Statistics performed were unpaired t test B , E , H , J , K , and L and two-way ANOVA with the Šidák post hoc test C , F , and I. Pancreatic α-cells express K ATP channels 48 , The observation that glucose decreased intracellular ATP in the presence of NEFA therefore prompted us to investigate the electrical activity in α-cells under these experimental conditions.

The addition of 0. Unlike in control recordings without NEFA and BSA Fig. This could indicate that the reduction in ATP caused by increasing glucose levels leads to opening of K ATP channels and suggests that membrane potential in α-cells is more negative than previously reported Electrical activity 11 and FAs 40 have both been suggested to regulate glucagon secretion through changes in cytosolic calcium.

To investigate whether the addition of 0. This suggests that at low glucose, the membrane potential is depolarized and that increasing glucose repolarizes the plasma membrane to inhibit electrical activity, calcium entry, and glucagon secretion.

Glucose-induced reduction in ATP repolarizes the plasma membrane in α-cells. E : Representative trace of calcium oscillations in an α-cells in intact WT islets.

Statistics performed were one-way ANOVA with the Tukey C , D , and F post hoc test. Here we propose that the regulation of ATP production in α-cells is highly dependent on enzymes that promote FAO, such as PDK4 and CPT1a.

We find that inhibition of pyruvate entry into the TCA cycle as acetyl-CoA, or FA transport into the mitochondria, disconnects changes in glucose levels from changes in ATP production and glucagon secretion. Based on the observations made here, we suggest that glucose regulates glucagon secretion, not by increasing intracellular ATP, but by inhibiting FAO to lower intracellular ATP.

Our findings suggest that in α-cells, FAO is subject to suppression from glucose, as suggested by the glucose-FA cycle. Despite this, α-cells do oxidize glucose to some extent 56 , 57 , at least in the absence of other substrates and BSA, where increases in extracellular glucose results in ATP production 11 , 19 , 21 , 24 , However, we show here that in the absence of BSA, α-cells do not secrete much glucagon and do not respond to glucose.

While it is not clear why BSA is important for α-cell function, albumin has previously been shown to impact both intracellular lipid, pH, and redox homeostasis 59 , Whether this discrepancy is due to differences in the experimental paradigm or the two cell types is unclear.

Previous hypotheses of how glucose regulates glucagon secretion suggest that increased ATP from glucose oxidation leads to membrane depolarization in α-cells 11 , However, as with the previous measurements of ATP, these experiments were performed with glucose as the only substrate. The findings we present here show that glucose repolarizes the plasma membrane in α-cells when applied in the presence of NEFA, consistent with the observed reduction in ATP under the same experimental conditions.

The finding that this effect was reversed by tolbutamide suggests it reflects activation of K ATP channels. It is, therefore, more likely that activation of K ATP channels drives the change in membrane potential in α-cells in response to increased glucose levels. In addition, the current observation that ATP is reduced may also be aligned with the proposed reduction in intracellular cAMP in α-cells The lower cAMP could also be caused by increases in intracellular FAs as a consequence of the lower FAO at higher glucose, as adenylate cyclase in other tissues has been suggested to be inhibited by increases in intracellular FA levels Under conditions with 0.

This suggests that the lowering of plasma levels of glucagon in response to a glucose tolerance test may also be driven by changes in FA availability.

This is supported by the ex vivo experiments presented here. However, overexpression of PDK4 in α-cells results in a rather mild phenotype. That PDK4 overexpression in α-cells alone is not enough to drive the development of hyperglycemia or hyperketonemia in vivo is not surprising.

Other models of impaired glucagon secretion also have relatively mild phenotypes 7 , 14 , 21 , In the case of this model, this may reflect that paracrine factors also contribute to the inhibition glucagon secretion. Despite this, our data indicate that changing PDH activity in α-cells can affect circulating glucagon levels.

Thus, α-cells may rely on sensing circulating levels of FA as well as glucose. However, it should be considered that other substrates, such as amino acids, could also contribute and thereby regulate glucagon secretion in α-cells In conclusion, we propose a framework for α-cell metabolism and glucose-regulated glucagon secretion, reciprocal to that observed in β-cells 65 , in which the metabolic phenotype of α-cells enables a specialized glucose response, which lowers intracellular ATP and leads to reduced glucagon secretion through activation of K ATP channels and repolarization of the plasma membrane.

This model of α-cell metabolism and glucagon secretion suggests that α-cells can act as sensors of changes in both circulating glucose and NEFA concentrations. The authors thank Dorthe Nielsen University of Copenhagen for technical assistance during data collection, Professor Leanne Hodson and Dr.

Katherine Pinnick University of Oxford for scientific advice, and Professor Seung Kim Stanford University for providing the GUTR2 construct used for live cell imaging experiments.

Imaging experiments were performed at the Centre for Advanced Bioimaging CAB at the University of Copenhagen. is supported by a fellowship from Svenska Sällskapet for Medicinsk Forskning SSMF. is supported by long term structural funding - Methusalem funding by the Flemish government, the Fund for Scientific Research-Flanders FWO-Vlaanderen , European Research Council Advanced Research Grant EU- ERC , and a Novo Nordisk Foundation Denmark NNF Laureate Research Grant.

is supported by the Novo Nordisk Foundation grant no. NNF18CC L. is supported by the Swedish Research grant SRA-Exodiab and project grant , the Swedish Foundation for Strategic Research IRC-LUDC , and The Swedish Diabetes Foundation.

is supported by the Swedish Research Council, the Helmsley Trust, and the Medical Research Council MRC , J. Duality of Interest. No potential conflicts of interest relevant to this article were reported.

Author Contributions. contributed to the investigation. reviewed and edited the manuscript. and J. conceptualized the study. conceived the experimental design. wrote the original draft. contributed materials.

is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. Parts of this study were presented as an abstract at the 56th Annual Meeting of the European Association for the Study of Diabetes, virtual meeting, 21—25 September , and at the 81st Scientific Sessions of the American Diabetes Association, virtual meeting, 25—29 June Sign In or Create an Account.

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Islet Studies July 26 Glucose Controls Glucagon Secretion by Regulating Fatty Acid Oxidation in Pancreatic α-Cells Sarah L. Armour ; Sarah L. This Site. Google Scholar. Alexander Frueh ; Alexander Frueh.

Margarita V. Chibalina ; Margarita V. Haiqiang Dou ; Haiqiang Dou. Lidia Argemi-Muntadas ; Lidia Argemi-Muntadas. Alexander Hamilton ; Alexander Hamilton. Georgios Katzilieris-Petras ; Georgios Katzilieris-Petras. Peter Carmeliet ; Peter Carmeliet.

Benjamin Davies ; Benjamin Davies. Thomas Moritz ; Thomas Moritz. Lena Eliasson ; Lena Eliasson. Patrik Rorsman ; Patrik Rorsman.

Jakob G. Knudsen Corresponding author: Jakob G. Knudsen, jgknudsen bio. Diabetes ;72 10 — Article history Received:. Get Permissions. toolbar search Search Dropdown Menu. toolbar search search input Search input auto suggest. Table 1 Human donor information.

Donor No. Age years. Donor 1 Female 59 4. View Large. Table 2 Time-lapse imaging parameters. Cat no. Loading conditions.

Excitation wavelength nm. Emission wavelength nm. Data and materials from this study will be available upon reasonable request. Figure 1. View large Download slide. Figure 2. Figure 3. Figure 4. Figure 5.

Figure 6. Search ADS. Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover. Impaired fasting glycaemia vs impaired glucose tolerance: similar impairment of pancreatic alpha and beta cell function but differential roles of incretin hormones and insulin action.

Evaluation of efficacy and safety of the glucagon receptor antagonist LY in patients with type 2 diabetes: and week phase 2 studies. Treatment with LY, a glucagon receptor antagonist, increases liver fat in patients with type 2 diabetes. Lower blood glucose, hyperglucagonemia, and pancreatic α cell hyperplasia in glucagon receptor knockout mice.

Glucose control of glucagon secretion: there is more to it than KATP channels. Role of KATP channels in glucose-regulated glucagon secretion and impaired counterregulation in type 2 diabetes.

A store-operated mechanism determines the activity of the electrically excitable glucagon-secreting pancreatic α-cell. Glucose controls glucagon secretion by directly modulating cAMP in alpha cells.

CPT1a-dependent long-chain fatty acid oxidation contributes to maintaining glucagon secretion from pancreatic islets.

Hepatic de novo lipogenesis is suppressed and fat oxidation is increased by omega-3 fatty acids at the expense of glucose metabolism. Pancreatic ectopic fat is characterized by adipocyte infiltration and altered lipid composition.

Periprandial regulation of lipid metabolism in insulin-treated diabetes mellitus. Tight coupling between electrical activity and exocytosis in mouse glucagon-secreting alpha-cells.

Reduced somatostatin signalling leads to hypersecretion of glucagon in mice fed a high-fat diet. Dysregulation of glucagon secretion by hyperglycemia-induced sodium-dependent reduction of ATP production. A K ATP channel-dependent pathway within α cells regulates glucagon release from both rodent and human islets of Langerhans.

Insulin inhibits glucagon release by SGLT2-induced stimulation of somatostatin secretion. Paracrine control of α-cell glucagon exocytosis is compromised in human type-2 diabetes. Le Marchand.

Glucose suppression of glucagon secretion: metabolic and calcium responses from α-cells in intact mouse pancreatic islets. TASK-1 potassium channels limit pancreatic α-cell calcium influx and glucagon secretion. Predominant role of active versus facilitative glucose transport for glucagon-like peptide-1 secretion.

Imaging energy status in live cells with a fluorescent biosensor of the intracellular ATP-to-ADP ratio. Functional identification of islet cell types by electrophysiological fingerprinting. Structural elucidation of 3-nitrophenylhydrazine derivatives of tricarboxylic acid cycle acids and optimization of their fragmentation to boost sensitivity in liquid chromatography-mass spectrometry.

Reduced mitochondrial malate dehydrogenase activity has a strong effect on photorespiratory metabolism as revealed by 13 C labelling. Patch-clamp characterisation of somatostatin-secreting -cells in intact mouse pancreatic islets.

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. Palmitate stimulation of glucagon secretion in mouse pancreatic alpha-cells results from activation of L-type calcium channels and elevation of cytoplasmic calcium.

A multisite-binding switchable fluorescent probe for monitoring mitochondrial ATP level fluctuation in live cells. Islet beta-cell secretion determines glucagon release from neighbouring alpha-cells. In support of the roles of malonyl-CoA and carnitine acyltransferase I in the regulation of hepatic fatty acid oxidation and ketogenesis.

The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Comprehensive alpha, beta and delta cell transcriptomes reveal that ghrelin selectively activates delta cells and promotes somatostatin release from pancreatic islets.

Navigating the depths and avoiding the shallows of pancreatic islet cell transcriptomes. Effect of short-term fasting and refeeding on transcriptional regulation of metabolic genes in human skeletal muscle. Selective modification of pyruvate dehydrogenase kinase isoform expression in rat pancreatic islets elicited by starvation and activation of peroxisome proliferator-activated receptor-α: implications for glucose-stimulated insulin secretion.

Metabolic interactions between peroxisomes and mitochondria with a special focus on acylcarnitine metabolism.

Peroxisomes can oxidize medium- and long-chain fatty acids through a pathway involving ABCD3 and HSD17B4. Peroxisomes contribute to the acylcarnitine production when the carnitine shuttle is deficient. Metabolic fate of glucose in purified islet cells. Glucose-regulated anaplerosis in beta cells.

Alloxan reversibly impairs glucagon release and glucose oxidation by pancreatic A2-cells. Regulation of glucagon release: effects of insulin on the pancreatic A2-cell of the guinea pig.

Albumin and mammalian cell culture: implications for biotechnology applications. The structure of a membrane adenylyl cyclase bound to an activated stimulatory G protein. Time-dependent effects of endogenous hyperglucagonemia on glucose homeostasis and hepatic glucagon action.

Lipid-associated metabolic signalling networks in pancreatic beta cell function. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

View Metrics. Email alerts Article Activity Alert. Online Ahead of Print Alert. Latest Issue Alert. Most Read Most Cited MRI Metrics of Cerebral Endothelial Cell—Derived Exosomes for the Treatment of Cognitive Dysfunction Induced in Aging Rats Subjected to Type 2 Diabetes.

