CREB3L3; cAMP responsive element binding protein 3 like 3 [KO: K ]. CREB3L4; cAMP responsive element binding protein 3 like 4 [KO: K ]. PPP4C; protein phosphatase 4 catalytic subunit [KO: K ] [EC: 3. SIK2; salt inducible kinase 2 [KO: K ] [EC: 2. CREBBP; CREB binding protein [KO: K ] [EC: 2.

EP; E1A binding protein p [KO: K ] [EC: 2. SIK; salt inducible kinase 1B putative [KO: K ] [EC: 2. SIK1; salt inducible kinase 1 [KO: K ] [EC: 2. PLCB1; phospholipase C beta 1 [KO: K ] [EC: 3.

PLCB2; phospholipase C beta 2 [KO: K ] [EC: 3. PLCB3; phospholipase C beta 3 [KO: K ] [EC: 3. PLCB4; phospholipase C beta 4 [KO: K ] [EC: 3. PPP3CA; protein phosphatase 3 catalytic subunit alpha [KO: K ] [EC: 3. PPP3CB; protein phosphatase 3 catalytic subunit beta [KO: K ] [EC: 3.

PPP3CC; protein phosphatase 3 catalytic subunit gamma [KO: K ] [EC: 3. PPP3R1; protein phosphatase 3 regulatory subunit B, alpha [KO: K ]. PPP3R2; protein phosphatase 3 regulatory subunit B, beta [KO: K ]. SIRT1; sirtuin 1 [KO: K ] [EC: 2. PRMT1; protein arginine methyltransferase 1 [KO: K ] [EC: 2.

G6PC1; glucosephosphatase catalytic subunit 1 [KO: K ] [EC: 3. G6PC2; glucosephosphatase catalytic subunit 2 [KO: K ] [EC: 3. G6PC3; glucosephosphatase catalytic subunit 3 [KO: K ] [EC: 3. PCK1; phosphoenolpyruvate carboxykinase 1 [KO: K ] [EC: 4. PCK2; phosphoenolpyruvate carboxykinase 2, mitochondrial [KO: K ] [EC: 4.

CPT1A; carnitine palmitoyltransferase 1A [KO: K ] [EC: 2. CPT1B; carnitine palmitoyltransferase 1B [KO: K ] [EC: 2. CPT1C; carnitine palmitoyltransferase 1C [KO: K ] [EC: 2.

GYS2; glycogen synthase 2 [KO: K ] [EC: 2. GYS1; glycogen synthase 1 [KO: K ] [EC: 2. PHKG1; phosphorylase kinase catalytic subunit gamma 1 [KO: K ] [EC: 2. PHKG2; phosphorylase kinase catalytic subunit gamma 2 [KO: K ] [EC: 2.

PYGL; glycogen phosphorylase L [KO: K ] [EC: 2. PYGM; glycogen phosphorylase, muscle associated [KO: K ] [EC: 2.

PYGB; glycogen phosphorylase B [KO: K ] [EC: 2. PRKAA1; protein kinase AMP-activated catalytic subunit alpha 1 [KO: K ] [EC: 2. Inhibition of glucagon secretion can improve alpha cell insulin resistance. Prohormone converting enzyme 2 PC2 gene knockout: proglucagon is a precursor of glucagon, which produces different products through different prohormone convertases in different tissue organs.

Study have showed that PC2 knockout mice have a significant decrease in blood glucagon, mild persistent hypoglycemia, and modern compensatory islet alpha cell proliferation, when using a micro-osmotic pump or intraperitoneal small dose.

After glucagon injection, blood glucose returned to normal; and after a long period of application, the morphology of islet α cells recovered to resemble that of wild-type mice.

Glucagon neutralizing antibodies: this method uses exogenous glucagon antibodies to bind to glucagon in the body, thereby blocking the effects of endogenous glucagon and ultimately lowering blood sugar.

