Holst, jjholst sund. Longuet, C. Gulcagon Glucagon pathway within the pancreatic islet determine Natural anticancer remedies glycemic set point. G protein-coupled receptors. Dalla Man, C. The glucagon signaling pathway activates hepatocyte phosphorylase and accelerates glycogenolysis through the cAMP-PK system.

Glucagon pathway -

The α-helical structure of the stalk interacts directly with glucagon, as it extends nearly three helical turns above the membrane. When the alpha helix of the stalk is disrupted, the affinity of glucagon for GCGR decreases with an to proline substitution having significantly lower affinity for glucagon.

The disulfide bond between serves to hold the helices in the proper orientation for binding and stabilizes the open conformation. Additionally, the salt bridges between hold the open conformation together for higher affinity.

Mutagenesis and photo cross-linking studies determined essential, conserved residues in glucagon and have been in red. The n-terminus of glucagon Figure 5 leads to a protuberance that fits into the deep, interior cavity of the GCGR 7TMD Figure 3 where four residues reside that play strong roles in ligand binding affinity.

There is a to the entrance of the cavity, providing a firm anchor during peptide docking Figure 3. Glucagon binds to the open conformation of GCGR on the plasma membrane. Glucagon binding to GCGR induces a conformational change in GCGR. This conformation change induces the active state of the protein Figure 2.

The active state of the protein exchanges a guanosine diphosphate GDP for guanosine triphosphate GTP that is bound to the alpha subunit. With the GTP in place, the activated alpha subunit dissociates from the heterotrimeric G protein's beta and gamma subunits.

Following dissociation, the alpha subunit can activate adenylate cyclase. Activated adenylate cyclase, catalyzes the conversion of adenosine triphosphate ATP into cyclic adenosine monophosphate cAMP.

cAMP then serves as a secondary messenger to activate, through allosteric binding, cAMP dependent protein kinase A PKA. PKA activates via phosphorylation the phosphorylase b kinase. The phosphorylase b kinase phosphorylates glycogen phosphorylase b to convert to the active form, phosphorylase a.

Phosphorylase a finally catalyzes the release of glucosephosphate into the bloodstream from glycogen polymers Figure 6. Because GCGR can interact with multiple types of G protein subfamilies, discovering small molecule inhibitors could lead to a wide range of focused therapies.

For example, GCGR interacts with inhibitory Gαi proteins that antagonize cAMP production. Current attempts to target the GCGR have however been relatively unsuccessful. Small molecule modulators have been reported with enhanced pharmaceutical regulation, but the progress has been modest.

PSI Structural Biology Database. G protein-coupled receptors. Entry hsa Pathway. Homo sapiens human [GN: hsa ]. PDE3B; phosphodiesterase 3B [KO: K ] [EC: 3. ADCY2; adenylate cyclase 2 [KO: K ] [EC: 4.

PRKACA; protein kinase cAMP-activated catalytic subunit alpha [KO: K ] [EC: 2. PRKACB; protein kinase cAMP-activated catalytic subunit beta [KO: K ] [EC: 2. PRKACG; protein kinase cAMP-activated catalytic subunit gamma [KO: K ] [EC: 2. CREB3L1; cAMP responsive element binding protein 3 like 1 [KO: K ].

CREB3L2; cAMP responsive element binding protein 3 like 2 [KO: K ]. 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. 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. Stanley S, Moheet A, Seaquist ER.

Central Mechanisms of Glucose Sensing and Counterregulation in Defense of Hypoglycemia. Endocr Rev — doi: PubMed Abstract CrossRef Full Text Google Scholar.

DCCT Research Group. Hypoglycemia in the Diabetes Control and Complications Trial. Diabetes — Unger R, Orci L. The Essential Role of Glucagon in the Pathogenesis of Diabetes Mellitus.