Management of Latent Autoimmune Diabetes in Adults: A Consensus Statement From an International Expert Panel. Genetic Influences of Adiponectin on Insulin Resistance, Type 2 Diabetes, and Cardiovascular Disease. A previous study reported that glucagon release from K IR 6.

This report focused on the central nervous system CNS component, concluding it is impaired. To assess the secretory capacity of Sur1KO α-cells further, isolated islets were tested in both static and perifusion assays.

When tested under hypoglycemic conditions 2 h in 1. control islets Fig. Isolated Sur1KO islets have an attenuated response to low glucose.

Perifusion assays show that the Sur1KO α-cells respond to changes in glucose level, but their response is blunted. Figure 3B illustrates the normal biphasic insulin response of WT islets to a stepwise change in glucose concentration.

Figure 3D shows that switching WT islets from low to high glucose 2. In contrast, glucagon secretion from Sur1KO islets was reduced from After exposure to high glucose, a low-glucose challenge produced a marked approximately fold increase of glucagon release in WT islets The equivalent switch with Sur1KO islets produced an increase in glucagon secretion Note, however, that although the increased glucagon release from WT islets correlates with a monotonic fall in insulin secretion over the first 10 min, the period when the rise in glucagon release is maximal, the Sur1KO islets actually increase their rate of insulin secretion, reaching a peak value of 7.

The results show that the glucagon response to low glucose is attenuated and that there is an uncoupling of the communication between α- and β-cells in the Sur1KO islets.

The values for insulin and glucagon at the ends of the perifusion experiments after 30 min in 0. The values are means ± se. P values comparing WT vs. Glibenclamide strongly stimulates insulin secretion from WT islets in 0. Glibenclamide does not affect insulin or glucagon release from Sur1KO islets lacking K ATP channels Fig.

Note that the levels of glucagon secretion from WT islets treated with glibenclamide mimic the impaired release observed for Sur1KO islets compare Fig. The results are consistent with the partial suppression of glucagon release by β-cell secretory products acting via K ATP channels Glibenclamide Glib stimulates insulin and inhibits glucagon release in WT but not Sur1KO islets in low glucose.

A, Response of WT islets. B, Response of Sur1KO islets. The perifusion protocol is the same as shown in Fig.

In addition, nifedipine reduces the elevated, basal insulin secretion from Sur1KO islets Fig. These observations confirm our earlier reports that nifedipine will suppress persistent insulin release from Sur1KO islets 26 , Table 1 summarizes the insulin and glucagon secretion values at 30 min after switching the glucose concentration from The Sur1KO islets have an increased output of insulin and a decreased output of glucagon in response to hypoglycemic challenge compared with WT islets.

Glibenclamide does not affect hormone secretion from Sur1KO islets after 30 min of incubation, whereas blocking L-type calcium channels with nifedipine effectively inhibits insulin secretion in both WT and Sur1KO islets.

Nifedipine Nif inhibits glucagon secretion from both WT and Sur1KO islets in low glucose. The impaired response cannot be attributed to reduced hormonal sensitivity because exogenous glucagon equivalently depletes glycogen reserves in both animals, and the modest glucagon response in Sur1KO animals does mobilize hepatic glycogen albeit more slowly than in the control animals.

Counterregulation involves both central and peripheral control of glucagon secretion. The results extend the analysis reported for K IR 6. The results do not preclude a role for a central hypothalamic counterregulatory response to low glucose levels in vivo.

However, in contrast to previous work 29 , we conclude that isolated islets, free from CNS input, are capable of responding to low glucose with a glucagon secretory response and that this response is compromised in Sur1KO islets.

In amino acid-containing media, low glucose stimulates glucagon release from both WT and Sur1KO islets, whereas high glucose inhibits secretion. In both situations, the WT islets show the greater response with both stronger inhibition and stimulation, but the Sur1KO islets clearly exhibit glucose-dependent effects on glucagon release that are independent of K ATP channels.

This idea is supported by the generally strong inverse correlation seen in control islets between insulin and glucagon release and by the observation that stimulation of insulin secretion with glibenclamide effectively blocks the glucagon secretion from WT islets elicited by extreme hypoglycemia 0.

Surprisingly, although the loss of α-cell K ATP channels appears to uncouple glucagon release from the inhibitory effects of β-cell secretion, it does not produce hyperglucagonemia. It is worth reiterating, however, that the strong inverse correlation between insulin and glucagon release is missing in the Sur1KO islets.

This can be seen clearly, for example, in Fig. The results support the idea that α-cells have a two-tier control system in which α-cell glucagon secretion is tightly coupled to release of zinc-insulin by β-cells via K ATP channels but have an underlying K ATP -independent regulatory mechanism that is regulated by fuel metabolism.

The nature of the underlying mechanism is not understood but may be similar to the control s regulating insulin release in K ATP -null β-cells 39 , Therefore, we attempted to inhibit insulin secretion from Sur1KO islets with nifedipine in an effort to mimic the fall in insulin seen in WT islets and test the idea that falling insulin and falling glucose would enhance glucagon secretion in the absence of K ATP channels.

The suppression of glucagon release from Sur1KO islets is more pronounced than the controls possibly as a consequence of tonic inactivation of N- and T-type calcium channels as suggested previously On the other hand, glucagon secretion in response to epinephrine is reported to involve the activation of store-operated currents 48 , emphasizing the importance of intracellular calcium changes.

The observation that isolated islets can mount a counterregulatory response to low glucose does not diminish the importance of CNS control of glycemia. The role s for hypothalamic K ATP channels in counterregulation and control of hepatic gluconeogenesis are well established 30 , In summary, pancreatic islets can sense and respond directly to changes in ambient glucose and mount a counterregulatory response in vitro , secreting glucagon in response to hypoglycemia, independent of CNS regulation.

Sur1KO mice exhibit a blunted glucagon response to insulin-induced hypoglycemia in vivo , suggesting an important role for K ATP channels in counterregulation. Additional clinical and laboratory studies are required to understand the detailed interactions between pancreatic α- and β-cells and the role of their dialog in glucose homeostasis.

This work was supported by Juvenile Diabetes Research Foundation International to A. and to J. Jiang G , Zhang BB Glucagon and regulation of glucose metabolism. Am J Physiol Endocrinol Metab : E — E Google Scholar. Shah P , Basu A , Basu R , Rizza R Impact of lack of suppression of glucagon on glucose tolerance in humans.

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Endocrine Society Journals. Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Materials and Methods. Journal Article. Regulation of Glucagon Secretion at Low Glucose Concentrations: Evidence for Adenosine Triphosphate-Sensitive Potassium Channel Involvement.

Alvaro Muñoz , Alvaro Muñoz. Oxford Academic. Min Hu. Khalid Hussain. Joseph Bryan. Lydia Aguilar-Bryan. Arun S. Rajan, One Baylor Plaza, BCMA B, Houston, Texas PDF Split View Views.

In addition to nutrients and paracrine signals, islet function is further regulated by sympathetic, parasympathetic and sensory nerves that go deeply into the islet Ahren Thus, multiple regulation levels determine hormone release from pancreatic islets.

Elevated glucose concentrations inhibit all these events. Consequently, lower ATP concentrations are required to obtain the maximal inhibition of K ATP conductance compared with mouse β-cells.

Recent evidence has indicated that the densities of these channels are similar in mouse α- and β-cells Leung et al. While L and N channels have been reported in rat α-cells Gromada et al. The low voltage-activated T-type channels work as pacemakers in the initiation of action potentials in mice Gopel et al.

A model to explain the glucose regulation of electrical activity in mouse α-cells has been postulated in the light of recent studies Fig. Thus, glucagon release from α-cells is mainly supported by an intermediate K ATP channel activity that maintains a membrane potential range able to sustain regenerative electrical activity MacDonald et al.

A similar model has been also proposed for human α-cells MacDonald et al. Nevertheless, this scheme has been argued by some reports indicating that glucose may be hyperpolarizing rather than depolarizing Liu et al.

Schematic model for glucose-dependent regulation of glucagon secretion in the mouse α-cell. Glucose is incorporated into the α-cell by the transporter SLC2A1. The function of L-type channels predominates when cAMP levels are elevated.

See text for further details. Citation: Journal of Endocrinology , 1; At low-glucose concentrations 0. Both fluorescence records were obtained by confocal microscopy from two cells within an intact mouse islet. However, in contrast to the situation in mice, the stimulus-secretion coupling in rat α-cells is similar to that of β-cells.

Accordingly, the pharmacological inhibition of glucose metabolism increases K ATP channel activity in rat α-cells Olsen et al. This model indicating a β-cell-like stimulus-secretion coupling is based on recent studies that have used isolated rat α-cells.

However, these results contrast with the observations showing that glucose inhibits α-cell electrical activity and glucagon secretion in intact rat islets Franklin et al. Therefore, the blocking effect observed in rat islets at high-glucose concentrations is most likely the result of paracrine signalling by β-cell activation Wendt et al.

Whether glucose inhibits α-cells directly or by paracrine mechanisms has been a matter of debate, and, probably, the predominant level of control may depend on the physiological situation. Part of this controversy is also due to the divergences found in the stimulus-secretion coupling of different animal models.

Although paracrine signalling may be critical for the glucose inhibition of glucagon secretion in rats Wendt et al.

In mice and humans, a glucose direct action on α-cells has been proven in isolated cells under conditions where paracrine effects are negligible, and in intact islets incubated with different paracrine signalling inhibitors Gromada et al. Moreover, secretion studies prove that glucose inhibits glucagon release at concentrations below the threshold for β-cell activation and insulin release MacDonald et al.

Several reports on experiments using genetic mouse models support the role of glucose-modulated K ATP channels in α-cell function. The regulation of glucagon secretion by glucose is impaired in ABCC8-deficient mice lacking functional K ATP channels Gromada et al. A similar situation occurs in KCNJ11Y12X mouse with a KCNJ11 mutation in the K ATP channel MacDonald et al.

In humans, the Glu23Lys polymorphism in the KCNJ11 subunit of these channels is associated with diminished suppression of glucagon release in response to hyperglycaemia Tschritter et al. Nevertheless, since K ATP channels seem to be essential for the α-cell regulation in the proposed models, some considerations on glucose metabolism should be taken into account.

Although α-cells possess the high-affinity, low-capacity glucose transporter SLC2A1, instead of the high-capacity SLC2A2 present in the β-cell, it has been demonstrated that glucose transport is not a limiting factor in α-cell glucose metabolism Gorus et al.

However, several studies indicate that important biochemical differences exist between both cell types. These biochemical differences indicate that β-cells are more efficient in the mitochondrial oxidation of glucose, while α-cells rely more on anaerobic glycolysis Schuit et al.

This lower coupling between glycolytic events in the cytosol and ATP synthesis in mitochondrial respiration of α-cells would explain the fact that, in response to glucose, cytosolic ATP increases are small in these cells Ishihara et al. Therefore, some aspects at the above-mentioned models for α-cell stimulus-secretion coupling deserve more attention, especially those concerning the modulation of K ATP channel activity by glucose metabolism and ATP production.

Other mechanisms regulating K ATP channels may also have an important role. Although the lipotoxicity theory and its role in obesity-induced diabetes have increased the interest in the interactions between fatty acids and islet functions, little is known about their effect on the regulation of the α-cell compared with those on β-cells.

While initial studies suggested an inhibitory effect on glucagon secretion Andrews et al. The short-term stimulatory action depends on the chain length, spatial configuration and degree of saturation of the fatty acid Hong et al.

The action of palmitate has been studied in mice at the cell level. A study using clonal α-cells on the long-term effect of palmitate and oleate concluded that they also enhance glucagon secretion and triglyceride accumulation in a time- and dose-dependent manner but inhibit cell proliferation Hong et al.

In agreement with this, the long-term exposure of rat islets to fatty acids induces a marked increase in glucagon release, a decrease in glucagon content and no changes in glucagon gene expression Gremlich et al.

In addition to fatty acids, amino acids are also relevant in the modulation of the α-cell function. Amino acids such as arginine, alanine and glutamine are potent stimulators of glucagon secretion Pipeleers et al. In any case, the function of amino acids and fatty acids in the α-cell requires further investigation at the cellular and molecular levels.