The brand is equivalent to an experiment conducted in using a high-capacity, high-affinity glucagon monoclonal antibody Glu-mAb in a normal, alloxan ALX -induced mild and severe diabetic rabbit model.

Tip: this antibody can completely block exogenous glucagon-induced hyperglycemia in normal animals; in low-glycemic zoos, lowering blood sugar is also obvious; in high-glycemic type 1 diabetic rabbits, Glu-mAb can still significantly reduce liver glucose output, reducing the fasting blood glucose of experimental rabbits from The use of glucagon antibodies to reduce the effects of glucagon can better control the effects of type 2 diabetes.

Barbato et al. found that the glycine-serine polymorphism Gly40Ser of the glucagon receptor gene exon 2 in French Caucasians is closely related to type 2 diabetes. The research focused on glucagon receptor blockers, glucagon receptor gene expression inhibitors, and glucagon receptor gene knockout.

Receptor blockers: the mechanism of action of glucagon receptor blockers is mainly through competitive binding to endogenous glucagon, thereby inhibiting glucagon-mediated adenylate cyclase activity, reducing glycogen output, reducing fasting blood glucose levels, and improving glucose tolerance.

The receptor blocker is classified into a peptide compound and a non-peptide small molecule compound according to the molecular structure.

Petersen et al. found that a non-peptide small molecule compound, Bay 27 , effectively blocks the increase in glucose production and blood glucose caused by exogenous glucagon in healthy adult males. This is also the only drug that has been used in humans for glucagon receptor antagonists. Although more clinical trials are needed to prove efficacy, it is undoubtedly an increase in the search for effective human glucagon receptor antagonists.

The above studies have shown that both glucagon receptor antagonists, whether peptide or non-peptide, block the liver glucagon receptor and exert a hypoglycemic effect.

Receptor gene expression inhibitors: the principle of action of these drugs is to block the expression of glucagon target receptor gene and reduce the expression of glucagon receptor mRNA, thereby achieving the role of treating diabetes.

Sloop and other antisense oligonucleotides ASO blocking glucagon receptors were used to treat type 2 diabetic animals. It was found that glucagon receptor mRNA expression decreased and plasma glucagon concentration increased significantly after treatment.

Glucose tolerance improved, and triglycerides and free fatty acids decreased significantly. Post-receptor regulation: there are still few intervention studies on glucagon receptors, but there are still some reports on G-protein coupled receptor alpha knockout animals. G protein-coupled receptors are present in multiple organs throughout the body.

The glucagon receptor is mainly in the liver. The use of liver-specific G protein knockout animals is a method of interfering with the glucagon signaling pathway.

Activation of glucagon signaling pathways and dysfunction play an important role in the pathophysiology of type 2 diabetes. More and more studies have shown that the decrease of the secretion of glucagon by inhibiting alpha-cell production, neutralizing blood circulation and hyperglycemia, changing glucagon receptor gene expression, and other methods to interfere signaling pathways may be new treatments for diabetes.

Recent studies have shown that obese patients have both dysfunction of islet β-cells and α-cells, impaired insulin secretion and excessive secretion of glucagon, which aggravates the disorder of blood glucose metabolism, so the glucagon signaling pathway regulated for obese patients treatment is especially important.

In the past two years, the levels of insulin and glucagon in the patients with coronary heart disease were significantly higher than those in the control group, and the inhibitors of the glucagon signaling pathway were improved, so the glucogon signaling pathway was involved in coronary heart disease.

But the detail has to be further studied. Inquiry Basket. The greatest advances in gleaning the mechanisms of glucagon granule exocytosis have been made using patch-clamp approaches in isolated rodent or human islets. In such preparations, alpha cells can identified by their unique electrophysiological signature under low glucose conditions or, in the case of mouse islets, by genetically-encoded fluorescence reporters such as YFP , or tdTomato After proglucagon processing and granule maturation, glucagon is stored in the alpha cell secretory granule until a stimulus triggers exocytosis.

