), although this mechanism was not supported in a similar islet model (Dean et al. 2017). Finally, fatty acids have been suggested to inhibit somatostatin secretion (Gromada et al. 2001), which would reduce somatostatin-mediated suppression of glucagon secretion from neighbouring alpha cells. However, this paracrine hypothesis has been challenged by others (Kristinsson et al. 2017).
Amino acid regulation of glucagon secretion
Given that glucagon regulates amino acid metabolising enzymes and transporters that drive gluconeogenesis in liver, it is not surprising that amino acids are potent stimulators of glucagon secretion (Galsgaard et al. 2019b, Eisenstein et al. 1979). The liver–alpha cell axis is not only limited to the regulation of secretion but also control of alpha cell mass. This topic is covered in more detail in the article by Brooks et al. within this special collection (Cantley et al. 2023). Glucagon secretion from the perfused pancreas of rats fed a high-protein diet has greater glucagon secretion in response to the individual amino acids. This suggests the alpha cell itself, or alpha cell mass, is remodelled to hyper-secrete glucagon upon chronic stimulation by elevated amino acids (Eisenstein & Strack 1978, Eisenstein et al. 1979), a notion that is supported by other models of hyperaminoacidaemia and hyperglucagonaemia (Dean et al. 2017, Kim et al. 2017, Galsgaard et al. 2018).
Many amino acids have been identified as stimulators of glucagon release, including cysteine, glycine, valine, alanine, arginine, leucine, serine and glutamate. Other amino acids, such as lysine, appear to have little effect on glucagon secretion, while some, such as leucine, have variable effects on secretion depending on the concentration (e.g. high leucine levels inhibit glucagon secretion) (Müller et al. 1971, Cabrera et al. 2008, Leclercq-Meyer et al. 1985). While we understand whether single amino acids stimulate or inhibit glucagon secretion, the mechanisms underlying these effects are unclear. Below, we describe the metabolic effect of the most studied amino acids in alpha cells.
Glutamate
Glutamate is the most widely studied amino acid in terms of its effect on glucagon secretion, perhaps due to its clearly defined effects on G-coupled protein receptors and ligand-gated ion channels. Glutamate is thought to predominantly act as an autocrine signal (Fig. 3). Glucagon granules are loaded with glutamate and at low glucose, glutamate is co-released with glucagon to activate ionotropic glutamate receptors, which leads to increased intracellular calcium and glucagon secretion (Cabrera et al. 2008). Both ionotropic and metabotropic glutamate receptors have been reported in alpha cells, although the species specificity varies, and targeting glutamate signalling in alpha cells may rescue hypoglycaemia by increasing glucagon secretion from type 1 diabetic alpha cells (Panzer et al. 2022).
Sodium-dependent versus sodium-independent amino acid transporters
For amino acids aside from glutamate, the mechanisms of stimulation or inhibition of glucagon secretion are less clear. However, the complement of amino acid transporters and catabolic enzymes may provide potential mechanisms of action (Spears et al. 2023). The most highly expressed amino acid transporters in human islets are the sodium-independent cationic amino acid transporter SLC7A2/CAT2 (Spears et al. 2023), the sodium-dependent SLC38A4/SNAT4 and the sodium-independent SLC7A8/LAT2 (Kim et al. 2019). Interestingly, while sodium uptake seems to play an important role in alpha cell function (Armour et al. 2022, Suga et al. 2019), how changes in intracellular sodium affect alpha cell function is unclear. Sodium uptake through sodium glucose co-transporters seems to elicit inhibitory effects at higher glucose concentrations (Bonner et al. 2015) and is required for normal alpha cell function (Suga et al. 2019). SLC38A4 transports alanine, glutamine and serine in a sodium-dependent manner and it could be speculated that sodium-dependent transporters may partly underlie the amino acid stimulation of glucagon secretion (Fig. 3). Similarly, this may also explain why some amino acids, such as leucine, can inhibit glucagon secretion. Since these amino acids are primarily transported via system L transporters, such SLC7A8/LAT2, which are sodium-independent transporters that exchange leucine for other intracellular amino acids, such as glutamine. Without concomitant sodium transport, the inhibitory metabolic effects of these amino acids might predominate as discussed below.
Glutamine
In addition to the high expression of various amino acid transporters, alpha cells express high levels of glutaminase (GLS) (Inagaki et al. 1995), which converts glutamine to glutamate and ammonia. Interestingly, mouse alpha cells express high levels of exon 15 of the Gls gene which encodes the mitochondrial isoform of GLS (glutaminase C/GAC). However, exons 16–19, which encode the cytosolic kidney GLS isoform (KGA), are detected at lower levels (DiGruccio et al. 2016). High expression of GAC is mostly associated with the Warburg effect in cancer cells (Wang et al. 2010). This aligns well with the glycolytic phenotype of alpha cells and suggests that glutamine may anaplerotically support TCA cycle activity. In support of this, glutamine oxidation is higher in alpha-cell-enriched islets (Ostenson & Grebing 1985). It is also possible that this might lead to reductive carboxylation in the TCA cycle when both glutamine and glucose are high (Fig. 3 red arrows). This could partially explain why glucose is unable to completely suppress glucagon secretion in response to amino acids (Gerich et al. 1974, Maruszczak et al. 2022). It may also explain why elevated glutamine levels, and the following increase in glutamine metabolism, result in increased proliferation of alpha cells through an mTOR-dependent pathway (Dean et al. 2017). Alpha cells appear to sense the increase in serum concentrations of glutamine and respond by activating mTOR to promote increased transcription of the glutamine transporter Slc38a5 in mice (Kim et al. 2017). In addition, the activation of mTOR signalling may also play a role in glucagon secretion by regulating KATP channel expression (Bozadjieva et al. 2017). This suggests that while the metabolism of glutamine might not acutely stimulate glucagon secretion, catabolism of glutamine clearly supports alpha cell function.