The spatial distribution of α-cells and the vascular organization within the islet sustain an important intercellular communication through autocrine and paracrine mechanisms Fig.

In addition to insulin, glucagon or somatostatin, secretory granules from islet cells contain other molecules with biological activity, which are released to the extracellular space by exocytosis, activating surface receptors in the same cell, in neighbouring islet cells, or in distant cells within the islet via the vascular system.

Several paracrine mechanisms are activated at high-glucose concentrations as a result of β- and δ-cell stimulations, and thus, they may participate in the glucose-induced inhibition of glucagon release.

Paracrine signalling in the α-cell. See text for details. ADCY, adenylate cyclase; AMPA-R, α-aminohydroxymethylisoxazolepropionic acid receptor; GABA, γ-aminobutyric acid; GLP1, glucagon-like peptide-1; GRM, metabotrophic glutamate receptor; PKA, protein kinase A; SSTR2, somatostatin receptor One of the most important paracrine mechanisms responsible for inhibiting glucagon release is conducted by insulin, acting via several pathways.

An appropriate expression of the insulin receptor in mouse α-cells seems to be essential for glucose-regulated glucagon secretion Diao et al. In INR1-G9 clonal α-cells, insulin has been found to inhibit glucagon release through the activation of phosphatidylinositol 3-kinase PIK3; Kaneko et al.

The insulin receptor—PIK3 signalling pathway is also involved in the modification of the sensitivity of K ATP channels to ATP in mouse α-cells, which may affect the secretory response Leung et al. Furthermore, insulin increases K ATP channel activity in isolated rat α-cells, inducing an inhibitory effect on glucagon release via membrane hyperpolarization Franklin et al.

In addition to the effects on K ATP channels, insulin can translocate A-type GABA receptors to the cell membrane, which increases the response to GABA secreted by β-cells, favouring membrane hyperpolarization and suppression of glucagon secretion Xu et al.

Therefore, several pieces of evidence indicate that insulin inhibits glucagon release mainly by altering α-cell membrane potential. After exocytosis, these hexameric crystals are exposed to a change in pH from 5. Recent studies have claimed that zinc atoms can also work as modulators of the α-cell function Gyulkhandanyan et al.

Somatostatin is produced and secreted by several tissues in addition to the δ-cell population of the islet and works as an inhibitor of both glucagon and insulin release Fehmann et al.

Immunocytochemical studies in human islets have demonstrated that, among the five identified somatostatin receptor SSTR subtypes, SSTR2 is highly expressed in α-cells while SSTR1 and SSTR5 are expressed in β-cells Kumar et al.

In mice and rats, SSTR2 also predominates in the α-cell and SSTR5 in the β-cell population Hunyady et al. These receptors are coupled to G-proteins and induce multiple intracellular effects. Also, a negative interaction of somatostatin with adenylate cyclase and cAMP levels has been reported in rat α-cells Schuit et al.

In addition to the effects of insulin and somatostatin on α-cells, glucagon itself works as an extracellular messenger. It exerts an autocrine positive feedback that stimulates secretion in both isolated rat and mouse α-cells by an increase in exocytosis associated to a rise in cAMP levels Ma et al.

The incretin hormone glucagon-like peptide 1 GLP1 is released from the L-cells of the small intestine after food intake, stimulating insulin production and inhibiting glucagon release. Because of this dual effect, GLP1 is a potential therapeutic agent in the treatment of diabetic patients that manifest insulin deficiency as well as hyperglucagonaemia Dunning et al.

The observed suppressing effect of GLP1 on glucagon secretion in vivo and in perfused pancreas contrasts with those effects found in single α-cells Dunning et al. In isolated rat α-cells, GLP1 stimulates glucagon secretion by interacting with specific receptors coupled to G-proteins that activate adenylate cyclase, which increases cAMP levels Ding et al.

Thus, it seems that paracrine mechanisms may be responsible for the GLP1 suppressing action Dunning et al. This possibility has been underscored by the findings in experiments using β-cell-specific knock-out mice for the transcription factor Pdx1.

In these mice, the lack of effect of GLP1 on β-cells is also accompanied by its inability to induce an inhibitory action on glucagon plasma levels Li et al. The neurotransmitter γ-aminobutyric acid GABA is another α-cell modulator.

Similar conclusions were obtained in mouse islets and clonal αTC1—9 cells Xu et al. The neurotransmitter l -glutamate also accumulates in the α-cell secretory granules because of vesicular glutamate transporters 1 and 2 found in these cells Hayashi et al. In low-glucose conditions, l -glutamate is cosecreted with glucagon, triggering GABA release from neighbouring β-cells and, subsequently, inhibiting the α-cell function as previously described Hayashi et al.

Additionally, glutamate can activate autocrine signalling pathways in α-cells through the multiple glutamate receptors expressed in these cells, which include ionotrophic AMPA and kainate subtypes and metabotrophic receptors Inagaki et al.

Although activation of ionotrophic receptors may stimulate glucagon release Bertrand et al. Another α-cell regulator is amylin or islet amyloid pancreatic polypeptide Iapp. This polypeptide is a 37 amino acid hormone mainly synthesized in β-cells, although it can be produced in δ-cells as well.

This peptide is cosecreted with insulin by exocytosis and has an inhibitory effect on glucagon basal concentrations as well as on those levels observed after arginine stimulation Akesson et al. This glucagonostatic effect has been reported in the plasma levels of mice and rats as well as in perfused pancreas or intact islets.

Since amylin also reduces somatostatin and insulin release, some authors have proposed that endogen amylin within the islet may establish a negative feedback to avoid excessive secretion from α-, β- and δ-cells Wang et al. Also, the purinergic messenger ATP is highly accumulated in β-cell secretory granules and in nerve terminals.

Purinergic regulation of glucagon release has also been described in rat islets Grapengiesser et al. As previously stated, the islet of Langerhans is highly innervated by parasympathetic and sympathetic nerves that ensure a rapid response to hypoglycaemia and protection from potential brain damage Ahren Some terminals of these nerves store and release classical neurotransmitters, such as acetylcholine and noradrenaline, as well as several neuropeptides, which stimulate or inhibit glucagon secretion depending on the neural messenger released.

Noradrenaline increases glucagon secretion as well Ahren et al. In addition to classical neurotransmitters, several neuropeptides such as vasoactive intestinal polypeptide, pituitary adenylate cyclase-activating polypeptide and gastrin-releasing peptide, which may stimulate glucagon release from pancreas, can be accumulated in parasympathetic nerves, while galanin and neuropeptide Y can be stored in sympathetic nerve terminals Ahren Multiple actions have been reported for the latter neuropeptides.

The effects and mechanisms involved in neural regulation of α-cells have yet to be established at the cellular and molecular levels. These systems are mainly regulated by glucose-sensing neurons of the ventromedial hypothalamus, which respond to plasma glucose levels with mechanisms very similar to those of the β-cell, including the activity of glucose-regulated K ATP channels Borg et al.

Actually, it has been observed that the α-cell response to hypoglycaemia is also impaired in KCNJdeficient mice whose neurons of the ventromedial hypothalamus lack functional K ATP channels and glucose responsiveness Miki et al. The preproglucagon-derived peptides glucagon, GLP1 and GLP2, are encoded by the preproglucagon gene, which is expressed in the central nervous system, intestinal L-cells and pancreatic α-cells.

A post-translational cleavage by prohormone convertases PC is responsible for the maturation of the preproglucagon hormone that generates all these peptides Mojsov et al. The different expression of PC subtypes in each tissue mediates the production of each different peptide.

In α-cells, the predominance of PCSK2 leads to a major production of glucagon together with the products glicentin, glicentin-related pancreatic polypeptide, intervening peptide 1 and the major proglucagon fragment Dey et al.

The absence of PCSK2 in knock-out mice leads to a lack of mature glucagon Furuta et al. The regulation of glucagon gene expression has not been studied as extensively as the insulin gene. The inhibitory effect of insulin on glucagon secretion has also been confirmed in gene expression and it occurs at the transcriptional level Philippe et al.

In diabetic rats, glucagon gene expression is augmented and is accompanied by hyperglucagonaemia in conditions of hyperglycaemia and insulin deficiency. Insulin treatment normalized glucagon expression and plasma levels in these rats, an effect that was not attributed to the restoration of normal glucose levels Dumonteil et al.

It was concluded that insulin, unlike glucose, modulates glucagon expression. The lack of response to glucose was further confirmed in isolated rat islets Gremlich et al.

The effect of amino acids on glucagon gene regulation has also been studied. While arginine increases glucagon expression in isolated rat islets: a process that is mediated by protein kinase C PKA; Yamato et al. Other nutrients, such as the fatty acid palmitate, produces a down-regulated glucagon expression at short term in rat islets in a dose-dependent manner Bollheimer et al.

By contrast, no effect with palmitate has been observed in other long-term studies Gremlich et al. Like insulin, somatostatin also inhibits glucagon expression. It has been reported that somatostatin down-regulates glucagon expression basal levels as well as those produced by forskolin stimulation in clonal INR1G9 cells Fehmann et al.

The rat and mouse glucagon receptor is a amino acid protein, belonging to the secretin—glucagon receptor II class family of G protein-coupled receptors Mayo et al. Glucagon binding to this receptor is coupled to GTP-binding heterotrimeric G proteins of the Gα s type that leads to the activation of adenylate cyclase, cAMP production and PKA.

The glucagon receptor is present in multiple tissues including the liver, pancreas, heart, kidney, brain and smooth muscle. Thus, it modulates multiple responses in these tissues, including effects on ion transport and glomerular filtration rate in kidney among others Ahloulay et al.

In any case, the regulation of glucose homeostasis is the major function of glucagon and its receptor. This role will be described in the next paragraph.

The role of glucagon and the glucagon receptor in the liver. ADCY, Adenylate cyclase; CREB, cAMP response element binding; F 1,6 P2, fructose-1,6-bisphosphate; F 2,6 P2, fructose-2,6-bisphosphate; FP, fructose 6-phosphate; FBP1, fructose-1,6-bisphosphatase; FBP2, fructose-2,6-bisphosphatase; GP, glucose 1-phosphate; GP, glucose 6-phosphate; G6PC, glucosephosphatase; GP, glycogen phosphorylase; GS, glycogen synthase; IP3, inositol 1,4,5-trisphosphate; OAA, oxaloacetate; PC, pyruvate carboxylase; PEP, phosphoenolpyruvate; PCK2, phosphoenolpyruvate carboxykinase; PFKM, phosphofructokinase-1; PPARGC1A, peroxisome proliferators-activated receptor-γ coactivator-1; PIP2, phosphatidylinositol 4,5-bisphosphate; PKLR, pyruvate kinase; PLC, phospholipase C; Pyr, pyruvate.

Dashed lines: red, inhibition; blue, stimulation. Several lines of defence protect the organism against hypoglycaemia and its potential damaging effects, especially in the brain, which depends on a continuous supply of glucose, its principal metabolic fuel. These defences include decreased insulin release and increased secretion of adrenaline and glucagon.

Additionally, glucose-sensing neurons of the ventromedial hypothalamus further control responses to glycaemia changes, as previously mentioned. Among all these regulatory systems, glucagon plays a central role in the response to hypoglycaemia and also opposes to insulin effects.

Glucagon stimulates gluconeogenesis and glycogenolysis, which increases hepatic glucose output, ensuring an appropriate supply of glucose to body and brain, and at the same time, it decreases glycogenesis and glycolysis.

The glucagon receptor in the liver is highly selective for glucagon, but it exhibits a modest affinity for glucagon-like peptides Hjorth et al.

Its main action on the liver is mediated by the activation of adenylyl cyclase and the PKA pathway. Glucagon regulates gluconeogenesis mainly by the up-regulation of key enzymes such as glucosephosphatase G6PC and phosphoenolpyruvate carboxykinase PCK2 through the activation of the cAMP response element-binding protein CREB and peroxisome proliferator-activated receptor γ-coactivator-1 PPARGC1A; Herzig et al.

PCK2 and G6PC, along with fructose-1,6-biphosphatase FBP1 have a key role in the rate of gluconeogenesis Fig. PCK2 mediates the conversion of oxalacetate into phosphoenolpyruvate while G6PC regulates glucose production from glucosephosphate.