As in beta cells, there may be different functional pools of secretory granules: a reserve pool and a readily releasable pool that is primed and situated at the sites of exocytosis. Quantitative ultrastructural analysis of murine islets has shown that, in the presence of 1mM glucose, the mouse α-cell contains ~ secretory granules, of which ~ are in close proximity to the plasma membrane, or primed This means that the reserve pool is large and can resupply the readily releasable pool to maintain euglycemia over extended periods of time.

In the presence of Following docking, secretory granules are primed through the action of the SNARE protein complex.

This complex contains two subsets of proteins; i the t-SNAREs syntaxin 1A and SNAP, located in the plasma membrane; and ii the v-SNAREs VAMP2 and synaptotagmin VII, which are located in the granule membrane Under low glucose conditions, SNAP and syntaxin 1A are translocated to the plasma membrane.

SNAP itself may play a role in the transportation of granules from the releasable pool to the readily releasable pool, and then mediates their fusion with plasma membrane via interaction with syntaxin 1A , Live imaging of exocytosis using a proglucagon-luciferase reporter showed spatial clustering of glucagon secretion sites in αTC cells Future studies may reveal some interesting dynamics with SNARE proteins that may fine-tune the alpha cell secretory response to glucose and paracrine inputs.

Could disruption of these molecular mechanisms contribute to the hyperglucagonemia of diabetes? However, neither membrane potential nor exocytosis was responsive to insulin or to a greater extent somatostatin, in contrast to normal alpha cells in which both were significantly reduced.

Therefore, in T2D, hyperglucagonemia may result from insulin and somatostatin resistance at the level of the readily releasable pool of granules.

In alpha cells of patients with T1D, expression levels of genes encoding SNARE proteins, ion channels and cAMP signalling molecules were disrupted , which could explain the impaired glucose counter-regulatory response and the inappropriately elevated levels of postprandial glucagon in T1D.

Combining patch-clamp electrophysiological measurements with single-cell RNA sequencing patch-seq in human islets has given high-resolution insight into mechanisms underlying impairments in alpha cell function in diabetes at the level of granule exocytosis.

Further characterization of the link between electrophysiological signatures and the genes regulating the dynamics of granule exocytosis will reveal new mechanisms of alpha cell dysfunction in diabetes. Identifying new pathways or networks that control glucagon granule biogenesis and trafficking may identify novel targets for the control of hyperglucagonemia in addition to yielding a greater understanding of alpha cell biology in both health and disease.

There is an emerging hypothesis that glucagon secretion can be controlled by trafficking through the endosomal-lysosomal pathway, similar to insulin , and below, we highlight some recent studies that suggest glucagon may regulated through such an alternate trafficking pathway. Brefeldin A-inhibited guanine nucleotide exchange protein 3 BIG3 is a member of the Arf-GEF family of proteins, and was initially found in a database search and found to inhibit insulin granule biogenesis and insulin secretion A subsequent study found that it had a similar role in regulating glucagon granule production and exocytosis Whether BIG3 can mediate glucagon trafficking through lysosomes remains to be investigated.

The composition and cargo of the alpha cell secretory granule may also hold some determinants of glucagon secretion. While it is known that granule contents and composition are modified during normal granule maturation, a more complete picture of granule remodeling and heterogeneity in the context of intracellular trafficking networks in normal physiology and in diabetes is required.

In an effort to identify networks of secretory granule proteins that interact with glucagon and regulate its trafficking and secretion, proteomic analysis was conducted on αTC cell secretory granule lysates immunoprecipitated with tagged glucagon This qualitative study demonstrated the plasticity in the network of proteins interacting with glucagon in response to insulin or GABA under high 25 mM or low 5.

Stathmin-2, a member of the family of neuronal phosphoproteins that associates with the secretory pathway in neurons, was identified as a candidate protein for the regulation of glucagon secretion and subsequently shown to modulate glucagon secretion through the lysosomal pathway and may be down-regulated in diabetes in humans and in mice Therefore, disruptions in the routing of glucagon through the lysosomal pathway may contribute to the hyperglucagonemia of diabetes Figure 4.