Arginine
Arginine is a potent secretagogue of glucagon secretion and is often used to test alpha cell function (Maruszczak et al. 2022). Despite this, the mechanism underlying its stimulatory effects remains somewhat controversial and understudied (Le Marchand & Piston 2012). Arginine is a cationic amino acid and has previously been described to stimulate voltage-gated calcium channels and insulin secretion through depolarisation of the plasma membrane (Fig. 3) (Henquin & Meissner 1981, Henquin & Meissner 1986, Malaisse et al. 1989). The amino acid is transported through the cationic transporter, SLC7A2 (DiGruccio et al. 2016). The loss of SLC7A2 in mice decreases alpha cell proliferation and results in a complete loss of responsiveness to both arginine and the strong depolarising agent KCl (Spears et al. 2023). The loss of KCl response suggests a wider impact of SLC7A2 deletion on the exocytosis of docked granules in alpha cells. Therefore, the simple model should be expanded to include studies investigating whether arginine-derived metabolites play an important role in glucagon secretion (Malaisse et al. 1989, Sener et al. 1989, Sener et al. 1990, Blachier et al. 1989, Malaisse et al. 1991). One such metabolite, nitric oxide, is produced following arginine breakdown by nitric oxide synthase (NOS). Nitric oxide donors promote glucagon secretion (Akesson et al. 1996, Gheibi & Ghasemi 2020). Therefore, one potential mechanism could involve increased nitric oxide levels stimulating cyclic guanosine 3′,5′-monophosphate (cGMP) production and leading to protein kinase G activation of ion channels involved in glucagon secretion (Mori et al. 2001, Kawano et al. 2009). Alternatively, KATP channels may be regulated by nitric oxide through S-nitrosylation of cysteine residues (Kawano et al. 2009, Zhou et al. 2022, Gui et al. 2018). In neurons, nitric oxide increases KATP channel activity through S-nitrosylation of the SUR1 subunit, which prevents inactivation, allowing KATP channels to remain active in the face of higher ATP/ADP ratios (Zhou et al. 2022). According to the KATP channel hypothesis (Zhang et al. 2020, Zhang et al. 2013), this same mechanism would activate alpha cells and lead to increased secretion of glucagon. Despite the wealth of data showing that arginine stimulates glucagon secretion, the most likely mechanism of action still seems to be through changes in membrane potential, but as indicated here, there are many other possible mechanisms under investigation.
Alanine
Alanine potently stimulates glucagon secretion at supra-physiological concentrations (Müller et al. 1971). Alanine is also a primary gluconeogenic substrate in the liver and has therefore been suggested to play a central role in the liver–alpha cell axis. There is, however, no consensus on how alanine stimulates glucagon secretion. Metabolically, alanine is converted to pyruvate, and given the inhibitory effects of glucose on glucagon secretion (see above), it seems unlikely that an increase in alanine metabolism or any other amino acid that increases pyruvate (e.g. cysteine, serine, glycine, glutamine) should lead to an increase in glucagon secretion. More likely, the effects are generated through transport of alanine which also can contribute to changes in intracellular sodium and possibly to depolarisation of the plasma membrane (Fig. 3). Given the complexity and contradictions of potential pathways involved, more work is needed to understand the exact mechanisms of how each individual amino acid regulates glucagon secretion.
Alpha cells as sensors of both nutrients and peripheral substrate metabolism
Based on the metabolic phenotype of alpha cells, it could be suggested that they are sensors of relative substrate levels rather than glucose sensors. Thus, alpha cells will relay signalling changes in peripheral tissue metabolism to the liver. This is not unlike the suggested liver–alpha cell axis. However, rather than being a feedback loop, in this model alpha cells sense release of amino acids from the skeletal muscle (Felig et al. 1970) and fatty acids from the adipose tissue (Marliss et al. 1970) when glucose is low. During fasting and/or starvation, the increase in fatty acid and amino acids levels would stimulate glucagon secretion from alpha cells. This results in increased hepatic glycogenolysis, increased hepatic fatty acid oxidation and increased amino acid catabolism (Unger 1985, Galsgaard et al. 2019a), thus driving hepatic glucose production and ketone body production. While glucagon does affect the metabolism of fatty acids in the liver, circulating levels of NEFA do not seem to be affected by the changes in plasma glucagon concentrations. Glucagon has previously been suggested to be involved in stimulating lipolysis in rodents and birds (Galsgaard et al. 2019a); however, the recent data from adipocyte-specific gcgr KO mice (Vasileva et al. 2022) and previous data from human adipocytes (Mosinger et al. 1965, Vizek et al. 1979, Gravholt et al. 2001) suggest that this is not the case. Release of NEFA from the liver in response to glucagon seems to occur but in small amounts (Galsgaard et al. 2022) and the importance of this remains unknown. The idea that alpha cells sense substrate levels that mediate carbohydrate oxidation status of peripheral tissues does not preclude the importance of the liver–alpha cell axis, rather it extends this concept, and it could be speculated that this axis may be especially relevant in subjects with non-alcoholic fatty liver disease or other conditions that affect glucagon action in the liver.
Alongside direct sensing of metabolic substrates, the secretory tone of alpha cells can be influenced by other hormones that relay metabolic status. For example, during the prandial state, alpha cells receive additional cues from gut-derived glucose-dependent insulinotropic polypeptide (GIP) which potentiates glucagon secretion in response to amino acids. Alpha cell-specific deletion of the GIP receptor impairs glucagon secretion in response to a mixed meal (El et al. 2021) suggesting that, in addition to interpreting overall nutrient status, the alpha cell may use additional cues to discern the source of nutrients, providing important context communicating nutrient status to the liver, balanced with input from insulin (i.e. the insulin:glucagon ratio) (Unger 1971).
Coda
Alpha cells play a significant role in the regulation of whole-body glucose metabolism. Whilst glucose plays a role in the regulation of glucagon secretion, the contribution of intrinsic glucose metabolism pathways in the alpha cell, relative to other nutrient sensing pathways and paracrine signalling, is less clear. The metabolism of alpha cells seems to differ significantly from that of other islet cell types, relying on substrates such as fatty acids, arginine and glutamine to maintain active secretion when circulating carbohydrates are low and to support proliferation to maintain alpha cell number and cellular structure. Yet glucose metabolism plays a central role in both the inhibition of glucagon secretion and possibly as a substrate for DNL and signalling through protein lipidation. Observations that alpha cells respond to a range of non-glucose metabolic substrates for ATP production do not support a simplistic glucose-centric model of regulated glucagon secretion: this calls for further investigation of cellular metabolism to increase our understanding of alpha cell function.
Declaration of interest
All authors declare no competing interests.
Funding
JC is funded by a Steve Morgan Foundation Type 1 Diabetes Grand Challenge Senior Research Fellowship (22/0006505), the Medical Research Council (MR/W019590/1) and Tenovus Scotland (T20-69). EDD and JES are funded by the NIH (R01DK132669, R01DK117147, R01DK130296; F31DK134158-JES) and are members of the NIH-supported Vanderbilt Diabetes Research and Training Center (P30DK020593). J.G.K. is supported by a Novo Nordisk Fonden Excellence Emerging Investigator Grant-Endocrinology & Metabolism (#0054300) and a Sapere Aude Fellowship from the Independent Research Fund Denmark.