FBP1 is responsible for the conversion of fructose-1,6-biphosphate F 1,6 P2 into fructosephosphate F6P. Additionally, this decrease in F 2,6 P2 also reduces the activity of phosphofructokinase-1 PFKM , down-regulating glycolysis. The glycolytic pathway is further inhibited by glucagon at the pyruvate kinase PKLR level Slavin et al.

Glycogen metabolism is mainly determined by the activity of glycogen synthase GS and glycogen phosphorylase GP. Glucagon can also stimulate the uptake of amino acids for gluconeogenesis in the liver.

Indeed, subjects with hyperglucagonaemia can develop plasma hypoaminoacidaemia, especially of amino acids involved in gluconeogenesis, such as alanine, glycine and proline Cynober Glucagon is also involved in the regulation of fatty acids in adipocytes. Hormone-sensitive lipase mediates the lipolysis of triacylglycerol into the non-esterified fatty acids and glycerol, which are released from adipocytes.

It has been reported that although glucagon does not modify the transcriptional levels of this enzyme, it increases the release of glycerol from adipocytes Slavin et al.

This mobilization of glycerol from adipose tissue can further be used in the liver during gluconeogenesis. However, the existence of a lipolytic action of glucagon observed in several animal models is still controversial in humans.

While a positive effect of glucagon on lipolysis has been reported in human subjects Carlson et al. An elevated glucagon to insulin ratio accelerates gluconeogenesis as well as fatty acid β-oxidation and ketone bodies formation Vons et al.

Thus, glucagon may also be involved in diabetic ketoacidosis, a medical complication in diabetes derived from the overproduction of ketone bodies Eledrisi et al.

According to this hypothesis, this metabolic disease is the result of an insulin deficiency or resistance along with an absolute or relative excess of glucagon, which can cause a higher rate of hepatic glucose production than glucose utilization, favouring hyperglycaemia.

At present, there exists multiple clinical and experimental evidence that support this hypothesis. The rate of hepatic glucose output has been correlated with the hyperglycaemia found in animal models of diabetes as well as in human diabetes, and the maintenance of this abnormality has also been associated with hyperglucagonaemia Baron et al.

In type 2 diabetes, the impairment of insulin release and development of insulin resistance is often accompanied by absolute or relative increased levels of glucagon in the fasting and postprandial states Reaven et al. In this situation, insulin is not effective as a negative feedback for hepatic glucose output while glucagon potentiates glucose mobilization from the liver, thus contributing to hyperglycaemia.

Another malfunction reported in diabetic patients is the lack of suppression of glucagon release in hyperglycaemic conditions, which would contribute further to postprandial hyperglycaemia in both type 1 and type 2 diabetes Dinneen et al.

However, this irregular α-cell behaviour does not occur when insulin levels are adequate, suggesting that abnormalities in glucagon release are relevant for hyperglycaemia in the context of diabetes or impairment of insulin secretion or action Shah et al.

Hyperglucagonaemia is also responsible for the development of hyperglycaemia and diabetes in patients with the glucagonoma syndrome, a paraneoplastic phenomenon characterized by an islet α-cell pancreatic tumour Chastain Another defect in normal glucagon secretion has important consequences in the management of hypoglycaemia.

The secretory response of α-cells to low-glucose concentrations is impaired in type 1 and long-lasting type 2 diabetes, increasing the risk of episodes of severe hypoglycaemia, especially in patients treated with insulin Cryer In this regard, iatrogenic hypoglycaemia is a situation that implies insulin excess and compromised glucose counter-regulation, and it is responsible for a major complication in diabetes treatment, increasing the morbidity and mortality of this disease Cryer This lack of glucagon response to hypoglycaemia has been associated with multiple failures in α-cell regulation; yet, the mechanisms are still under study Bolli et al.

Even though islet allotransplantation can provide prolonged insulin independence in patients with type 1 diabetes, the lack of α-cell response to hypoglycaemia usually persists after transplantation, indicating that this procedure does not restore the physiological behaviour of α-cells Paty et al.

All these problems in the glucagon secretory response observed in diabetes have been attributed to several defects in α-cell regulation including defective glucose sensing, loss of β-cell function, insulin resistance or autonomic malfunction.

However, the mechanisms involved in α-cell pathophysiology still remain largely unknown and deserve more investigation for better design of therapeutic strategies. In this regard, although direct therapeutic approaches to correct the lack of α-cell response to hypoglycaemia are missing, several proposals have been developed to amend glucagon excess, as we will see in the next section.

The specific control of glucagon secretion by pharmacological modulation is complex since several components of the α-cell stimulus-secretion coupling are also present in β- and δ-cells. Thus, the manipulation of glucagon action by modulating the glucagon receptor signalling seems to be an effective alternative Li et al.

This strategy has been supported by several studies. Glucagon receptor knock-out mice have hyperglucagonaemia and α-cell hyperplasia, but their glucose tolerance is improved and they develop only a mild fasting hypoglycaemia Gelling et al.

These mice have a normal body weight, food intake and energy expenditure although less adiposity and lower leptin levels. These results are consistent with the experiments with anti-sense oligonucleotides for the glucagon receptor. Therefore, these experimental results are a further support that glucagon antagonism may be beneficial for diabetes treatment.

Sulphonylureas are efficient K ATP channel blockers that have been extensively used for the clinical treatment of diabetes. This biphasic effect is due to the mouse α-cell electrical behaviour Fig.

Accordingly, with this scheme, the K ATP channel opener diazoxide can also have a biphasic effect on glucagon secretion. These effects will change depending on the extracellular glucose concentrations that necessarily influence K ATP channel activity MacDonald et al. This biphasic behaviour may explain the disparity of effects found for sulphonylureas Loubatieres et al.

In humans, sulphonylureas are associated to a glucagon secretion decrease in healthy and type 2 diabetic subjects Landstedt-Hallin et al. Since sulphonylureas also induce insulin and somatostatin secretion, which affect α-cells, these drugs offer a poor specific control of glucagon secretion.

In addition to stimulating insulin release, GLP1 can suppress glucagon secretion in humans, perfused rat pancreas and isolated rat islets in a glucose-dependent manner Guenifi et al.

Because GLP1 is rapidly cleaved and inactivated by the enzyme dipeptidyl peptidase-IV DPP4 , a good alternative would be to design either GLP1 derivatives with higher resistance to DPP4 or agents that increase GLP1 endogenous levels.

Among the GLP1 mimetics, exenatide is a synthetic polypeptide with high resistance to DPP4 cleavage that decreases glucagon levels in normal and diabetic subjects Degn et al. Liraglutide, another GLP1 derivative with long-lasting actions, can reduce glucagon release after a meal in patients with type 2 diabetes Juhl et al.

Alternatively, DPP4 inhibitors like sitagliptin and vildagliptin increase the endogen effects of GLP1, reducing glucagon plasma concentrations in diabetic individuals Rosenstock et al. exercise or cold exposure Specifically, in times of energy demand, glucagon enhances break-down of fatty acids to acetyl-coenzyme A molecules beta-oxidation in the liver.

These intermediates are either reduced to generate ATP in the tricarboxylic acid cycle or converted to ketone bodies ketogenesis — a process also stimulated by glucagon. Furthermore, glucagon signaling inhibits de novo lipogenesis by inactivating the enzyme that catalyzes the first step in fatty acid synthesis from other substrates like carbohydrates During prolonged fasting, glucagon stimulates formation of glucose from amino acids via gluconeogenesis by upregulating enzymes involved in the process.

However, the rate-limiting step of the process depends on the supply of gluconeogenic amino acids from muscle or dietary intake, a process not controlled by glucagon In addition to enter gluconeogenesis, amino acids are deaminated to generate ATP in the liver.

Glucagon is involved in this process by promoting the conversion of ammonia — a toxic biproduct from deamination — to urea, which is excreted in the urine. Thereby glucagon reduces ammonia levels in the blood Disruption of glucagon action by inhibition of the glucagon receptor 37 leads to increased plasma levels of amino acids and pancreatic alpha cell hyperplasia, which in turn, leads to glucagon hypersecretion.

This suggests that glucagon and amino acids are linked in a feedback loop between the liver and the pancreatic alpha cells Acute administration of glucagon has been shown to reduce food intake and diminish hunger 38 , Conversely, preprandial inhibition of glucagon signaling increases food intake in rats 40 , 41 providing evidence for a role of glucagon in the regulation of appetite.

It is somewhat counterintuitive that glucagon should reduce food intake given that glucagon levels are typically elevated upon fasting and decrease upon feeding.

Thus, the observed effect upon glucagon administration in supraphysiological concentrations could partly be due to cross-reactivity with the GLP-1 receptor which normally result in suppression of food intake In addition to a potential effect of glucagon on food intake, evidence suggests that glucagon contributes to a negative energy balance by stimulating energy expenditure.

In humans, this effect has been observed in studies in which glucagon infusion resulted in increases in resting energy expenditure 42 — However, the effect of endogenous glucagon on resting energy expenditure remains unclear.

Also, the exact mechanisms behind the increase in resting energy expenditure elicited by exogenous glucagon remain to be determined. It has been speculated that glucagon activates brown adipose tissue 12 , however this was recently challenged in an in vivo study that found no direct effect of glucagon on brown adipose tissue Rodent studies indicate that the actions of glucagon to increase energy expenditure might be indirectly mediated partly by fibroblast growth factor 21 FGF21 as glucagon-induced increase in energy expenditure is abolished in animals with FGF21 receptor deletion Infusion of high doses of glucagon increases heart rate and cardiac contractility In fact, infusion of glucagon in pharmacological doses milligram is often used in the treatment of acute cardiac depression caused by calcium channel antagonist or beta-blocker overdoses 47 despite limited evidence In comparison, glucagon concentrations within the normal physiological range do not appear to affect heart rate or contractility 49 and any physiological role of endogenous glucagon in the regulation of pulse rate remains questionable.

This is supported by studies investigating the effect of glucagon receptor antagonist for the treatment of type 2 diabetes in which no effect of pulse rate were observed Nevertheless, whether increased glucagon concentrations have a sustained effect on the heart remains unknow.

Of note, most studies use bolus injections of glucagon which cause only a transient increase in heart rate and contractility potentially reflecting the rapid elimination of glucagon from circulation Taken together, it remains uncertain whether glucagon has a place in the treatment of heart failure or hold a cardioprotective effect in healthy subjects.

Patients with type 2 diabetes exhibit an impaired regulation of glucagon secretion which contributes importantly to diabetic hyperglycemia. Specifically, type 2 diabetes is characterized by elevated levels of glucagon during fasting while suppression of glucagon in response to oral intake of glucose is impaired or even paradoxically elevated Fig.

The mechanisms behind hyperglucagonemia are not fully understood but is usually explained by a diminished suppressive effect of insulin on alpha cells due to hypoinsulinemia and insulin resistance at the level of the alpha cells 53 , Interestingly, subjects with type 2 diabetes, who exhibit a hyperglucagonemic response to oral glucose, respond with a normal suppression of glucagon after intravenous glucose administration Accordingly, hormones secreted from the gastrointestinal tract may play an important role 55 , It has recently been confirmed that glucagon can be secreted from extrapancreatic tissue demonstrated in experiments with totally pancreatectomized subjects This supports the notion that postprandial hypersecretion of glucagon in patients with type 2 diabetes might be of extrapancreatic origin.

Schematic illustration of plasma glucagon concentrations in patients with type 2 diabetes and in normal physiology healthy subjects. Type 2 diabetes is characterized by elevated fasting plasma glucagon levels and impaired suppression of plasma glucagon levels in response to oral glucose.

Traditionally type 1 diabetic hyperglycemia has been explained by selective loss of beta cell mass and resulting decrease in insulin secretion. However, emerging evidence indicate that glucagon plays a major role in type 1 diabetes pathophysiology. The glucagon dyssecretion that characterizes patients with type 1 diabetes is associated with two clinical manifestations: Postprandial hyperglucagonemia and impaired glucagon counterregulation to hypoglycemia Data regarding fasting plasma glucagon concentrations in type 1 diabetes are inconsistent 57 , Thus, the general notion that glucagon hypersecretion plays a role in type 1 diabetes hyperglycemia is mainly based on elevated postprandial glucagon concentrations The explanation behind this is unclear, although a common explanation is, that in type 1 diabetes the postprandial increase in plasma glucose is not followed by an increase in insulin secretion from beta cells, which in normal physiology would inhibit glucagon secretion.