Lancet —6. Unger RH, Cherrington AD. Glucagonocentric Restructuring of Diabetes: A Pathophysiologic and Therapeutic Makeover. J Clin Invest — Lee Y, Wang M-Y, Du XQ, Charron MJ, Unger RH. Glucagon Receptor Knockout Prevents Insulin-Deficient Type 1 Diabetes in Mice.

Diabetes —7. Conarello SL, Jiang G, Mu J, Li Z, Woods J, Zycband E, et al. Glucagon Receptor Knockout Mice are Resistant to Diet-Induced Obesity and Streptozotocin-Mediated Beta Cell Loss and Hyperglycaemia. Diabetologia — Neumann UH, Ho JSS, Mojibian M, Covey SD, Charron MJ, Kieffer TJ.

Glucagon Receptor Gene Deletion in Insulin Knockout Mice Modestly Reduces Blood Glucose and Ketones But Does Not Promote Survival. Mol Metab —6. Damond N, Thorel F, Moyers JS, Charron MJ, Vuguin PM, Powers AC, et al.

Blockade of Glucagon Signaling Prevents or Reverses Diabetes Onset Only If Residual β-Cells Persist. Elife — CrossRef Full Text Google Scholar. Kazda CM, Ding Y, Kelly RP, Garhyan P, Shi C, Lim CN, et al. Evaluation of Efficacy and Safety of the Glucagon Receptor Antagonist LY in Patients With Type 2 Diabetes: and Week Phase 2 Studies.

Diabetes Care —9. Yang B, Gelfanov VM, Perez-Tilve D, DuBois B, Rohlfs R, Levy J, et al. Optimization of Truncated Glucagon Peptides to Achieve Selective, High Potency, Full Antagonists. J Med Chem — Lee CY, Choi H, Park EY, Nguyen TTL, Maeng HJ, Mee Lee K, et al. Synthesis and Anti-Diabetic Activity of Novel Biphenylsulfonamides as Glucagon Receptor Antagonists.

Chem Biol Drug Des — Okamoto H, Cavino K, Na E, Krumm E, Kim SY, Cheng X, et al. Glucagon Receptor Inhibition Normalizes Blood Glucose in Severe Insulin-Resistant Mice.

Proc Natl Acad Sci —8. Liang Y, Osborne MC, Monia BP, Bhanot S, Gaarde WA, Reed C, et al. Kim J, Okamoto H, Huang ZJ, Anguiano G, Chen S, Liu Q, et al. Amino Acid Transporter Slc38a5 Controls Glucagon Receptor Inhibition-Induced Pancreatic α Cell Hyperplasia in Mice.

Cell Metab — Wei R, Gu L, Yang J, Yang K, Liu J, Le Y, et al. Antagonistic Glucagon Receptor Antibody Promotes α-Cell Proliferation and Increases β-Cell Mass in Diabetic Mice.

iScience — Galsgaard KD, Winther-Sørensen M, Ørskov C, Kissow H, Poulsen SS, Vilstrup H, et al. Disruption of Glucagon Receptor Signaling Causes Hyperaminoacidemia Exposing a Possible Liver-Alpha-Cell Axis. Am J Physiol Metab E93—E Wewer Albrechtsen NJ, Pedersen J, Galsgaard KD, Winther-Sørensen M, Suppli MP, Janah L, et al.

The Liver—α-Cell Axis and Type 2 Diabetes. Guan H-P, Yang X, Lu K, Wang S-P, Castro-Perez JM, Previs S, et al. Glucagon Receptor Antagonism Induces Increased Cholesterol Absorption. J Lipid Res — Tooze S. Biogenesis of Secretory Granules in the Trans-Golgi Network of Neuroendocrine and Endocrine Cells.

Biochim Biophys Acta — Cool DR, Fenger M, Snell CR, Loh YP. Identification of the Sorting Signal Motif Within Pro-Opiomelanocortin for the Regulated Secretory Pathway.