References
Abu-Elheiga L, Brinkley WR, Zhong L, Chirala SS, Woldegiorgis G & & Wakil SJ 2000 The subcellular localization of acetyl-CoA carboxylase 2. Proceedings of the National Academy of Sciences of the United States of America 97 1444–1449. (https://doi.org/10.1073/pnas.97.4.1444)
Ackermann AM, Wang Z, Schug J, Naji A & & Kaestner KH 2016 Integration of ATAC-seq and RNA-seq identifies human alpha cell and beta cell signature genes. Molecular Metabolism 5 233–244. (https://doi.org/10.1016/j.molmet.2016.01.002)
Ahlborg G, Felig P, Hagenfeldt L, Hendler R & & Wahren J 1974 Substrate turnover during prolonged exercise in man: splanchnic and leg metabolism of glucose, free fatty acids, and amino acids. Journal of Clinical Investigation 53 1080–1090. (https://doi.org/10.1172/JCI107645)
Akesson B, Mosén H, Panagiotidis G & & Lundquist I 1996 Interaction of the islet nitric oxide system with L-arginine-induced secretion of insulin and glucagon in mice. British Journal of Pharmacology 119 758–764. (https://doi.org/10.1111/j.1476-5381.1996.tb15737.x)
Araki M, Nozaki Y & & Motojima K 2007 Transcriptional regulation of metabolic switching PDK4 gene under various physiological conditions. Yakugaku Zasshi 127 153–162. (https://doi.org/10.1248/yakushi.127.153)
Armour SL, Frueh A & & Knudsen JG 2022 Sodium, glucose and dysregulated glucagon secretion: the potential of sodium glucose transporters. Frontiers in Pharmacology 13 837664. (https://doi.org/10.3389/fphar.2022.837664)
Baenke F, Dubuis S, Brault C, Weigelt B, Dankworth B, Griffiths B, Jiang M, Mackay A, Saunders B, Spencer-Dene B, et al.2015 Functional screening identifies MCT4 as a key regulator of breast cancer cell metabolism and survival. Journal of Pathology 237 152–165. (https://doi.org/10.1002/path.4562)
Bahl V, Lee May C, Perez A, Glaser B & & Kaestner KH 2021 Genetic activation of α-cell glucokinase in mice causes enhanced glucose-suppression of glucagon secretion during normal and diabetic states. Molecular Metabolism 49 101193. (https://doi.org/10.1016/j.molmet.2021.101193)
Basco D, Zhang Q, Salehi A, Tarasov A, Dolci W, Herrera P, Spiliotis I, Berney X, Tarussio D, Rorsman P, et al.2018 α-cell glucokinase suppresses glucose-regulated glucagon secretion. Nature Communications 9 546. (https://doi.org/10.1038/s41467-018-03034-0)
Benner C, Van Der Meulen T, Caceres E, Tigyi K, Donaldson CJ & & Huising MO 2014 The transcriptional landscape of mouse beta cells compared to human beta cells reveals notable species differences in long non-coding RNA and protein-coding gene expression. BMC Genomics 15 620. (https://doi.org/10.1186/1471-2164-15-620)
Ben-Zvi D, Barrandon O, Hadley S, Blum B, Peterson QP & & Melton DA 2015 Angptl4 links α-cell proliferation following glucagon receptor inhibition with adipose tissue triglyceride metabolism. Proceedings of the National Academy of Sciences of the United States of America 112 15498–15503. (https://doi.org/10.1073/pnas.1513872112)
Blachier F, Mourtada A, Sener A & & Malaisse WJ 1989 Stimulus-secretion coupling of arginine-induced insulin release. Uptake of metabolized and nonmetabolized cationic amino acids by pancreatic islets. Endocrinology 124 134–141. (https://doi.org/10.1210/endo-124-1-134)
Bollheimer LC, Landauer HC, Troll S, Schweimer J, Wrede CE, Schölmerich J & & Buettner R 2004 Stimulatory short-term effects of free fatty acids on glucagon secretion at low to normal glucose concentrations. Metabolism: Clinical and Experimental 53 1443–1448. (https://doi.org/10.1016/j.metabol.2004.06.011)
Bolli GB, Gottesman IS, Cryer PE & & Gerich JE 1984 Glucose counterregulation during prolonged hypoglycemia in normal humans. American Journal of Physiology 247 E206–E214. (https://doi.org/10.1152/ajpendo.1984.247.2.E206)
Bonen A 2001 The expression of lactate transporters (MCT1 and MCT4) in heart and muscle. European Journal of Applied Physiology 86 6–11. (https://doi.org/10.1007/s004210100516)
Bonner C, Kerr-Conte J, Gmyr V, Queniat G, Moerman E, Thevenet J, Beaucamps C, Delalleau N, Popescu I, Malaisse WJ, et al.2015 Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion. Nature Medicine 21 512–517. (https://doi.org/10.1038/nm.3828)
Bozadjieva N, Blandino-Rosano M, Chase J, Dai XQ, Cummings K, Gimeno J, Dean D, Powers AC, Gittes GK, Rüegg MA, et al.2017 Loss of mTORC1 signaling alters pancreatic α cell mass and impairs glucagon secretion. Journal of Clinical Investigation 127 4379–4393. (https://doi.org/10.1172/JCI90004)
Briant LJB, Dodd MS, Chibalina MV, Rorsman NJG, Johnson PRV, Carmeliet P, Rorsman P & & Knudsen JGJCR 2018 CPT1a-dependent long-chain fatty acid oxidation contributes to maintaining glucagon secretion from pancreatic islets. Cell Reports 23 3300–3311. (https://doi.org/10.1016/j.celrep.2018.05.035)
Browning JD, Baxter J, Satapati S & & Burgess SC 2012 The effect of short-term fasting on liver and skeletal muscle lipid, glucose, and energy metabolism in healthy women and men. Journal of Lipid Research 53 577–586. (https://doi.org/10.1194/jlr.P020867)
Cabrera O, Jacques-Silva MC, Speier S, Yang SN, Köhler M, Fachado A, Vieira E, Zierath JR, Kibbey R, Berman DM, et al.2008 Glutamate is a positive autocrine signal for glucagon release. Cell Metabolism 7 545–554. (https://doi.org/10.1016/j.cmet.2008.03.004)
Cantley J, Davenport A, Vetterli L, Nemes NJ, Whitworth PT, Boslem E, Thai LM, Mellett N, Meikle PJ, Hoehn KL, et al.2019 Disruption of beta cell acetyl-CoA carboxylase-1 in mice impairs insulin secretion and beta cell mass. Diabetologia 62 99–111. (https://doi.org/10.1007/s00125-018-4743-7)