Figure 4 Stathminmediated lysosomal trafficking modulates glucagon secretion. Glucagon dark blue and stathmin-2 light blue are normally sorted to secretory granules from the Golgi in alpha cells.

Stathmin-2 overexpression diverts glucagon-containing secretory granules to lysosomes black arrows , thus reducing glucagon secretion. Additionally, secretion from secretory granules is also enhanced solid red arrow.

Glucagon trafficking and exocytosis may also be controlled through nutrient-driven pathways. The nutrient sensor O-GlcNAc transferase OGT catalyses the O-glycosylation of several proteins including those involved in the conventional secretory pathway and autophagosome-lysosome fusion In mice lacking OGT specifically in alpha cells, glucagon secretion, cell content and alpha cell mass are reduced Possible mechanisms include lack of O-glycosylation of FOXA1 and FOXA2, which regulate genes encoding proteins involved in proglucagon processing and glucagon secretion Whether other trafficking proteins are affected, and how alpha cell function is affected in diabetes in these mice, is not yet known.

So what are the implications of glucagon trafficking through the lysosomal pathway in diabetes? Lysosomal trafficking and autophagy in the beta cell may be a possible mechanism of insulin secretory defects in diabetes, with a recent study providing evidence for impairment of lysosomal function in human T1D How does lysosomal function contribute to defects in alpha cell function?

It is tempting to hypothesize that impairments in lysosomal biogenesis and trafficking result in both reduced insulin secretion in the beta cell and unregulated glucagon secretion from the alpha cell. Further investigation into the altered dynamics of glucagon trafficking in the alpha cell in diabetes may reveal key roles for the lysosome in the regulation of glucagon secretion, thus identifying a potential new target for the treatment of hyperglucagonemia.

Finally, some excellent single-cell transcriptomics and epigenomics databases are being generated that reveal the dynamics of intracellular trafficking networks at the transcriptional level in human pancreatic alpha cells in both health and diabetes — The mapping of T2D-associated genetic variants with RNA-seq of human islets may reveal risk factors associated with defects in alpha cell function A novel immunocompromised mouse model in which glucagon-encoding codons were deleted while preserving both GLP-1 and GLP-2 will provide an innovative and much-needed resource for the study of the regulation of glucagon secretion from human islets in vivo In this study, transplantation of islets from people with T2D resulted in hyperglucagonemia with apparent alpha cell insulin resistance, revealing intrinsic alpha cell defects in T2D.

Moreover, defects in alpha cell function were more apparent than in isolated islets, thus emphasizing the utility of such an in vivo system to investigate the molecular mechanisms of glucagon secretion in human islets, and the testing of possible treatments for hyperglucagonemia.

While the development of glucagon receptor antagonists and other inhibitors of glucagon action has provided some possibilities for the treatment of hyperglucagonemia, there are significant side effects that result from impaired hepatic metabolism and potentially uncontrolled alpha cell proliferation.

The advantage to developing such drugs, however, lie in the fact that the glucagon receptor is an easily available target. In contrast, targeting glucagon secretion as a means to treat hyperglucagonemia may alleviate concerns about effects on the liver and alpha cell mass; however, there are potentially many more targets within the alpha cell secretory pathway, and many of those may not be easily accessible for drug treatment.

The ongoing discovery of novel proteins and networks that regulate the secretion of glucagon will shed further light on alpha cell biology in health and disease while also searching for improved means to control hyperglucagonemia and hyperglycemia of diabetes.

SD and FA co-wrote the manuscript. All authors contributed to the article and approved the submitted version. This work was funded by a Natural Sciences and Engineering Research Council Discovery Grant to SD. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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As mentioned above, when the alpha cell insulin is resistant, its signal transduction pathway is impaired. Exploring its mechanisms may be related to the mediation of inflammatory mediators.