The absence of that restraining signal from endogenous insulin could result in an increase in glucagon secretion from alpha cells after a meal Fig.

However, like in type 2 diabetes, subjects with type 1 diabetes preserve their ability to suppress glucagon after intravenous glucose administration.

Schematic illustration of plasma glucagon concentrations in patients with type 1 diabetes and in normal physiology healthy subjects.

Type 1 diabetes is characterized by elevated concentrations of glucagon in response to a meal or oral glucose intake. Hypoglycemia is a frequent and feared side effect of insulin therapy in type 1 diabetes and it represents a common barrier in obtaining glycemic control In normal physiology hypoglycemia is prevented by several mechanisms: 1 Reduced insulin secretion from beta cells diminishing glucose uptake in peripheral tissues; 2 increased glucagon secretion from alpha cells increasing hepatic glucose output; and 3 increased symphathetic neural response and adrenomedullary epinephrine secretion.

The latter will stimulate hepatic glucose production and cause clinical symptoms that enables the individual to recognize hypoglycemia and ultimately ingest carbohydrates 57 , 61 , In type 1 diabetes, insulin-induced hypoglycemia fails to elicit adequate glucagon responses compromising counterregulation to insulin-induced hypoglycemia; a phenomenon which seems to worsen with the duration of type 1 diabetes.

This defect likely involves a combination of defective alpha cells and reduced alpha cell mass 57 , Dysregulated glucagon secretion is not only observed in patients with type 2 diabetes but also in normoglucose-tolerant individuals with obesity 64 and patients with non-alcoholic fatty liver disease NAFLD 65 , This suggests that dysregulated glucagon secretion may represent hepatic steatosis rather than dysregulated glucose metabolism.

Interestingly, fasting hyperglucagonemia seems to relate to circulating amino acids in addition to hepatic fat content This hyperaminoacidemia suggests that impairment of amino acid turnover in the liver and ensuing elevations of circulating amino acids constitutes a feedback on the alpha cell to secrete more glucagon with increasing hepatic amino acid turnover and ureagenesis needed for clearance of toxic ammonia from the body.

The implication of hyperglucagonemia in obesity and NAFLD has renewed the scientific interest in actions of glucagon and the role of glucagon in the pathophysiology of these metabolic disorders.

Clearly, glucagon may represent a potential target for treatments of obesity and NAFLD. A simple way to restrain the undesirable hyperglycemic effect of glucagon while realizing its actions on lipolysis and energy expenditure could be by co-treating with a glucose-lowering drug. This may be done by mimicking the gut hormone oxyntomodulin which acts as a ligand to both the glucagon and the GLP-1 receptor.

Glucagon is a glucoregulatory peptide hormone that counteracts the actions of insulin by stimulating hepatic glucose production and thereby increases blood glucose levels. Additionally, glucagon mediates several non-glucose metabolic effects of importance for maintaining whole-body energy balance in times of limited nutrient supply.

These actions include mobilization of energy resources through hepatic lipolysis and ketogenesis; stimulation of hepatic amino acid turnover and related ureagenesis. Also, glucagon has been shown to increase energy expenditure and inhibit food intake, but whether endogenous glucagon is involved in the regulation of these processes remains uncertain.

Glucagon plays an important role in the pathophysiology of diabetes as elevated glucagon levels observed in these patients stimulate hepatic glucose production, thereby contributing to diabetic hyperglycemia. Used under Creative Commons License 3. This electronic version has been made freely available under a Creative Commons CC-BY-NC-ND license.

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Show details Feingold KR, Anawalt B, Blackman MR, et al. Contents www. Search term. Glucagon Physiology Iben Rix , Christina Nexøe-Larsen , Natasha C Bergmann , Asger Lund , and Filip K Knop. hnoiger nesretep. Christina Nexøe-Larsen Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark, Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Natasha C Bergmann Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark. Asger Lund Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark. Filip K Knop Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark, Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Steno Diabetes Center Copenhagen, Gentofte, Denmark Email: kd.

hnoiger ABSTRACT Glucagon is a peptide hormone secreted from the alpha cells of the pancreatic islets of Langerhans. STRUCTURE AND SYNTHESIS OF GLUCAGON Glucagon is a amino acid peptide hormone predominantly secreted from the alpha cells of the pancreas. GLUCAGON SECRETION Glucagon is secreted in response to hypoglycemia, prolonged fasting, exercise and protein-rich meals Regulation of Glucagon Secretion by Glucose The most potent regulator of glucagon secretion is circulating glucose.

Glucagon Concentrations in The Circulation In normal physiology, circulating glucagon concentrations are in the picomolar range. Glucagon concentrations in response to hypoglycemia, euglycemia, and hyperglycemia. GLUCAGON ACTIONS Glucagon Increases Hepatic Glucose Production Glucagon controls plasma glucose concentrations during fasting, exercise and hypoglycemia by increasing hepatic glucose output to the circulation.

Glucagon Stimulates Break-Down of Fatty Acids and Inhibits Lipogenesis in the Liver Glucagon promotes formation of non-carbohydrate energy sources in the form of lipids and ketone bodies.

Glucagon Promotes Break-Down of Amino Acids During prolonged fasting, glucagon stimulates formation of glucose from amino acids via gluconeogenesis by upregulating enzymes involved in the process.

Glucagon Reduces Food Intake Acute administration of glucagon has been shown to reduce food intake and diminish hunger 38 , Glucagon Increases Energy Expenditure In addition to a potential effect of glucagon on food intake, evidence suggests that glucagon contributes to a negative energy balance by stimulating energy expenditure.

Glucagon May Regulate Heart Rate and Contractility Infusion of high doses of glucagon increases heart rate and cardiac contractility Organ specific actions of glucagon. GIP, glucose-dependent insulinotropic polypeptide. Glucagon in Type 1 Diabetes Traditionally type 1 diabetic hyperglycemia has been explained by selective loss of beta cell mass and resulting decrease in insulin secretion.

Glucagon in Obesity and Hepatic Steatosis Dysregulated glucagon secretion is not only observed in patients with type 2 diabetes but also in normoglucose-tolerant individuals with obesity 64 and patients with non-alcoholic fatty liver disease NAFLD 65 , Habegger KM, Heppner KM, Geary N, Bartness TJ, DiMarchi R, Tschöp MH.

The metabolic actions of glucagon revisited. Nat Rev Endocrinol. Kimball CP, Murlin JR. Aqueous Extracts of Pancreas Iii. Some Precipitation Reactions of Insulin. Bromer WW, Sinn LG, Staub A, Behrens OK. The amino acid sequence of glucagon. Blackman B. The use of glucagon in insulin coma therapy.

Psychiatr Q. Esquibel AJ, Kurland AA, Mendelsohn D. The use of glucagon in terminating insulin coma. Dis Nerv Syst. Unger RH, Eisentraut AM. McCALL MS, Madison LL.

Glucagon antibodies and an immunoassay for glucagon. Unger RH, Orci L. The essential role of glucagon in the pathogenesis of diabetes mellitus. Drucker DJ, Asa S. Glucagon gene expression in vertebrate brain. Mojsov S, Heinrich G, Wilson IB, Ravazzola M, Orci L, Habener JF.

Preproglucagon gene expression in pancreas and intestine diversifies at the level of post-translational processing. Gerich JE, Lorenzi M, Hane S, Gustafson G, Guillemin R, Forsham PH. Islets store FAs as triglycerides 41 , which can potentially be used for FAO at low glucose.

However, adding 0. These findings were not due to changes in insulin secretion Supplementary Fig. The presence of NEFA also affected glucose-stimulated insulin secretion in the presence of 0. Collectively, this suggests that α-cells rely on the presence of NEFA to maintain the inhibitory effect of glucose on glucagon secretion.

NEFAs are required for glucagon secretion. B : Glucagon content for A. D : Glucagon content for C. All data are represented as mean ± SEM. See also Supplemental Fig. Statistics performed were two-way ANOVA with Šidák post hoc test A and C , one-way ANOVA B and D , and paired t test E.

We explored how addition of NEFA affected intracellular ATP by expressing the ATP sensor PercevalHR 33 specifically in α-cells Fig. Exposing mouse or human islets to 0. The observed reduction in ATP was not an artifact due to changes in intracellular pH Supplementary Fig.

Similar data were obtained using ATP-Red 1 dye 42 in α-cells with nuclear GFP expression Supplementary Fig. In these experiments, the non-GFP cells tended to increase fluorescence intensity Supplementary Fig.

The response to glucose was variable in these cells, which could suggest that the degree of intracellular FA depletion may differ between individual α-cells.

Notably, these ATP measurements were performed in a buffer containing BSA 6. Previous ATP measurements that show increased intracellular ATP in response to increased glucose were performed without the addition of BSA 11 , 14 , 19 , 21 , This suggested that α-cell function may be affected by the presence of BSA.

In the presence of BSA, glucagon secretion responded as expected Supplementary Fig. These differences were present without changes in glucagon content Supplementary Fig. Together, these data suggest that under physiological conditions, α-cells use FAs for ATP production and that elevations of extracellular glucose lead to reductions in intracellular ATP.

Glucose lowers intracellular ATP in α-cells. C : Average ATP fluorescence measured specifically in α-cells in isolated islets from WT mice in the presence of 0.

D : Dot plots of the last three frames in each condition in C. E : Average ATP fluorescence measured specifically in α-cells in isolated islets from human donors in the presence of 0. F : Dot plots of the last three frames in each condition in E. H : Dot plots of the last three frames in each condition in G.

J : Dot plots of the last three frames in each condition in I. L : Dot plots of the last three frames in each condition in K. Statistics were performed with one-way ANOVA with the Tukey post hoc test in D , F , H , J , and L.

Normal fuel homeostasis requires reciprocal regulation of glucose and FAO. In the fed state, FAO is inhibited by the increased availability of glucose through the glucose-FA cycle 44 — The pathway requires pyruvate, derived from glycolysis, to enter the tricarboxylic acid cycle TCA.

Once pyruvate is converted to acetyl-CoA by pyruvate dehydrogenase PDH , it is condensed with oxaloacetate by citrate synthase to form citrate.

Citrate is either used in the TCA cycle or exported to the cytosol, where it acts as substrate for malonyl-CoA synthesis. Production of malonyl-CoA near the mitochondrial membrane leads to inhibition of carnitine palmitoyl 1a CPT1a and thereby inhibits long-chain FAO Therefore, to understand how glucose lowers intracellular ATP in α-cells, we used stable isotope glucose tracer metabolite profiling.

To obtain a pure fraction, α-cells were FACS sorted using flavin-adenine dinucleotide autofluorescence Under these conditions, flavin-adenine dinucleotide fluorescence is high in other islet cells, and α-cells can be sorted as the least fluorescent fraction Fig.

Increased glucose metabolism leads to citrate—α-ketoglutarate cycling in α-cells. A : Schematic of experimental approach. D : Proposed model for glucose metabolism in α-cells.

All data presented are mean ± SEM. Statistics were performed with the Student t test B and C. The similar citrate content and small increase in 13 C enrichment could suggest that citrate is being used to generate other metabolites not measured here.

The increased percentage of 13 C enrichment in α-KG could suggest that citrate may be converted to α-KG. Alternatively, cataplerosis of citrate could explain why there is no increase in the total content of the metabolite Fig.

The combination of increased α-KG and decreased succinate enrichment suggests that the increases in total concentrations of fumarate, malate, and succinate content may be derived from anaplerotic metabolism.

On the basis of the findings in this experimental setup, it is likely that a proportion of citrate is used in the glucose FA cycle or for FA synthesis Fig. For glucose to contribute to the glucose FA cycle, pyruvate derived from glucose must enter the TCA cycle as oxaloacetate through pyruvate carboxylase or as acetyl-CoA through PDH.

The two metabolites can then be condensed by citrate synthase to form citrate. The activity of PDH is determined partly through inhibitory phosphorylation by pyruvate dehydrogenase kinases PDK Fig. Mouse and human α-cells both express high levels of Pdk4 mRNA compared with other islet cell types 47 , PDK4 expression is regulated by changes in substrate availability, and consequently, expression is increased in both skeletal muscle 49 and islets 50 during fasting.