Cantley J, Poitout V & & Hull-Meichle RL 2023 100 years of glucagon anniversary. Journal of Endocrinology 258 e230138. (https://doi.org/10.1530/JOE-23-0138)
Charidemou E, Ashmore T, Li X, Mcnally BD, West JA, Liggi S, Harvey M, Orford E & & Griffin JL 2019 A randomized 3-way crossover study indicates that high-protein feeding induces de novo lipogenesis in healthy humans. JCI Insight 4. (https://doi.org/10.1172/jci.insight.124819)
De Feo P, Perriello G, De Cosmo S, Ventura MM, Campbell PJ, Brunetti P, Gerich JE & & Bolli GB 1986 Comparison of glucose counterregulation during short-term and prolonged hypoglycemia in normal humans. Diabetes 35 563–569. (https://doi.org/10.2337/diabetes.35.5.563)
Dean ED, Li M, Prasad N, Wisniewski SN, Von Deylen A, Spaeth J, Maddison L, Botros A, Sedgeman LR, Bozadjieva N, et al.2017 Interrupted glucagon signaling reveals hepatic α cell axis and role for L-glutamine in α cell proliferation. Cell Metabolism 25 1362–1373.e5. (https://doi.org/10.1016/j.cmet.2017.05.011)
Dean ED 2020 A primary role for α-cells as amino acid sensors. Diabetes 69 542–549. (https://doi.org/10.2337/dbi19-0021)
Detimary P, Dejonghe S, Ling Z, Pipeleers D, Schuit F & & Henquin JC 1998 The changes in adenine nucleotides measured in glucose-stimulated rodent islets occur in β cells but not in α cells and are also observed in human islets. Journal of Biological Chemistry 273 33905–33908. (https://doi.org/10.1074/jbc.273.51.33905)
Diao J, Allister EM, Koshkin V, Lee SC, Bhattacharjee A, Tang C, Giacca A, Chan CB & & Wheeler MB 2008 UCP2 is highly expressed in pancreatic α-cells and influences secretion and survival. Proceedings of the National Academy of Sciences of the United States of America 105 12057–12062. (https://doi.org/10.1073/pnas.0710434105)
DiGruccio MR, Mawla AM, Donaldson CJ, Noguchi GM, Vaughan J, Cowing-Zitron C, Van Der Meulen T & & Huising MO 2016 Comprehensive alpha, beta and delta cell transcriptomes reveal that ghrelin selectively activates delta cells and promotes somatostatin release from pancreatic islets. Molecular Metabolism 5 449–458. (https://doi.org/10.1016/j.molmet.2016.04.007)
Edwards JC & & Taylor KW 1970 Fatty acids and the release of glucagon from isolated guinea-pig islets of langerhans incubated in vitro. Biochimica et Biophysica Acta 215 310–315. (https://doi.org/10.1016/0304-4165(7090029-2)
Eisenstein AB & & Strack I 1978 Amino acid stimulation of glucagon secretion by perifused islets of high-protein-fed rats. Diabetes 27 370–376. (https://doi.org/10.2337/diab.27.4.370)
Eisenstein AB, Strack I, Gallo-Torres H, Georgiadis A & & Miller ON 1979 Increased glucagon secretion in protein-fed rats: lack of relationship to plasma amino acids. American Journal of Physiology 236 E20–E27. (https://doi.org/10.1152/ajpendo.1979.236.1.E20)
El K, Gray SM, Capozzi ME, Knuth ER, Jin E, Svendsen B, Clifford A, Brown JL, Encisco SE, Chazotte BM, et al.2021 GIP mediates the incretin effect and glucose tolerance by dual actions on α cells and β cells. Science Advances 7 eabf1948. (https://doi.org/10.1126/sciadv.abf1948)
Felig P, Marliss E, Owen OE & & Cahill GF 1969a Blood glucose and gluconeogenesis in fasting man. Archives of Internal Medicine 123 293–298. (https://doi.org/10.1001/archinte.1969.00300130075011)
Felig P, Owen OE, Wahren J & & Cahill GF 1969b Amino acid metabolism during prolonged starvation. Journal of Clinical Investigation 48 584–594. (https://doi.org/10.1172/JCI106017)
Felig P, Pozefsk T, Marlis E & & Cahill GF 1970 Alanine: key role in gluconeogenesis. Science 167 1003–1004. (https://doi.org/10.1126/science.167.3920.1003)
Ferdaoussi M, Bergeron V, Zarrouki B, Kolic J, Cantley J, Fielitz J, Olson EN, Prentki M, Biden T, Macdonald PE, et al.2012 G protein-coupled receptor (GPR)40-dependent potentiation of insulin secretion in mouse islets is mediated by protein kinase D1. Diabetologia 55 2682–2692. (https://doi.org/10.1007/s00125-012-2650-x)
Flodgren E, Olde B, Meidute-Abaraviciene S, Winzell MS, Ahrén B & & Salehi A 2007 GPR40 is expressed in glucagon producing cells and affects glucagon secretion. Biochemical and Biophysical Research Communications 354 240–245. (https://doi.org/10.1016/j.bbrc.2006.12.193)
Fujiwara K, Maekawa F, Dezaki K, Nakata M, Yashiro T & & Yada T 2007 Oleic acid glucose-independently stimulates glucagon secretion by increasing cytoplasmic Ca2+ via endoplasmic reticulum Ca2+ release and Ca2+ influx in the rat islet alpha-cells. Endocrinology 148 2496–2504. (https://doi.org/10.1210/en.2006-1156)
Galsgaard KD, Winther-Sørensen M, Ørskov C, Kissow H, Poulsen SS, Vilstrup H, Prehn C, Adamski J, Jepsen SL, Hartmann B, et al.2018 Disruption of glucagon receptor signaling causes hyperaminoacidemia exposing a possible liver-alpha-cell axis. American Journal of Physiology. Endocrinology and Metabolism 314 E93–E103. (https://doi.org/10.1152/ajpendo.00198.2017)
Galsgaard KD, Pedersen J, Knop FK, Holst JJ & & Wewer Albrechtsen NJ 2019a Glucagon receptor signaling and lipid metabolism. Frontiers in Physiology 10 413. (https://doi.org/10.3389/fphys.2019.00413)
Galsgaard KD, Winther-Sørensen M, Pedersen J, Kjeldsen SAS, Rosenkilde MM, Albrechtsen NJW & & Holst JJ 2019b Glucose and amino acid metabolism in mice depend mutually on glucagon and insulin receptor signaling. American Journal of Physiology-Endocrinology and Metabolism 316 E660–E673. (https://doi.org/10.1152/ajpendo.00410.2018)
Galsgaard KD, Elmelund E, Johansen CD, Bomholt AB, Kizilkaya HS, Ceutz F, Hunt JE, Kissow H, Winther-Sørensen M, Sørensen CM, et al.2022 Glucagon receptor antagonism impairs and glucagon receptor agonism enhances triglycerides metabolism in mice. Molecular Metabolism 66 101639. (https://doi.org/10.1016/j.molmet.2022.101639)