Studies have shown that inflammatory factors play an important role in peripheral insulin resistance, and the effect of nuclear factor kappa B NF-κB on alpha cells in a model of insulin resistance in rat islet alpha cells induced by high-fat feeding mediates activation of the inflammatory pathway.

Ellingsgaard et al found that IL-7 receptors were expressed on islet α cells compared with other tissues. IL6 induced the expression and secretion of glucagon in rats with high-fat diet.

After using the IL6 receptor gene knockout model, the body's metabolic disorder was corrected. The use of thiazolidinediones TZD drugs can not only improve peripheral insulin resistance in SD rats induced by high-fat feeding, but also inhibit the proliferation of α cells, and and significantly increase glucagon levels and α-cell glucagon mRNA expression.

This effect is achieved by the binding of TZDs to the peroxisome proliferator-activated receptor on islet alpha cells, which directly inhibits glucagon gene transcription. In recent years, there are many studies on the treatment of diabetes with incretin hormone, which is represented by glucagon like peptide1 GLP1 and its analogs.

GLP1 is a 30 amino acid peptide hormone secreted mainly by L cells of the distal ileum, rectum and colon. It not only acts on glucose-dependent β-cells, but also promotes insulin secretion.

It also acts on islet α cells. Inhibition of glucagon secretion can improve alpha cell insulin resistance. Prohormone converting enzyme 2 PC2 gene knockout: proglucagon is a precursor of glucagon, which produces different products through different prohormone convertases in different tissue organs.

Study have showed that PC2 knockout mice have a significant decrease in blood glucagon, mild persistent hypoglycemia, and modern compensatory islet alpha cell proliferation, when using a micro-osmotic pump or intraperitoneal small dose. After glucagon injection, blood glucose returned to normal; and after a long period of application, the morphology of islet α cells recovered to resemble that of wild-type mice.

Glucagon neutralizing antibodies: this method uses exogenous glucagon antibodies to bind to glucagon in the body, thereby blocking the effects of endogenous glucagon and ultimately lowering blood sugar. The brand is equivalent to an experiment conducted in using a high-capacity, high-affinity glucagon monoclonal antibody Glu-mAb in a normal, alloxan ALX -induced mild and severe diabetic rabbit model.

Tip: this antibody can completely block exogenous glucagon-induced hyperglycemia in normal animals; in low-glycemic zoos, lowering blood sugar is also obvious; in high-glycemic type 1 diabetic rabbits, Glu-mAb can still significantly reduce liver glucose output, reducing the fasting blood glucose of experimental rabbits from The use of glucagon antibodies to reduce the effects of glucagon can better control the effects of type 2 diabetes.

Barbato et al. found that the glycine-serine polymorphism Gly40Ser of the glucagon receptor gene exon 2 in French Caucasians is closely related to type 2 diabetes. The research focused on glucagon receptor blockers, glucagon receptor gene expression inhibitors, and glucagon receptor gene knockout.

Receptor blockers: the mechanism of action of glucagon receptor blockers is mainly through competitive binding to endogenous glucagon, thereby inhibiting glucagon-mediated adenylate cyclase activity, reducing glycogen output, reducing fasting blood glucose levels, and improving glucose tolerance.

The receptor blocker is classified into a peptide compound and a non-peptide small molecule compound according to the molecular structure. Petersen et al. found that a non-peptide small molecule compound, Bay 27 , effectively blocks the increase in glucose production and blood glucose caused by exogenous glucagon in healthy adult males.

This is also the only drug that has been used in humans for glucagon receptor antagonists. Although more clinical trials are needed to prove efficacy, it is undoubtedly an increase in the search for effective human glucagon receptor antagonists.