To determine whether the glucose-FA cycle is important for the effect of glucose on intracellular ATP and glucagon secretion, we generated a mouse model in which Pdk4 was specifically overexpressed in α-cells Pdk4αKI. In these mice, the higher PDH phosphorylation would lead to lower influx of pyruvate into the TCA cycle through PDH.

PDK4 staining intensity was observed exclusively in α-cells and was twofold higher in Pdk4αKI mice than in controls Fig. In these mice, the glucose-induced reduction in intracellular ATP Fig. This suggests that PDK4 plays a key role in the regulation of glucagon secretion and that entry of pyruvate as acetyl-CoA into the TCA cycle is important for the reduction of glucagon secretion and intracellular ATP in α-cells.

Regulation of FAO is vital for glucose-induced glucagon repression. A : A depiction of the interaction between glucose and FAO pathways.

PC, pyruvate carboxylase. B : From left to right: glucagon cyan , Pdk4 yellow , and composite staining in pancreatic sections from control and Pdk4αKI mice. E : Dot plots of the last three frames of each condition in D. G : Glucagon content for F.

I : Glucagon content for H. K : Dot plots of the last three frames of each condition in J. See also Supplementary Fig. Statistics performed were unpaired t test C , G , and I , two-way ANOVA with the Tukey E and K or Šidák F and H post hoc test, and mixed-effects analysis with the Šidák post hoc test L.

Cpt1a KO in α-cells leads to decreased long-chain FAO and reduced glucagon secretion at low glucose 14 , identical to the effects observed when islets are incubated with low substrate levels Fig.

We therefore investigated the effect of glucose on ATP levels in islets from mice with Cpt1a KO specifically in α-cells αCPT1aKO. Intracellular ATP did not change in α-cells from these mice when exposed to 0. Some studies have suggested that inhibition of mitochondrial FAO can activate peroxisomal FAO 52 — These findings indicate that the glucose-FA cycle is active in α-cells and that glucose inhibits glucagon secretion by lowering FAO and intracellular ATP.

To test whether PDK4 expression in α-cells contributes to the regulation of glucagon secretion in vivo, we measured blood glucose and plasma glucagon in Pdk4αKI mice Fig.

Glucose tolerance and plasma glucagon levels were unaffected in male and female Pdk4αKI mice Fig. However, unlike controls, glucagon levels failed to reduce in female Pdk4αKI mice after glucose administration Fig.

This was also the case when sexes were combined to increase statistical power Fig. No changes in body weight, blood glucose, or ketones were observed between genotypes Fig. This suggests that, while PDK4 expression in α-cells is an important regulator of glucose-regulated glucagon secretion, it is not enough to drive the development of hyperglycemia or hyperketonemia in vivo.

Overexpression of Pdk4 in α-cells affects glucose-regulated glucagon secretion in vivo. A : Intraperitoneal i. B : Area under the curve AUC for A.

C : Plasma glucagon at 0 and 30 min after i. Statistics performed were unpaired t test B , E , H , J , K , and L and two-way ANOVA with the Šidák post hoc test C , F , and I. Pancreatic α-cells express K ATP channels 48 , The observation that glucose decreased intracellular ATP in the presence of NEFA therefore prompted us to investigate the electrical activity in α-cells under these experimental conditions.

The addition of 0. Unlike in control recordings without NEFA and BSA Fig. This could indicate that the reduction in ATP caused by increasing glucose levels leads to opening of K ATP channels and suggests that membrane potential in α-cells is more negative than previously reported Electrical activity 11 and FAs 40 have both been suggested to regulate glucagon secretion through changes in cytosolic calcium.

To investigate whether the addition of 0. This suggests that at low glucose, the membrane potential is depolarized and that increasing glucose repolarizes the plasma membrane to inhibit electrical activity, calcium entry, and glucagon secretion.

Glucose-induced reduction in ATP repolarizes the plasma membrane in α-cells. E : Representative trace of calcium oscillations in an α-cells in intact WT islets. Statistics performed were one-way ANOVA with the Tukey C , D , and F post hoc test.

Here we propose that the regulation of ATP production in α-cells is highly dependent on enzymes that promote FAO, such as PDK4 and CPT1a. We find that inhibition of pyruvate entry into the TCA cycle as acetyl-CoA, or FA transport into the mitochondria, disconnects changes in glucose levels from changes in ATP production and glucagon secretion.

Based on the observations made here, we suggest that glucose regulates glucagon secretion, not by increasing intracellular ATP, but by inhibiting FAO to lower intracellular ATP.

Our findings suggest that in α-cells, FAO is subject to suppression from glucose, as suggested by the glucose-FA cycle. Despite this, α-cells do oxidize glucose to some extent 56 , 57 , at least in the absence of other substrates and BSA, where increases in extracellular glucose results in ATP production 11 , 19 , 21 , 24 , However, we show here that in the absence of BSA, α-cells do not secrete much glucagon and do not respond to glucose.

While it is not clear why BSA is important for α-cell function, albumin has previously been shown to impact both intracellular lipid, pH, and redox homeostasis 59 , Whether this discrepancy is due to differences in the experimental paradigm or the two cell types is unclear.

Previous hypotheses of how glucose regulates glucagon secretion suggest that increased ATP from glucose oxidation leads to membrane depolarization in α-cells 11 , However, as with the previous measurements of ATP, these experiments were performed with glucose as the only substrate.

The findings we present here show that glucose repolarizes the plasma membrane in α-cells when applied in the presence of NEFA, consistent with the observed reduction in ATP under the same experimental conditions.

The finding that this effect was reversed by tolbutamide suggests it reflects activation of K ATP channels. It is, therefore, more likely that activation of K ATP channels drives the change in membrane potential in α-cells in response to increased glucose levels.

In addition, the current observation that ATP is reduced may also be aligned with the proposed reduction in intracellular cAMP in α-cells The lower cAMP could also be caused by increases in intracellular FAs as a consequence of the lower FAO at higher glucose, as adenylate cyclase in other tissues has been suggested to be inhibited by increases in intracellular FA levels Under conditions with 0.

This suggests that the lowering of plasma levels of glucagon in response to a glucose tolerance test may also be driven by changes in FA availability. This is supported by the ex vivo experiments presented here.

However, overexpression of PDK4 in α-cells results in a rather mild phenotype. That PDK4 overexpression in α-cells alone is not enough to drive the development of hyperglycemia or hyperketonemia in vivo is not surprising. Other models of impaired glucagon secretion also have relatively mild phenotypes 7 , 14 , 21 ,

Glibenclamide Glib stimulates insulin and inhibits glucagon release in WT but not Sur1KO islets in low glucose. A, Response of WT islets. B, Response of Sur1KO islets. The perifusion protocol is the same as shown in Fig. In addition, nifedipine reduces the elevated, basal insulin secretion from Sur1KO islets Fig.

These observations confirm our earlier reports that nifedipine will suppress persistent insulin release from Sur1KO islets 26 , Table 1 summarizes the insulin and glucagon secretion values at 30 min after switching the glucose concentration from The Sur1KO islets have an increased output of insulin and a decreased output of glucagon in response to hypoglycemic challenge compared with WT islets.

Glibenclamide does not affect hormone secretion from Sur1KO islets after 30 min of incubation, whereas blocking L-type calcium channels with nifedipine effectively inhibits insulin secretion in both WT and Sur1KO islets. Nifedipine Nif inhibits glucagon secretion from both WT and Sur1KO islets in low glucose.

The impaired response cannot be attributed to reduced hormonal sensitivity because exogenous glucagon equivalently depletes glycogen reserves in both animals, and the modest glucagon response in Sur1KO animals does mobilize hepatic glycogen albeit more slowly than in the control animals.

Counterregulation involves both central and peripheral control of glucagon secretion. The results extend the analysis reported for K IR 6.

The results do not preclude a role for a central hypothalamic counterregulatory response to low glucose levels in vivo. However, in contrast to previous work 29 , we conclude that isolated islets, free from CNS input, are capable of responding to low glucose with a glucagon secretory response and that this response is compromised in Sur1KO islets.

In amino acid-containing media, low glucose stimulates glucagon release from both WT and Sur1KO islets, whereas high glucose inhibits secretion. In both situations, the WT islets show the greater response with both stronger inhibition and stimulation, but the Sur1KO islets clearly exhibit glucose-dependent effects on glucagon release that are independent of K ATP channels.

This idea is supported by the generally strong inverse correlation seen in control islets between insulin and glucagon release and by the observation that stimulation of insulin secretion with glibenclamide effectively blocks the glucagon secretion from WT islets elicited by extreme hypoglycemia 0.

Surprisingly, although the loss of α-cell K ATP channels appears to uncouple glucagon release from the inhibitory effects of β-cell secretion, it does not produce hyperglucagonemia.

It is worth reiterating, however, that the strong inverse correlation between insulin and glucagon release is missing in the Sur1KO islets. This can be seen clearly, for example, in Fig. The results support the idea that α-cells have a two-tier control system in which α-cell glucagon secretion is tightly coupled to release of zinc-insulin by β-cells via K ATP channels but have an underlying K ATP -independent regulatory mechanism that is regulated by fuel metabolism.

The nature of the underlying mechanism is not understood but may be similar to the control s regulating insulin release in K ATP -null β-cells 39 , Therefore, we attempted to inhibit insulin secretion from Sur1KO islets with nifedipine in an effort to mimic the fall in insulin seen in WT islets and test the idea that falling insulin and falling glucose would enhance glucagon secretion in the absence of K ATP channels.

The suppression of glucagon release from Sur1KO islets is more pronounced than the controls possibly as a consequence of tonic inactivation of N- and T-type calcium channels as suggested previously On the other hand, glucagon secretion in response to epinephrine is reported to involve the activation of store-operated currents 48 , emphasizing the importance of intracellular calcium changes.

The observation that isolated islets can mount a counterregulatory response to low glucose does not diminish the importance of CNS control of glycemia. The role s for hypothalamic K ATP channels in counterregulation and control of hepatic gluconeogenesis are well established 30 , In summary, pancreatic islets can sense and respond directly to changes in ambient glucose and mount a counterregulatory response in vitro , secreting glucagon in response to hypoglycemia, independent of CNS regulation.

Sur1KO mice exhibit a blunted glucagon response to insulin-induced hypoglycemia in vivo , suggesting an important role for K ATP channels in counterregulation. Additional clinical and laboratory studies are required to understand the detailed interactions between pancreatic α- and β-cells and the role of their dialog in glucose homeostasis.

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Stagner JI , Samols E The vascular order of islet cellular perfusion in the human pancreas. While arginine increases glucagon expression in isolated rat islets: a process that is mediated by protein kinase C PKA; Yamato et al.

Other nutrients, such as the fatty acid palmitate, produces a down-regulated glucagon expression at short term in rat islets in a dose-dependent manner Bollheimer et al. By contrast, no effect with palmitate has been observed in other long-term studies Gremlich et al.

Like insulin, somatostatin also inhibits glucagon expression. It has been reported that somatostatin down-regulates glucagon expression basal levels as well as those produced by forskolin stimulation in clonal INR1G9 cells Fehmann et al.

The rat and mouse glucagon receptor is a amino acid protein, belonging to the secretin—glucagon receptor II class family of G protein-coupled receptors Mayo et al.

Glucagon binding to this receptor is coupled to GTP-binding heterotrimeric G proteins of the Gα s type that leads to the activation of adenylate cyclase, cAMP production and PKA. The glucagon receptor is present in multiple tissues including the liver, pancreas, heart, kidney, brain and smooth muscle.

Thus, it modulates multiple responses in these tissues, including effects on ion transport and glomerular filtration rate in kidney among others Ahloulay et al.

In any case, the regulation of glucose homeostasis is the major function of glucagon and its receptor. This role will be described in the next paragraph. The role of glucagon and the glucagon receptor in the liver.

ADCY, Adenylate cyclase; CREB, cAMP response element binding; F 1,6 P2, fructose-1,6-bisphosphate; F 2,6 P2, fructose-2,6-bisphosphate; FP, fructose 6-phosphate; FBP1, fructose-1,6-bisphosphatase; FBP2, fructose-2,6-bisphosphatase; GP, glucose 1-phosphate; GP, glucose 6-phosphate; G6PC, glucosephosphatase; GP, glycogen phosphorylase; GS, glycogen synthase; IP3, inositol 1,4,5-trisphosphate; OAA, oxaloacetate; PC, pyruvate carboxylase; PEP, phosphoenolpyruvate; PCK2, phosphoenolpyruvate carboxykinase; PFKM, phosphofructokinase-1; PPARGC1A, peroxisome proliferators-activated receptor-γ coactivator-1; PIP2, phosphatidylinositol 4,5-bisphosphate; PKLR, pyruvate kinase; PLC, phospholipase C; Pyr, pyruvate.