Gerich JE, Charles MA & & Grodsky GM 1974 Characterization of the effects of arginine and glucose on glucagon and insulin release from the perfused rat pancreas. Journal of Clinical Investigation 54 833–841. (https://doi.org/10.1172/JCI107823)
Gheibi S & & Ghasemi A 2020 Insulin secretion: the nitric oxide controversy. Excli Journal 19 1227–1245. (https://doi.org/10.17179/excli2020-2711)
Goodpaster BH & & Sparks LM 2017 Metabolic flexibility in health and disease. Cell Metabolism 25 1027–1036. (https://doi.org/10.1016/j.cmet.2017.04.015)
Gorovits N & & Charron MJ 2003 What we know about facilitative glucose transporters: lessons from cultured cells, animal models, and human studies. Biochemistry and Molecular Biology Education 31 163–172. (https://doi.org/10.1002/bmb.2003.494031030227)
Gravholt CH, Møller N, Jensen MD, Christiansen JS & & Schmitz O 2001 Physiological levels of glucagon do not influence lipolysis in abdominal adipose tissue as assessed by microdialysis. Journal of Clinical Endocrinology and Metabolism 86 2085–2089. (https://doi.org/10.1210/jcem.86.5.7460)
Gromada J, Høy M, Buschard K, Salehi A & & Rorsman P 2001 Somatostatin inhibits exocytosis in rat pancreatic alpha-cells by G(i2)-dependent activation of calcineurin and depriming of secretory granules. Journal of Physiology 535 519–532. (https://doi.org/10.1111/j.1469-7793.2001.00519.x)
Gui L, Zhu J, Lu X, Sims SM, Lu WY, Stathopulos PB & & Feng Q 2018 S-Nitrosylation of STIM1 by neuronal nitric oxide synthase inhibits store-operated Ca(2+) entry. Journal of Molecular Biology 430 1773–1785. (https://doi.org/10.1016/j.jmb.2018.04.028)
Gylfe E 2016 Glucose control of glucagon secretion-'There's a brand-new gimmick every year'. Upsala Journal of Medical Sciences 121 120–132. (https://doi.org/10.3109/03009734.2016.1154905)
Heimberg H, De Vos A, Pipeleers D, Thorens B & & Schuit F 1995 Differences in glucose transporter gene expression between rat pancreatic alpha- and beta-cells are correlated to differences in glucose transport but not in glucose utilization. Journal of Biological Chemistry 270 8971–8975. (https://doi.org/10.1074/jbc.270.15.8971)
Henquin JC & & Meissner HP 1981 Effects of amino acids on membrane potential and 86Rb+ fluxes in pancreatic beta-cells. American Journal of Physiology 240 E245–E252. (https://doi.org/10.1152/ajpendo.1981.240.3.E245)
Henquin JC & & Meissner HP 1986 Cyclic adenosine monophosphate differently affects the response of mouse pancreatic beta-cells to various amino acids. Journal of Physiology 381 77–93. (https://doi.org/10.1113/jphysiol.1986.sp016314)
Hong J, Abudula R, Chen J, Jeppesen PB, Dyrskog SEU, Xiao J, Colombo M & & Hermansen K 2005 The short-term effect of fatty acids on glucagon secretion is influenced by their chain length, spatial configuration, and degree of unsaturation: studies in vitro. Metabolism: Clinical and Experimental 54 1329–1336. (https://doi.org/10.1016/j.metabol.2005.04.022)
Hong J, Jeppesen PB, Nordentoft I & & Hermansen K 2007 Fatty acid‐induced effect on glucagon secretion is mediated via fatty acid oxidation. Diabetes/Metabolism Research and Reviews 23 202–210. (https://doi.org/10.1002/dmrr.663)
Hue L & & Taegtmeyer H 2009 The Randle cycle revisited: a new head for an old hat. American Journal of Physiology - Endocrinology and Metabolism 297 E578–E591. (https://doi.org/10.1152/ajpendo.00093.2009)
Inagaki N, Kuromi H, Gonoi T, Okamoto Y, Ishida H, Seino Y, Kaneko T, Iwanaga T & & Seino S 1995 Expression and role of ionotropic glutamate receptors in pancreatic islet cells. FASEB Journal 9 686–691. (https://doi.org/10.1096/fasebj.9.8.7768362)
Ishihara H, Maechler P, Gjinovci A, Herrera PL & & Wollheim CB 2003 Islet beta-cell secretion determines glucagon release from neighbouring alpha-cells. Nature Cell Biology 5 330–335. (https://doi.org/10.1038/ncb951)
Iynedjian PB, Pilot PR, Nouspikel T, Milburn JL, Quaade C, Hughes S, Ucla C & & Newgard CB 1989 Differential expression and regulation of the glucokinase gene in liver and islets of Langerhans. Proceedings of the National Academy of Sciences of the United States of America 86 7838–7842. (https://doi.org/10.1073/pnas.86.20.7838)
Jelinek BA & & Moxley MA 2021 Detailed evaluation of pyruvate dehydrogenase complex inhibition in simulated exercise conditions. Biophysical Journal 120 936–949. (https://doi.org/10.1016/j.bpj.2021.01.018)
Kawano T, Zoga V, Kimura M, Liang MY, Wu HE, Gemes G, Mccallum JB, Kwok WM, Hogan QH & & Sarantopoulos CD 2009 Nitric oxide activates ATP-sensitive potassium channels in mammalian sensory neurons: action by direct S-nitrosylation. Molecular Pain 5 12. (https://doi.org/10.1186/1744-8069-5-12)
Kerksick C & & Willoughby D 2005 The antioxidant role of glutathione and N-acetyl-cysteine supplements and exercise-induced oxidative stress. Journal of the International Society of Sports Nutrition 2 38–44. (https://doi.org/10.1186/1550-2783-2-2-38)
Kim J, Okamoto H, Huang Z, Anguiano G, Chen S, Liu Q, Cavino K, Xin Y, Na E, Hamid R, et al.2017 Amino acid transporter Slc38a5 controls glucagon receptor inhibition-induced pancreatic α cell hyperplasia in mice. Cell Metabolism 25 1348–1361.e8. (https://doi.org/10.1016/j.cmet.2017.05.006)
Kim J, Dominguez Gutierrez G, Xin Y, Cavino K, Sung B, Sipos B, Kloeppel G, Gromada J & & Okamoto H 2019 Increased SLC38A4 amino acid transporter expression in human pancreatic α-cells after glucagon receptor inhibition. Endocrinology 160 979–988. (https://doi.org/10.1210/en.2019-00022)
Kimball CP & & Murlin JR 1923 Aqueous extracts of pancreas. Journal of Biological Chemistry Some Precipitation Reactions of Insulin 58 337–346.