The above studies have shown that both glucagon receptor antagonists, whether peptide or non-peptide, block the liver glucagon receptor and exert a hypoglycemic effect. Receptor gene expression inhibitors: the principle of action of these drugs is to block the expression of glucagon target receptor gene and reduce the expression of glucagon receptor mRNA, thereby achieving the role of treating diabetes.

Sloop and other antisense oligonucleotides ASO blocking glucagon receptors were used to treat type 2 diabetic animals. Mol Ther —8. Wideman RD, Covey SD, Webb GC, Drucker DJ, Kieffer TJ.

Galvin SG, Kay RG, Foreman R, Larraufie P, Meek CL, Biggs E, et al. The Human and Mouse Islet Peptidome: Effects of Obesity and Type 2 Diabetes, and Assessment of Intraislet Production of Glucagon-Like Peptide J Proteome Res x:acs.

Runge S, Wulff BS, Madsen K, Bräuner-Osborne H, Knudsen LB. Different Domains of the Glucagon and Glucagon-Like Peptide-1 Receptors Provide the Critical Determinants of Ligand Selectivity.

Br J Pharmacol — Salehi A, Vieira E, Gylfe E. Paradoxical Stimulation of Glucagon Secretion by High Glucose Concentrations.

Gylfe E. Ups J Med Sci — Whalley NM, Pritchard LE, Smith DM. White a. Processing of Proglucagon to GLP-1 in Pancreatic α-Cells: Is This a Paracrine Mechanism Enabling GLP-1 to Act on β-Cells? Asadi F, Dhanvantari S. Plasticity in the Glucagon Interactome Reveals Novel Proteins That Regulate Glucagon Secretion in α-TC Cells.

Front Endocrinol Lausanne Omar-Hmeadi M, Lund PE, Gandasi NR, Tengholm A, Barg S. Paracrine Control of α-Cell Glucagon Exocytosis is Compromised in Human Type-2 Diabetes. Nat Commun — Le Marchand SJ, Piston DW. Glucose Suppression of Glucagon Secretion: Metabolic and Calcium Responses From Alpha-Cells in Intact Mouse Pancreatic Islets.

Quoix N, Cheng-xue R, Mattart L, Zeinoun Z, Guiot Y, Beauvois M, et al. Ramracheya R, Ward C, Shigeto M, Walker JN, Amisten S, Zhang Q, et al. Membrane Potential-Dependent Inactivation of Voltage-Gated Ion Channels in α-Cells Inhibits Glucagon Secretion From Human Islets.

Zhang Q, Ramracheya R, Lahmann C, Tarasov A, Bengtsson M, Braha O, et al. Role of KATP Channels in Glucose-Regulated Glucagon Secretion and Impaired Counterregulation in Type 2 Diabetes.

Zhang Q, Dou H, Rorsman P. J Physiol — Liu Y-J, Vieira E, Gylfe E. A Store-Operated Mechanism Determines the Activity of the Electrically Excitable Glucagon-Secreting Pancreatic α-Cell.

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A service of the National Library of Medicine, National Institutes of Health. Feingold KR, Anawalt B, Blackman MR, et al. Endotext [Internet]. South Dartmouth MA : MDText. com, Inc. Iben Rix , Christina Nexøe-Larsen , Natasha C Bergmann , Asger Lund , and Filip K Knop. Glucagon is a peptide hormone secreted from the alpha cells of the pancreatic islets of Langerhans.

Hypoglycemia is physiologically the most potent secretory stimulus and the best known action of glucagon is to stimulate glucose production in the liver and thereby to maintain adequate plasma glucose concentrations.

However, glucagon is also involved in hepatic lipid and amino acid metabolism and may increase resting energy expenditure. Based on satiety-inducing and food intake-lowering effects of exogenous glucagon, a role for glucagon in the regulation of appetite has also been proposed.

This chapter provides an overview of the structure, secretion, degradation and elimination of glucagon, and reviews the actions of glucagon including its role in glucose metabolism and its effects on lipolysis, ketogenesis, energy expenditure, appetite and food intake.