Dashed lines: red, inhibition; blue, stimulation. Several lines of defence protect the organism against hypoglycaemia and its potential damaging effects, especially in the brain, which depends on a continuous supply of glucose, its principal metabolic fuel.

These defences include decreased insulin release and increased secretion of adrenaline and glucagon. Additionally, glucose-sensing neurons of the ventromedial hypothalamus further control responses to glycaemia changes, as previously mentioned.

Among all these regulatory systems, glucagon plays a central role in the response to hypoglycaemia and also opposes to insulin effects. Glucagon stimulates gluconeogenesis and glycogenolysis, which increases hepatic glucose output, ensuring an appropriate supply of glucose to body and brain, and at the same time, it decreases glycogenesis and glycolysis.

The glucagon receptor in the liver is highly selective for glucagon, but it exhibits a modest affinity for glucagon-like peptides Hjorth et al.

Its main action on the liver is mediated by the activation of adenylyl cyclase and the PKA pathway. Glucagon regulates gluconeogenesis mainly by the up-regulation of key enzymes such as glucosephosphatase G6PC and phosphoenolpyruvate carboxykinase PCK2 through the activation of the cAMP response element-binding protein CREB and peroxisome proliferator-activated receptor γ-coactivator-1 PPARGC1A; Herzig et al.

PCK2 and G6PC, along with fructose-1,6-biphosphatase FBP1 have a key role in the rate of gluconeogenesis Fig. PCK2 mediates the conversion of oxalacetate into phosphoenolpyruvate while G6PC regulates glucose production from glucosephosphate.

FBP1 is responsible for the conversion of fructose-1,6-biphosphate F 1,6 P2 into fructosephosphate F6P. Additionally, this decrease in F 2,6 P2 also reduces the activity of phosphofructokinase-1 PFKM , down-regulating glycolysis.

The glycolytic pathway is further inhibited by glucagon at the pyruvate kinase PKLR level Slavin et al. Glycogen metabolism is mainly determined by the activity of glycogen synthase GS and glycogen phosphorylase GP.

Glucagon can also stimulate the uptake of amino acids for gluconeogenesis in the liver. Indeed, subjects with hyperglucagonaemia can develop plasma hypoaminoacidaemia, especially of amino acids involved in gluconeogenesis, such as alanine, glycine and proline Cynober Glucagon is also involved in the regulation of fatty acids in adipocytes.

Hormone-sensitive lipase mediates the lipolysis of triacylglycerol into the non-esterified fatty acids and glycerol, which are released from adipocytes. It has been reported that although glucagon does not modify the transcriptional levels of this enzyme, it increases the release of glycerol from adipocytes Slavin et al.

This mobilization of glycerol from adipose tissue can further be used in the liver during gluconeogenesis. However, the existence of a lipolytic action of glucagon observed in several animal models is still controversial in humans.

While a positive effect of glucagon on lipolysis has been reported in human subjects Carlson et al. An elevated glucagon to insulin ratio accelerates gluconeogenesis as well as fatty acid β-oxidation and ketone bodies formation Vons et al.

Thus, glucagon may also be involved in diabetic ketoacidosis, a medical complication in diabetes derived from the overproduction of ketone bodies Eledrisi et al. According to this hypothesis, this metabolic disease is the result of an insulin deficiency or resistance along with an absolute or relative excess of glucagon, which can cause a higher rate of hepatic glucose production than glucose utilization, favouring hyperglycaemia.

At present, there exists multiple clinical and experimental evidence that support this hypothesis. The rate of hepatic glucose output has been correlated with the hyperglycaemia found in animal models of diabetes as well as in human diabetes, and the maintenance of this abnormality has also been associated with hyperglucagonaemia Baron et al.

In type 2 diabetes, the impairment of insulin release and development of insulin resistance is often accompanied by absolute or relative increased levels of glucagon in the fasting and postprandial states Reaven et al.

In this situation, insulin is not effective as a negative feedback for hepatic glucose output while glucagon potentiates glucose mobilization from the liver, thus contributing to hyperglycaemia. Another malfunction reported in diabetic patients is the lack of suppression of glucagon release in hyperglycaemic conditions, which would contribute further to postprandial hyperglycaemia in both type 1 and type 2 diabetes Dinneen et al.

However, this irregular α-cell behaviour does not occur when insulin levels are adequate, suggesting that abnormalities in glucagon release are relevant for hyperglycaemia in the context of diabetes or impairment of insulin secretion or action Shah et al.

Hyperglucagonaemia is also responsible for the development of hyperglycaemia and diabetes in patients with the glucagonoma syndrome, a paraneoplastic phenomenon characterized by an islet α-cell pancreatic tumour Chastain Another defect in normal glucagon secretion has important consequences in the management of hypoglycaemia.

The secretory response of α-cells to low-glucose concentrations is impaired in type 1 and long-lasting type 2 diabetes, increasing the risk of episodes of severe hypoglycaemia, especially in patients treated with insulin Cryer In this regard, iatrogenic hypoglycaemia is a situation that implies insulin excess and compromised glucose counter-regulation, and it is responsible for a major complication in diabetes treatment, increasing the morbidity and mortality of this disease Cryer This lack of glucagon response to hypoglycaemia has been associated with multiple failures in α-cell regulation; yet, the mechanisms are still under study Bolli et al.

Even though islet allotransplantation can provide prolonged insulin independence in patients with type 1 diabetes, the lack of α-cell response to hypoglycaemia usually persists after transplantation, indicating that this procedure does not restore the physiological behaviour of α-cells Paty et al.

All these problems in the glucagon secretory response observed in diabetes have been attributed to several defects in α-cell regulation including defective glucose sensing, loss of β-cell function, insulin resistance or autonomic malfunction.

However, the mechanisms involved in α-cell pathophysiology still remain largely unknown and deserve more investigation for better design of therapeutic strategies. In this regard, although direct therapeutic approaches to correct the lack of α-cell response to hypoglycaemia are missing, several proposals have been developed to amend glucagon excess, as we will see in the next section.

The specific control of glucagon secretion by pharmacological modulation is complex since several components of the α-cell stimulus-secretion coupling are also present in β- and δ-cells. Thus, the manipulation of glucagon action by modulating the glucagon receptor signalling seems to be an effective alternative Li et al.

This strategy has been supported by several studies. Glucagon receptor knock-out mice have hyperglucagonaemia and α-cell hyperplasia, but their glucose tolerance is improved and they develop only a mild fasting hypoglycaemia Gelling et al.

These mice have a normal body weight, food intake and energy expenditure although less adiposity and lower leptin levels. These results are consistent with the experiments with anti-sense oligonucleotides for the glucagon receptor.

Therefore, these experimental results are a further support that glucagon antagonism may be beneficial for diabetes treatment.

Sulphonylureas are efficient K ATP channel blockers that have been extensively used for the clinical treatment of diabetes. This biphasic effect is due to the mouse α-cell electrical behaviour Fig. Accordingly, with this scheme, the K ATP channel opener diazoxide can also have a biphasic effect on glucagon secretion.

These effects will change depending on the extracellular glucose concentrations that necessarily influence K ATP channel activity MacDonald et al. This biphasic behaviour may explain the disparity of effects found for sulphonylureas Loubatieres et al. In humans, sulphonylureas are associated to a glucagon secretion decrease in healthy and type 2 diabetic subjects Landstedt-Hallin et al.

Since sulphonylureas also induce insulin and somatostatin secretion, which affect α-cells, these drugs offer a poor specific control of glucagon secretion. In addition to stimulating insulin release, GLP1 can suppress glucagon secretion in humans, perfused rat pancreas and isolated rat islets in a glucose-dependent manner Guenifi et al.

Because GLP1 is rapidly cleaved and inactivated by the enzyme dipeptidyl peptidase-IV DPP4 , a good alternative would be to design either GLP1 derivatives with higher resistance to DPP4 or agents that increase GLP1 endogenous levels. Among the GLP1 mimetics, exenatide is a synthetic polypeptide with high resistance to DPP4 cleavage that decreases glucagon levels in normal and diabetic subjects Degn et al.

Liraglutide, another GLP1 derivative with long-lasting actions, can reduce glucagon release after a meal in patients with type 2 diabetes Juhl et al. Alternatively, DPP4 inhibitors like sitagliptin and vildagliptin increase the endogen effects of GLP1, reducing glucagon plasma concentrations in diabetic individuals Rosenstock et al.

Since all these alternatives produce opposing actions on insulin and glucagon, they generate promising expectations for diabetes treatment. Given that imidazoline compounds stimulate insulin release while inhibiting glucagon secretion, these drugs are potentially valuable in diabetes.

Because of the different expression of SSTR in the islet Kumar et al. It has been shown that SSTR2 is the subtype receptor predominantly expressed in rodent α-cells, and that SSTR2-deficient mice develop hyperglycaemia and non-fasting hyperglucagonaemia Singh et al.

In mice, the use of a highly SSTR2-selective non-peptide agonist inhibited glucagon release without affecting insulin release Strowski et al.

However, there is some overlapping in human islets between the different SSTR subtypes in α- and β-cells that limit, at present, the use of subtype-specific somatostatin analogues Singh et al. Amylin, which is cosecreted with insulin from β-cells, inhibits glucagon secretion stimulated by amino acids but does not affect hypoglycaemia-induced glucagon release Young Since α-cell response to amino acids is often exaggerated in diabetic patients, amylin or amylinomimetic compounds such as pramlintide are used as an effective alternative for the treatment of postprandial and amino acid-induced excess of glucagon secretion Dunning et al.

Several linear and cyclic glucagon analogues have been developed to work as glucagon receptor antagonists. Essentially, they impair the ability of glucagon to stimulate adenylate cyclase activity in liver, thus reducing hepatic glucose output and improving plasma glucose levels.

This is the case of [des-His 1 , des-Phe 6 , Glu 9 ] glucagon-NH 2 , which reduces glucose levels in streptozotocin-induced diabetic rats Van Tine et al. Recent investigations have demonstrated that the antagonist des-His-glucagon binds preferentially to the hepatic glucagon receptor in vivo , and this correlates with the glucose lowering effects Dallas-Yang et al.

For instance, a novel competitive antagonist N -[3-cyano 1, 1-dimethylpropyl -4, 5, 6, 7-tetrahydrobenzothienyl]ethylbutanamide was recently shown to inhibit glucagon-mediated glycogenolysis in primary human hepatocytes and to block the increase in glucose levels after the administration of exogenous glucagon in mice Qureshi et al.

The information about the effect of these antagonists on humans is, however, scarce. Despite the success of several approaches to modulate glucagon secretion or action and improve glucose control in animal models or in humans, more information is still required.

Long-standing studies should address whether the utilization of these agents could lead to undesired hypoglycaemia in humans, accumulation of lipids or compensatory mechanisms that decrease the benefits of these therapies in the long term.

In this aspect, the results obtained in animal models are positive: although the glucagon receptor knock-out mouse develops hyperglucagonaemia, it is not hypoglycaemic and does not have an abnormal accumulation of lipids Gelling et al.

Additionally, recent long-term studies in mice further prove the viability of glucagon antagonism Winzell et al. Thus, present data are promising and indicate that several therapeutic agents targeted to glucagon signalling and α-cell secretion may be useful for the management of diabetes.

Pancreatic α-cells and glucagon secretion are fundamental components of the regulatory mechanisms that control glucose homeostasis. However, α-cell physiology has remained elusive compared with the overwhelming information about insulin secretion and the β-cell.

In recent years, however, several groups have initiated intensive efforts to understand α-cell physiology and identified essential pieces of its stimulus-secretion coupling. Additionally, important aspects of the regulation of α-cell metabolism and the control of glucagon expression are being elucidated.

All of this information will favour an overall comprehension of the α-cell function and its role in glucose homeostasis. Nevertheless, more research is required to understand the α-cell behaviour, not only in healthy subjects but in pathological conditions as well.