Knudsen JG, Hamilton A, Ramracheya R, Tarasov AI, Brereton M, Haythorne E, Chibalina MV, Spegel P, Mulder H, Zhang Q, et al.2019 Dysregulation of glucagon secretion by hyperglycemia-induced sodium-dependent reduction of ATP production. Cell Metabolism 29 430–442.e4. (https://doi.org/10.1016/j.cmet.2018.10.003)
Koepsell H 2020 Glucose transporters in the small intestine in health and disease. Pflugers Archiv 472 1207–1248. (https://doi.org/10.1007/s00424-020-02439-5)
Kristinsson H, Sargsyan E, Manell H, Smith DM, Gopel SO & & Bergsten P 2017 Basal hypersecretion of glucagon and insulin from palmitate-exposed human islets depends on FFAR1 but not decreased somatostatin secretion. Scientific Reports 7 4657. (https://doi.org/10.1038/s41598-017-04730-5)
Laffel L 1999 Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes/Metabolism Research and Reviews 15 412–426. (https://doi.org/10.1002/(sici)1520-7560(199911/12)15:6<412::aid-dmrr72>3.0.co;2-8)
Le Marchand SJ & & Piston DW 2012 Glucose decouples intracellular Ca2+ activity from glucagon secretion in mouse pancreatic islet alpha-cells. PLoS One 7 e47084. (https://doi.org/10.1371/journal.pone.0047084)
Leclercq-Meyer V, Marchand J, Woussen-Colle MC, Giroix MH & & Malaisse WJ 1985 Multiple effects of leucine on glucagon, insulin, and somatostatin secretion from the perfused rat pancreas. Endocrinology 116 1168–1174. (https://doi.org/10.1210/endo-116-3-1168)
Leone TC, Weinheimer CJ & & Kelly DP 1999 A critical role for the peroxisome proliferator-activated receptor α (PPARα) in the cellular fasting response: the PPARα-null mouse as a model of fatty acid oxidation disorders. Proceedings of the National Academy of Sciences of the United States of America 96 7473–7478. (https://doi.org/10.1073/pnas.96.13.7473)
Li J, Yu Q, Ahooghalandari P, Gribble FM, Reimann F, Tengholm A & & Gylfe E 2015 Submembrane ATP and Ca2+ kinetics in α-cells: unexpected signaling for glucagon secretion. FASEB Journal 29 3379–3388. (https://doi.org/10.1096/fj.14-265918)
Liu YJ, Vieira E & & Gylfe E 2004 A store-operated mechanism determines the activity of the electrically excitable glucagon-secreting pancreatic α-cell. Cell Calcium 35 357–365. (https://doi.org/10.1016/j.ceca.2003.10.002)
Luyckx AS & & Lefebvre PJ 1970 Arguments for a regulation of pancreatic glucagon secretion by circulating plasma free fatty acids. Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine 133 524–528. (https://doi.org/10.3181/00379727-133-34511)
MacDonald PE, De Marinis YZ, Ramracheya R, Salehi A, Ma X, Johnson PR, Cox R, Eliasson L & & Rorsman P 2007 A KATP channel-dependent pathway within α cells regulates glucagon release from both rodent and human islets of Langerhans. PLOS Biology 5 e143. (https://doi.org/10.1371/journal.pbio.0050143)
MacDonald MJ, Dobrzyn A, Ntambi J & & Stoker SW 2008 The role of rapid lipogenesis in insulin secretion: insulin secretagogues acutely alter lipid composition of INS-1 832/13 cells. Archives of Biochemistry and Biophysics 470 153–162. (https://doi.org/10.1016/j.abb.2007.11.017)
Madison LL, Seyffert WA, Unger RH & & Barker B 1968 Effect of plasma free fatty acids on plasma glucagon and serum insulin concentrations. Metabolism: Clinical and Experimental 17 301–304. (https://doi.org/10.1016/0026-0495(6890097-8)
Malaisse WJ, Blachier F, Mourtada A, Camara J, Albor A, Valverde I & & Sener A 1989 Stimulus-secretion coupling of arginine-induced insulin release. Metabolism of l-arginine and l-ornithine in pancreatic islets. Biochimica et Biophysica Acta 1013 133–143. (https://doi.org/10.1016/0167-4889(8990041-4)
Malaisse WJ, Plasman PO, Blachier F, Herchuelz A & & Sener A 1991 Stimulus-secretion coupling of arginine-induced insulin release: significance of changes in extracellular and intracellular pH. Cell Biochemistry and Function 9 1–7. (https://doi.org/10.1002/cbf.290090102)
Malmgren S & & Ahren B 2015 Deciphering the hypoglycemic glucagon response: development of a graded hyperinsulinemic hypoglycemic clamp technique in female mice. Endocrinology 156 3866–3871. (https://doi.org/10.1210/EN.2015-1314)
Marliss EB, Aoki TT, Unger RH, Soeldner JS, & Cahill GF, JR 1970 Glucagon levels and metabolic effects in fasting man. Journal of Clinical Investigation 49 2256–2270. (https://doi.org/10.1172/JCI106445)
Maruszczak K, Rasmussen C, Ceutz FR, Ørgaard A, Elmelund E, Richter MM, Holst JJ, Winther-Sørensen M & & Wewer Albrechtsen NJ 2022 Arginine-induced glucagon secretion and glucagon-induced enhancement of amino acid catabolism are not influenced by ambient glucose levels in mice. American Journal of Physiology-Endocrinology and Metabolism 323 E207–E214. (https://doi.org/10.1152/ajpendo.00122.2022)
Mawla AM & & Huising MO 2019 Navigating the depths and avoiding the shallows of pancreatic islet cell transcriptomes. Diabetes 68 1380–1393. (https://doi.org/10.2337/dbi18-0019)
Meek CL, Lewis HB, Burling K, Reimann F & & Gribble F 2021 Expected values for gastrointestinal and pancreatic hormone concentrations in healthy volunteers in the fasting and postprandial state. Annals of Clinical Biochemistry 58 108–116. (https://doi.org/10.1177/0004563220975658)
Metallo CM, Gameiro PA, Bell EL, Mattaini KR, Yang J, Hiller K, Jewell CM, Johnson ZR, Irvine DJ, Guarente L, et al.2011 Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481 380–384. (https://doi.org/10.1038/nature10602)
Miki A, Ricordi C, Sakuma Y, Yamamoto T, Misawa R, Mita A, Molano RD, Vaziri ND, Pileggi A & & Ichii H 2018 Divergent antioxidant capacity of human islet cell subsets: a potential cause of beta-cell vulnerability in diabetes and islet transplantation. PLoS One 13 e0196570. (https://doi.org/10.1371/journal.pone.0196570)
Moede T, Leibiger B, Vaca Sanchez P, Daré E, Köhler M, Muhandiramlage TP, Leibiger IB & & Berggren PO 2020 Glucokinase intrinsically regulates glucose sensing and glucagon secretion in pancreatic alpha cells. Scientific Reports 10 20145. (https://doi.org/10.1038/s41598-020-76863-z)
Mori T, Murakami Y, Koshimura K, Hamaguchi K & & Kato Y 2001 Involvement of cyclic guanosine 3',5'-monophosphate in nitric oxide-induced glucagon secretion from pancreatic alpha cells. Metabolism: Clinical and Experimental 50 703–707. (https://doi.org/10.1053/meta.2001.23301)
Mosinger B, Kuhn E & & Kujalova V 1965 Action of adipokinetic hormones on human adipose tissue in vitro. Journal of Laboratory and Clinical Medicine 66 380–389.