Finally, the role of glucagon in the pathophysiology of diabetes, obesity and hepatic steatosis is discussed and emerging glucagon-based therapies for these conditions are outlined. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.

Glucagon secreted from pancreatic alpha cells in the islet of Langerhans plays an important role in maintaining glucose homeostasis by stimulating hepatic glucose production 1. Thus, in contrast to the glucose-depositing nature of insulin action, glucagon acts as a glucose-mobilizing hormone.

In line with these opposed actions, high plasma glucose concentrations stimulating insulin secretion from pancreatic beta cells, inhibit glucagon secretion whereas low plasma glucose concentrations represent one of the most potent glucagon secretory stimuli.

Accordingly, normal plasma glucose concentrations depend largely on the balanced secretion of insulin and glucagon from the pancreatic beta cells and alpha cells, respectively.

In the s glucagon was purified and crystallized at Eli Lilly and Co. This led to the development of medical use of glucagon for the treatment of severe insulin-induced hypoglycemia 4 , 5.

The development of a radioimmunoassay for the detection of glucagon in spurred further investigations of glucagon physiology and its role in health and disease 6. Since then it has become evident that glucagon not only acts by increasing hepatic glucose production but affects overall energy homeostasis in times of limited energy supply by stimulating lipid and protein catabolism, reducing appetite and food intake and increasing energy expenditure.

Glucagon is a amino acid peptide hormone predominantly secreted from the alpha cells of the pancreas. It is derived from the precursor proglucagon which can be processed into a number of related peptide hormones Fig.

Proglucagon is expressed in pancreatic islet alpha cells, intestinal enteroendocrine L cells, and to a minor extent in neurons in the brain stem and hypothalamus 8 , 9. In the pancreas, PC2 processes proglucagon to glucagon while processing of proglucagon in the intestine and the brain is undertaken by PC1 leading to the formation of glucagon-like peptide 1 GLP-1 and glucagon-like peptide 2 GLP-2 9.

Tissue specific processing of proglucagon. In the pancreas proglucagon is processed into glucagon, glicentin-related pancreatic polypeptide GRPP , intervening peptide 1 IP1 , and major proglucagon fragment MPGF by the processing enzyme prohormone convertase 2 PC2.

Glucagon is secreted in response to hypoglycemia, prolonged fasting, exercise and protein-rich meals Glucagon release is regulated through endocrine and paracrine pathways; by nutritional substances; and by the autonomic nervous system Glucagon secretion occurs as exocytosis of stored peptide vesicles initiated by secretory stimuli of the alpha cell.

Stimulatory regulators of glucagon release include hypoglycemia, amino acids and the gut hormone glucose-dependent insulinotropic peptide GIP , whereas hyperglycemia and GLP-1 inhibit glucagon release. Additionally, glucagon release is inhibited in a paracrine fashion by factors like somatostatin, insulin, zinc and possibly amylin.

Glucagon may regulate its own secretion indirectly via stimulatory effect on beta cells to secrete insulin 12 , In contrast to glucose, non-glucose regulators of glucagon secretion seem to mediate their action through changes in cAMP levels rather than through the calcium-dependent pathway outlined below 14 , The most potent regulator of glucagon secretion is circulating glucose.

Hypoglycemia stimulates the pancreatic alpha cell to release glucagon and hyperglycemia inhibits glucagon secretion Fig. The cellular mechanism behind this glucose-dependent regulation of glucagon secretion involves uptake of glucose by the glucose transporter 1 GLUT1 in the cell membrane of pancreatic alpha cells and subsequent glycolysis which ultimately generates adenosine triphosphate ATP in the mitochondria of the alpha cell.

Thus, the intracellular ATP level in the alpha cell reflects plasma glucose levels. Conversely, increasing circulating glucose levels increase glucose influx to the alpha cell generating an increase in intracellular ATP concentration, which opens K ATP -channels.