In conclusion, since the malfunction of the glucagon secretory response is involved in diabetes and its complications, a complete understanding of the α-cell will allow for a better design of therapeutic approaches for the treatment of this disease.

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. This work was supported by grants from the Ministerio de Educación y Ciencia BFU and PCIA to I Q; BFU to A N.

CIBERDEM is an initiative of the Instituto de Salud Carlos III. American Journal of Physiology. Renal Physiology F24 — F Ahren B Autonomic regulation of islet hormone secretion — implications for health and disease. Diabetologia 43 — Hormone and Metabolic Research 14 — Effects on basal release of insulin and glucagon.

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American Journal of the Medical Sciences — European Journal of Biochemistry — Cryer PE Hypoglycaemia: the limiting factor in the glycaemic management of Type I and Type II diabetes.

Diabetologia 45 — Cynober LA Plasma amino acid levels with a note on membrane transport: characteristics, regulation, and metabolic significance. Nutrition 18 — European Journal of Pharmacology — Diabetes 53 — Journal of Biological Chemistry — Diabetes 46 — Diabetologia 38 — Endocrine Reviews 28 — Diabetologia 48 — Endocrinology and Metabolism E40 — E Diabetes 54 — Regulatory Peptides — Journal of Physiology — Journal of Clinical Endocrinology and Metabolism 86 — Journal of General Physiology — Endocrine Reviews 28 84 — Pancreas 22 58 — Diabetes 52 — PNAS 93 — Nature — Metabolism 54 — FASEB Journal 9 — Nature Cell Biology 5 — Diabetes 51 — Diabetes Research and Clinical Practice 44 83 — Journal of Clinical Investigation 96 — Endocrinology and Metabolism E21 — E Diabetes 48 77 — Protein Science 4 — Journal of Clinical Endocrinology and Metabolism 84 — Diabetes Care 23 — Clinical Science — Cell Calcium 35 — Diabetologia 10 — Molecular Endocrinology 19 — PLoS Biology 5 e The glucagon receptor family.

Pharmacological Reviews 55 — Nature Neuroscience 4 — Journal of Physiology 85 — Journal of Clinical Endocrinology and Metabolism 87 — Diabetologia 29 — Journal of Nutrition — Thus, the observed effect upon glucagon administration in supraphysiological concentrations could partly be due to cross-reactivity with the GLP-1 receptor which normally result in suppression of food intake In addition to a potential effect of glucagon on food intake, evidence suggests that glucagon contributes to a negative energy balance by stimulating energy expenditure.

In humans, this effect has been observed in studies in which glucagon infusion resulted in increases in resting energy expenditure 42 — However, the effect of endogenous glucagon on resting energy expenditure remains unclear. Also, the exact mechanisms behind the increase in resting energy expenditure elicited by exogenous glucagon remain to be determined.

It has been speculated that glucagon activates brown adipose tissue 12 , however this was recently challenged in an in vivo study that found no direct effect of glucagon on brown adipose tissue Rodent studies indicate that the actions of glucagon to increase energy expenditure might be indirectly mediated partly by fibroblast growth factor 21 FGF21 as glucagon-induced increase in energy expenditure is abolished in animals with FGF21 receptor deletion Infusion of high doses of glucagon increases heart rate and cardiac contractility In fact, infusion of glucagon in pharmacological doses milligram is often used in the treatment of acute cardiac depression caused by calcium channel antagonist or beta-blocker overdoses 47 despite limited evidence In comparison, glucagon concentrations within the normal physiological range do not appear to affect heart rate or contractility 49 and any physiological role of endogenous glucagon in the regulation of pulse rate remains questionable.

This is supported by studies investigating the effect of glucagon receptor antagonist for the treatment of type 2 diabetes in which no effect of pulse rate were observed Nevertheless, whether increased glucagon concentrations have a sustained effect on the heart remains unknow.

Of note, most studies use bolus injections of glucagon which cause only a transient increase in heart rate and contractility potentially reflecting the rapid elimination of glucagon from circulation Taken together, it remains uncertain whether glucagon has a place in the treatment of heart failure or hold a cardioprotective effect in healthy subjects.

Patients with type 2 diabetes exhibit an impaired regulation of glucagon secretion which contributes importantly to diabetic hyperglycemia. Specifically, type 2 diabetes is characterized by elevated levels of glucagon during fasting while suppression of glucagon in response to oral intake of glucose is impaired or even paradoxically elevated Fig.

The mechanisms behind hyperglucagonemia are not fully understood but is usually explained by a diminished suppressive effect of insulin on alpha cells due to hypoinsulinemia and insulin resistance at the level of the alpha cells 53 , Interestingly, subjects with type 2 diabetes, who exhibit a hyperglucagonemic response to oral glucose, respond with a normal suppression of glucagon after intravenous glucose administration Accordingly, hormones secreted from the gastrointestinal tract may play an important role 55 , It has recently been confirmed that glucagon can be secreted from extrapancreatic tissue demonstrated in experiments with totally pancreatectomized subjects This supports the notion that postprandial hypersecretion of glucagon in patients with type 2 diabetes might be of extrapancreatic origin.

Schematic illustration of plasma glucagon concentrations in patients with type 2 diabetes and in normal physiology healthy subjects. Type 2 diabetes is characterized by elevated fasting plasma glucagon levels and impaired suppression of plasma glucagon levels in response to oral glucose.

Traditionally type 1 diabetic hyperglycemia has been explained by selective loss of beta cell mass and resulting decrease in insulin secretion. However, emerging evidence indicate that glucagon plays a major role in type 1 diabetes pathophysiology.

The glucagon dyssecretion that characterizes patients with type 1 diabetes is associated with two clinical manifestations: Postprandial hyperglucagonemia and impaired glucagon counterregulation to hypoglycemia Data regarding fasting plasma glucagon concentrations in type 1 diabetes are inconsistent 57 , Thus, the general notion that glucagon hypersecretion plays a role in type 1 diabetes hyperglycemia is mainly based on elevated postprandial glucagon concentrations The explanation behind this is unclear, although a common explanation is, that in type 1 diabetes the postprandial increase in plasma glucose is not followed by an increase in insulin secretion from beta cells, which in normal physiology would inhibit glucagon secretion.

The absence of that restraining signal from endogenous insulin could result in an increase in glucagon secretion from alpha cells after a meal Fig.

However, like in type 2 diabetes, subjects with type 1 diabetes preserve their ability to suppress glucagon after intravenous glucose administration. Schematic illustration of plasma glucagon concentrations in patients with type 1 diabetes and in normal physiology healthy subjects.

Type 1 diabetes is characterized by elevated concentrations of glucagon in response to a meal or oral glucose intake. Hypoglycemia is a frequent and feared side effect of insulin therapy in type 1 diabetes and it represents a common barrier in obtaining glycemic control In normal physiology hypoglycemia is prevented by several mechanisms: 1 Reduced insulin secretion from beta cells diminishing glucose uptake in peripheral tissues; 2 increased glucagon secretion from alpha cells increasing hepatic glucose output; and 3 increased symphathetic neural response and adrenomedullary epinephrine secretion.

The latter will stimulate hepatic glucose production and cause clinical symptoms that enables the individual to recognize hypoglycemia and ultimately ingest carbohydrates 57 , 61 , In type 1 diabetes, insulin-induced hypoglycemia fails to elicit adequate glucagon responses compromising counterregulation to insulin-induced hypoglycemia; a phenomenon which seems to worsen with the duration of type 1 diabetes.

This defect likely involves a combination of defective alpha cells and reduced alpha cell mass 57 , Dysregulated glucagon secretion is not only observed in patients with type 2 diabetes but also in normoglucose-tolerant individuals with obesity 64 and patients with non-alcoholic fatty liver disease NAFLD 65 , This suggests that dysregulated glucagon secretion may represent hepatic steatosis rather than dysregulated glucose metabolism.

Interestingly, fasting hyperglucagonemia seems to relate to circulating amino acids in addition to hepatic fat content This hyperaminoacidemia suggests that impairment of amino acid turnover in the liver and ensuing elevations of circulating amino acids constitutes a feedback on the alpha cell to secrete more glucagon with increasing hepatic amino acid turnover and ureagenesis needed for clearance of toxic ammonia from the body.

The implication of hyperglucagonemia in obesity and NAFLD has renewed the scientific interest in actions of glucagon and the role of glucagon in the pathophysiology of these metabolic disorders. Clearly, glucagon may represent a potential target for treatments of obesity and NAFLD.

A simple way to restrain the undesirable hyperglycemic effect of glucagon while realizing its actions on lipolysis and energy expenditure could be by co-treating with a glucose-lowering drug.

This may be done by mimicking the gut hormone oxyntomodulin which acts as a ligand to both the glucagon and the GLP-1 receptor.

Glucagon is a glucoregulatory peptide hormone that counteracts the actions of insulin by stimulating hepatic glucose production and thereby increases blood glucose levels. Additionally, glucagon mediates several non-glucose metabolic effects of importance for maintaining whole-body energy balance in times of limited nutrient supply.

These actions include mobilization of energy resources through hepatic lipolysis and ketogenesis; stimulation of hepatic amino acid turnover and related ureagenesis. Also, glucagon has been shown to increase energy expenditure and inhibit food intake, but whether endogenous glucagon is involved in the regulation of these processes remains uncertain.

Glucagon plays an important role in the pathophysiology of diabetes as elevated glucagon levels observed in these patients stimulate hepatic glucose production, thereby contributing to diabetic hyperglycemia.

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Show details Feingold KR, Anawalt B, Blackman MR, et al. Contents www. Search term. Glucagon Physiology Iben Rix , Christina Nexøe-Larsen , Natasha C Bergmann , Asger Lund , and Filip K Knop.

hnoiger nesretep. Christina Nexøe-Larsen Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark, Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Natasha C Bergmann Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark. Asger Lund Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark. Filip K Knop Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark, Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Steno Diabetes Center Copenhagen, Gentofte, Denmark Email: kd.

hnoiger ABSTRACT Glucagon is a peptide hormone secreted from the alpha cells of the pancreatic islets of Langerhans. STRUCTURE AND SYNTHESIS OF GLUCAGON Glucagon is a amino acid peptide hormone predominantly secreted from the alpha cells of the pancreas.

GLUCAGON SECRETION Glucagon is secreted in response to hypoglycemia, prolonged fasting, exercise and protein-rich meals Regulation of Glucagon Secretion by Glucose The most potent regulator of glucagon secretion is circulating glucose. Glucagon Concentrations in The Circulation In normal physiology, circulating glucagon concentrations are in the picomolar range.

Glucagon concentrations in response to hypoglycemia, euglycemia, and hyperglycemia. GLUCAGON ACTIONS Glucagon Increases Hepatic Glucose Production Glucagon controls plasma glucose concentrations during fasting, exercise and hypoglycemia by increasing hepatic glucose output to the circulation.

Glucagon Stimulates Break-Down of Fatty Acids and Inhibits Lipogenesis in the Liver Glucagon promotes formation of non-carbohydrate energy sources in the form of lipids and ketone bodies. Glucagon Promotes Break-Down of Amino Acids During prolonged fasting, glucagon stimulates formation of glucose from amino acids via gluconeogenesis by upregulating enzymes involved in the process.

Glucagon Reduces Food Intake Acute administration of glucagon has been shown to reduce food intake and diminish hunger 38 , Glucagon Increases Energy Expenditure In addition to a potential effect of glucagon on food intake, evidence suggests that glucagon contributes to a negative energy balance by stimulating energy expenditure.

Glucagon May Regulate Heart Rate and Contractility Infusion of high doses of glucagon increases heart rate and cardiac contractility Organ specific actions of glucagon.

GIP, glucose-dependent insulinotropic polypeptide. Glucagon in Type 1 Diabetes Traditionally type 1 diabetic hyperglycemia has been explained by selective loss of beta cell mass and resulting decrease in insulin secretion.

Glucagon in Obesity and Hepatic Steatosis Dysregulated glucagon secretion is not only observed in patients with type 2 diabetes but also in normoglucose-tolerant individuals with obesity 64 and patients with non-alcoholic fatty liver disease NAFLD 65 , Habegger KM, Heppner KM, Geary N, Bartness TJ, DiMarchi R, Tschöp MH.

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