Mourtzakis M, Saltin B, Graham T & & Pilegaard H 2006 Carbohydrate metabolism during prolonged exercise and recovery: interactions between pyruvate dehydrogenase, fatty acids, and amino acids. Journal of Applied Physiology 100 1822–1830. (https://doi.org/10.1152/japplphysiol.00571.2005)
Müller WA, Faloona GR, Aguilar-Parada E & & Unger RH 1970 Abnormal alpha-cell function in diabetes. Response to carbohydrate and protein ingestion. New England Journal of Medicine 283 109–115. (https://doi.org/10.1056/NEJM197007162830301)
Müller WA, Faloona GR & & Unger RH 1971 The effect of alanine on glucagon secretion. Journal of Clinical Investigation 50 2215–2218. (https://doi.org/10.1172/JCI106716)
Olofsson CS, Salehi A, Göpel SO, Holm C & & Rorsman P 2004 Palmitate stimulation of glucagon secretion in mouse pancreatic α-cells results from activation of l-type calcium channels and elevation of cytoplasmic calcium. Diabetes 53 2836–2843. (https://doi.org/10.2337/diabetes.53.11.2836)
Östenson CG 1979 Regulation of glucagon release: effects of insulin on the pancreatic A2-cell of the guinea pig. Diabetologia 17 325–330. (https://doi.org/10.1007/BF01235889)
Östenson CG 1980 Alloxan reversibly impairs glucagon release and glucose oxidation by pancreatic A2-cells. Biochemical Journal 188 201–206. (https://doi.org/10.1042/bj1880201)
Ostenson CG & & Grebing C 1985 Evidence for metabolic regulation of pancreatic glucagon secretion by L-glutamine. Acta Endocrinologica 108 386–391. (https://doi.org/10.1530/acta.0.1080386)
Panzer JK, Tamayo A & & Caicedo A 2022 Restoring glutamate receptor signaling in pancreatic alpha cells rescues glucagon responses in type 1 diabetes. Cell Reports 41 111792. (https://doi.org/10.1016/j.celrep.2022.111792)
Patra KC & & Hay N 2014 The pentose phosphate pathway and cancer. Trends in Biochemical Sciences 39 347–354. (https://doi.org/10.1016/j.tibs.2014.06.005)
Pilegaard H, Saltin B & & Neufer PD 2003 Effect of short-term fasting and refeeding on transcriptional regulation of metabolic genes in human skeletal muscle. Diabetes 52 657–662. (https://doi.org/10.2337/diabetes.52.3.657)
Printz RL, Magnuson MA & & Granner DK 1993 Mammalian glucokinase. Annual Review of Nutrition 13 463–496. (https://doi.org/10.1146/annurev.nu.13.070193.002335)
Purich DL, Fromm HJ & & Rudolph FB 1973 The hexokinases: kinetic, physical, and regulatory properties. Advances in Enzymology and Related Areas of Molecular Biology 39 249–326. (https://doi.org/10.1002/9780470122846.ch4)
Quesada I, Todorova MG & & Soria B 2006 Different metabolic responses in alpha-, beta-, and delta-cells of the islet of Langerhans monitored by redox confocal microscopy. Biophysical Journal 90 2641–2650. (https://doi.org/10.1529/biophysj.105.069906)
Quoix N, Cheng-Xue R, Mattart L, Zeinoun Z, Guiot Y, Beauvois MC, Henquin JC & & Gilon P 2009 Glucose and pharmacological modulators of ATP-sensitive K+ channels control [Ca2+]c by different mechanisms in isolated mouse alpha-cells. Diabetes 58 412–421. (https://doi.org/10.2337/db07-1298)
Rakhshandehroo M, Hooiveld G, Müller M & & Kersten S 2009 Comparative analysis of gene regulation by the transcription factor PPARα between mouse and human. PLoS One 4 e6796. (https://doi.org/10.1371/journal.pone.0006796)
Rocha DM, Faloona GR & & Unger RH 1972 Glucagon-stimulating activity of 20 amino acids in dogs. Journal of Clinical Investigation 51 2346–2351. (https://doi.org/10.1172/JCI107046)
Roduit R, Nolan C, Alarcon C, Moore P, Barbeau A, Delghingaro-Augusto V, Przybykowski E, Morin J, Massé F, Massie B, et al.2004 A role for the malonyl-CoA/long-chain acyl-CoA pathway of lipid signaling in the regulation of insulin secretion in response to both fuel and nonfuel stimuli. Diabetes 53 1007–1019. (https://doi.org/10.2337/diabetes.53.4.1007)
Ronnebaum SM, Joseph JW, Ilkayeva O, Burgess SC, Lu D, Becker TC, Sherry AD & & Newgard CB 2008 Chronic suppression of acetyl-CoA carboxylase 1 in beta-cells impairs insulin secretion via inhibition of glucose rather than lipid metabolism. Journal of Biological Chemistry 283 14248–14256. (https://doi.org/10.1074/jbc.M800119200)
Rutter GA, Georgiadou E, Martinez-Sanchez A & & Pullen TJ 2020 Metabolic and functional specialisations of the pancreatic beta cell: gene disallowance, mitochondrial metabolism and intercellular connectivity. Diabetologia 63 1990–1998. (https://doi.org/10.1007/s00125-020-05205-5)
Sanchez PKM, Khazaei M, Gatineau E, Geravandi S, Lupse B, Liu H, Dringen R, Wojtusciszyn A, Gilon P, Maedler K, et al.2021 LDHA is enriched in human islet alpha cells and upregulated in type 2 diabetes. Biochemical and Biophysical Research Communications 568 158–166. (https://doi.org/10.1016/j.bbrc.2021.06.065)
Schuit F, De Vos A, Farfari S, Moens K, Pipeleers D, Brun T & & Prentki M 1997 Metabolic fate of glucose in purified islet cells. Glucose-regulated anaplerosis in beta cells. Journal of Biological Chemistry 272 18572–18579. (https://doi.org/10.1074/jbc.272.30.18572)
Sener A, Blachier F, Rasschaert J, Mourtada A, Malaisse-Lagae F & & Malaisse WJ 1989 Stimulus-secretion coupling of arginine-induced insulin release: comparison with lysine-induced insulin secretion. Endocrinology 124 2558–2567. (https://doi.org/10.1210/endo-124-5-2558)
Sener A, Blachier F, Rasschaert J & & Malaisse WJ 1990 Stimulus-secretion coupling of arginine-induced insulin release: comparison with histidine-induced insulin release. Endocrinology 127 107–113. (https://doi.org/10.1210/endo-127-1-107)
Shinohara Y, Yamamoto K, Inoo K, Yamazaki N & & Terada H 1998 Quantitative determinations of the steady state transcript levels of hexokinase isozymes and glucose transporter isoforms in normal rat tissues and the malignant tumor cell line AH130. Biochimica et Biophysica Acta 1368 129–136. (https://doi.org/10.1016/s0005-2736(9700189-2)
Spears E, Stanley JE, Shou M, Yin L, Li X, Dai C, Bradley A, Sellick K, Poffenberger G & Coate KC et al. 2023 Pancreatic islet α cell function and proliferation requires the arginine transporter SLC7A2. bioRxiv [epub]. (https://doi.org/10.1101/2023.08.10.552656)