Glucose-dependent glucagon secretion from the alpha cell. During hypoglycemia intracellular glucose concentration falls with a subsequent reduction in glycolysis-generated adenosine triphosphate ATP in the mitochondria of the cell.

depolarization of the cell membrane. In normal physiology, circulating glucagon concentrations are in the picomolar range. Basal glucagon secretion balances the effect of basal insulin secretion resulting in a steady-state between glucose uptake and endogenous glucose production in the fasted state; i.

stable blood glucose concentrations. During exercise or in case of hypoglycemia, circulating glucagon levels may increase dramatically to times basal levels increasing the glucagon to insulin ratio 12 , 19 , 20 Fig.

The effects of glucagon are mediated through binding to and activation of the glucagon receptor. The glucagon receptor is a seven transmembrane G protein-coupled receptor Fig.

The main mode of intracellular signaling involves activation of G s and G q. G s activation stimulates adenylyl cyclase which produces cyclic adenosine monophosphate cAMP that activates protein kinase A PKA. The activated PKA migrates to the nucleus and activates transcription factors like cAMP response element-binding protein CREB through phosphorylation.

This enables CREB to bind to response elements of target genes resulting in the recruitment of coactivators and ultimately promoting gene expression. Activation of G q by glucagon leads to activation of phospholipase C PLC and subsequent increase in inositol 1,4,5-triphosphate IP 3 , which signals to enhance release of calcium from the endoplasmic reticulum.

This, in turn, activates downstream signaling cascades including CREB-regulated transcription co-activator CRTC2 which enhance CREB-dependent gene expression. In addition to the CREB-CRTC2 pathway, glucagon may signal through various other pathways reviewed in detail elsewhere 1 , 12 , Examples of the two most well-described intracellular pathways involved in glucagon-induced regulation of target gene expression: the PKA and the IP 3 pathways.

AC, adenylyl cyclase; CRTC2, CREB-regulated transcription co-activator; CREB, cAMP response element-binding protein; IP 3 , inositol 1,4,5-triphosphate; PIP 2 , phosphatidyl-inositol-4,5-bisphosphate; PKA, protein kinase A; PLC, phospholipase C.

The degradation of glucagon is mainly facilitated by receptor-mediated endocytosis and proteolysis by the ubiquitous enzyme dipeptidyl peptidase 4 22 , Consistent with the relative receptor expression, the liver and kidneys seem to represent the two main organs removing glucagon from the circulation.

The circulating half-life of glucagon in plasma is reported to be between four to seven minutes in humans 24 , Glucagon controls plasma glucose concentrations during fasting, exercise and hypoglycemia by increasing hepatic glucose output to the circulation.

Specifically, glucagon promotes hepatic conversion of glycogen to glucose glycogenolysis , stimulates de novo glucose synthesis gluconeogenesis , and inhibits glucose breakdown glycolysis and glycogen formation glycogenesis Fig. Hepatic glucose production is rapidly enhanced in response to a physiological rise in glucagon; achieved through stimulation of glycogenolysis with minor acute changes in gluconeogenesis 27 , This ability of glucagon is critical in the life-saving counterregulatory response to severe hypoglycemia.

Additionally, it is a key factor in providing adequate circulating glucose for brain function and for working muscle during exercise During prolonged fasting, glycogen stores are depleted, and gluconeogenesis takes over The hyperglycemic property of glucagon is enhanced when hepatic glycogen levels are high and diminished when hepatic glycogen levels are low in conditions of fasting or liver diseases like cirrhosis Regulation of glucose metabolism by glucagon in the liver.

Glucagon increases hepatic glucose production by stimulating glycogenolysis and glycogenogenesis green arrows while inhibiting glycolysis and glycogenesis red arrows.

Glucagon promotes formation of non-carbohydrate energy sources in the form of lipids and ketone bodies. Thereby, glucagon contributes to a stable energy homeostasis during conditions where energy supply is limited fasting or in states of increased energy demand e.

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 ,