Stamenkovic JA, Andersson LE, Adriaenssens AE, Bagge A, Sharoyko VV, Gribble F, Reimann F, Wollheim CB, Mulder H & & Spégel P 2015 Inhibition of the malate–aspartate shuttle in mouse pancreatic islets abolishes glucagon secretion without affecting insulin secretion. Biochemical Journal 468 49–63. (https://doi.org/10.1042/BJ20140697)
Stern JH, Smith GI, Chen S, Unger RH, Klein S & & Scherer PE 2019 Obesity dysregulates fasting-induced changes in glucagon secretion. Journal of Endocrinology 243 149–160. (https://doi.org/10.1530/JOE-19-0201)
Suga T, Kikuchi O, Kobayashi M, Matsui S, Yokota-Hashimoto H, Wada E, Kohno D, Sasaki T, Takeuchi K, Kakizaki S, et al.2019 SGLT1 in pancreatic α cells regulates glucagon secretion in mice, possibly explaining the distinct effects of SGLT2 inhibitors on plasma glucagon levels. Molecular Metabolism 19 1–12. (https://doi.org/10.1016/j.molmet.2018.10.009)
Sugden MC, Bulmer K, Augustine D & & Holness MJ 2001 Selective modification of pyruvate dehydrogenase kinase isoform expression in rat pancreatic islets elicited by starvation and activation of peroxisome proliferator–activated receptor-α. Diabetes 50 2729–2736. (https://doi.org/10.2337/diabetes.50.12.2729)
Sun G, Da Silva Xavier G, Gorman T, Priest C, Solomou A, Hodson DJ, Foretz M, Viollet B, Herrera PL, Parker H, et al.2015 LKB1 and AMPKα1 are required in pancreatic alpha cells for the normal regulation of glucagon secretion and responses to hypoglycemia. Molecular Metabolism 4 277–286. (https://doi.org/10.1016/j.molmet.2015.01.006)
Unger RH 1971 Glucagon physiology and pathophysiology. New England Journal of Medicine 285 443–449. (https://doi.org/10.1056/NEJM197108192850806)
Unger RH 1985 Glucagon physiology and pathophysiology in the light of new advances. Diabetologia 28 574–578. (https://doi.org/10.1007/BF00281991)
Vasileva A, Marx T, Beaudry JL & & Stern JH 2022 Glucagon receptor signaling at white adipose tissue does not regulate lipolysis. American Journal of Physiology-Endocrinology and Metabolism 323 E389–E401. (https://doi.org/10.1152/ajpendo.00078.2022)
Veprik A, Denwood G, Liu D, Bany Bakar R, Morfin V, Mchugh K, Tebeka NN, Vetterli L, Yonova-Doing E, Gribble F, et al.2022 Acetyl-CoA-carboxylase 1 (ACC1) plays a critical role in glucagon secretion. Communications Biology 5 238. (https://doi.org/10.1038/s42003-022-03170-w)
Vieira E, Salehi A & & Gylfe E 2007 Glucose inhibits glucagon secretion by a direct effect on mouse pancreatic alpha cells. Diabetologia 50 370–379. (https://doi.org/10.1007/s00125-006-0511-1)
Vizek K, Razova M & & Melichar V 1979 Lipolytic effect of TSH, glucagon and hydrocortisone on the adipose tissue of newborns and adults in vitro. Physiologia Bohemoslovaca 28 325–331.
Wamelink MMC, Struys EA & & Jakobs C 2008 The biochemistry, metabolism and inherited defects of the pentose phosphate pathway: a review. Journal of Inherited Metabolic Disease 31 703–717. (https://doi.org/10.1007/s10545-008-1015-6)
Wang JB, Erickson JW, Fuji R, Ramachandran S, Gao P, Dinavahi R, Wilson KF, Ambrosio AL, Dias SM, Dang CV, et al.2010 Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell 18 207–219. (https://doi.org/10.1016/j.ccr.2010.08.009)
Wang L, Zhao Y, Gui B, Fu R, Ma F, Yu J, Qu P, Dong L & & Chen C 2011 Acute stimulation of glucagon secretion by linoleic acid results from GPR40 activation and [Ca2+]I increase in pancreatic islet {alpha}-cells. Journal of Endocrinology 210 173–179. (https://doi.org/10.1530/JOE-11-0132)
Wilson JE 2003 Isozymes of mammalian hexokinase: structure, subcellular localization and metabolic function. Journal of Experimental Biology 206 2049–2057. (https://doi.org/10.1242/jeb.00241)
Wu P, Sato J, Zhao Y, Jaskiewicz J, Popov KM & & Harris RA 1998 Starvation and diabetes increase the amount of pyruvate dehydrogenase kinase isoenzyme 4 in rat heart. Biochemical Journal 329 197–201. (https://doi.org/10.1042/bj3290197)
Wu CT, Hilgendorf KI, Bevacqua RJ, Hang Y, Demeter J, Kim SK & & Jackson PK 2021 Discovery of ciliary G protein-coupled receptors regulating pancreatic islet insulin and glucagon secretion. Genes and Development 35 1243–1255. (https://doi.org/10.1101/gad.348261.121)
Yashiro H, Tsujihata Y, Takeuchi K, Hazama M, Johnson PR & & Rorsman P 2012 The effects of TAK-875, a selective G protein-coupled receptor 40/free fatty acid 1 agonist, on insulin and glucagon secretion in isolated rat and human islets. Journal of Pharmacology and Experimental Therapeutics 340 483–489. (https://doi.org/10.1124/jpet.111.187708)
Zaborska KE, Dadi PK, Dickerson MT, Nakhe AY, Thorson AS, Schaub CM, Graff SM, Stanley JE, Kondapavuluru RS, Denton JS, et al.2020 Lactate activation of α-cell K(ATP) channels inhibits glucagon secretion by hyperpolarizing the membrane potential and reducing Ca(2+) entry. Molecular Metabolism 42 101056. (https://doi.org/10.1016/j.molmet.2020.101056)
Zhang S & & Kim KH 1998 Essential role of acetyl-CoA carboxylase in the glucose-induced insulin secretion in a pancreatic beta-cell line. Cellular Signalling 10 35–42. (https://doi.org/10.1016/s0898-6568(9700070-3)
Zhang P, Liu C, Zhang C, Zhang Y, Shen P, Zhang J & & Zhang CY 2005 Free fatty acids increase PGC-1α expression in isolated rat islets. FEBS Letters 579 1446–1452. (https://doi.org/10.1016/j.febslet.2005.01.046)
Zhang Q, Ramracheya R, Lahmann C, Tarasov A, Bengtsson M, Braha O, Braun M, Brereton M, Collins S, Galvanovskis J, et al.2013 Role of KATP channels in glucose-regulated glucagon secretion and impaired counterregulation in Type 2 diabetes. Cell Metabolism 18 871–882. (https://doi.org/10.1016/j.cmet.2013.10.014)
Zhang Q, Dou H & & Rorsman P 2020 ‘Resistance is futile?’ – paradoxical inhibitory effects of KATP channel closure in glucagon-secreting α-cells. Journal of Physiology 598 4765–4780. (https://doi.org/10.1113/JP279775)
Zhang GF, Jensen MV, Gray SM, El K, Wang Y, Lu D, Becker TC, Campbell JE & & Newgard CB 2021 Reductive TCA cycle metabolism fuels glutamine- and glucose-stimulated insulin secretion. Cell Metabolism 33 804–817.e5. (https://doi.org/10.1016/j.cmet.2020.11.020)
Zhou HL, Premont RT & & Stamler JS 2022 The manifold roles of protein S-nitrosylation in the life of insulin. Nature Reviews. Endocrinology 18 111–128. (https://doi.org/10.1038/s41574-021-00583-1)