J Biol Chem —9. Dhanvantari S, Shen F, Adams T, Snell CR, Zhang C, Mackin RB, et al. Disruption of a Receptor-Mediated Mechanism for Intracellular Sorting of Proinsulin in Familial Hyperproinsulinemia.

Mol Endocrinol — Zhang C-F, Dhanvantari S, Lou H, Loh YP. Sorting of Carboxypeptidase E to the Regulated Secretory Pathway Requires Interaction of its Transmembrane Domain With Lipid Rafts. Biochem J — Dikeakos JD, Mercure C, Lacombe M-J, Seidah NG, Reudelhuber TL. FEBS J — Dikeakos JD, Di Lello P, Lacombe M-J, Ghirlando R, Legault P, Reudelhuber TL, et al.

Proc Natl Acad Sci USA — Dhanvantari S, Loh YP. Lipid Raft Association of Carboxypeptidase E Is Necessary for Its Function as a Regulated Secretory Pathway Sorting Receptor. J Biol Chem — Cool DR, Normant E, Shen F, Chen H, Pannell L, Zhang Y, et al.

Carboxypeptidase E Is a Regulated Secretory Pathway Sorting Receptor: Genetic Obliteration Leads to Endocrine Disorders in Cpe Fat Mice. Cell — Irminger JC, Verchere CB, Meyer K, Halban PA. J Biol Chem —4. McGirr R, Guizzetti L, Dhanvantari S. The Sorting of Proglucagon to Secretory Granules is Mediated by Carboxypeptidase E and Intrinsic Sorting Signals.

J Endocrinol — Hosaka M, Watanabe T, Sakai Y, Kato T, Takeuchi T. Interaction Between Secretogranin III and Carboxypeptidase E Facilitates Prohormone Sorting Within Secretory Granules. J Cell Sci — Plá V, Paco S, Ghezali G, Ciria V, Pozas E, Ferrer I, et al. Brain Pathol — Arvan P, Halban PA.

Sorting Ourselves Out: Seeking Consensus on Trafficking in the Beta-Cell. Traffic — Guizzetti L, McGirr R, Dhanvantari S. Two Dipolar α-Helices Within Hormone-Encoding Regions of Proglucagon are Sorting Signals to the Regulated Secretory Pathway.

Dey A, Lipkind GM, Rouillé Y, Norrbom C, Stein J, Zhang C, et al. Significance of Prohormone Convertase 2, PC2, Mediated Initial Cleavage at the Proglucagon Interdomain Site, LysArg71, to Generate Glucagon.

Endocrinology — Rouille Y, Westermark G, Martin SK, Steiner DF. Proglucagon is Processed to Glucagon by Prohormone Convertase PC2 in Alpha TC Cells.

Proc Natl Acad Sci —6. Dhanvantari S, Seidah NG, Brubaker PL. Role of Prohormone Convertases in the Tissue-Specific Processing of Proglucagon. Furuta M, Zhou A, Webb G, Carroll R, Ravazzola M, Orci L, et al. Severe Defect in Proglucagon Processing in Islet Alpha-Cells of Prohormone Convertase 2 Null Mice.

Campbell SA, Golec DP, Hubert M, Johnson J, Salamon N, Barr A, et al. Human Islets Contain a Subpopulation of Glucagon-Like Peptide-1 Secreting α Cells That is Increased in Type 2 Diabetes. Mol Metab Nie Y, Nakashima M, Brubaker PL, Li QL, Perfetti R, Jansen E, et al.

Regulation of Pancreatic PC1 and PC2 Associated With Increased Glucagon-Like Peptide 1 in Diabetic Rats. McGirr R, Ejbick CE, Carter DE, Andrews JD, Nie Y, Friedman TC, et al. Glucose Dependence of the Regulated Secretory Pathway in αtc Cells.

Liu P, Song J, Liu H, Yan F, He T, Wang L, et al. Insulin Regulates Glucagon-Like Peptide-1 Secretion by Pancreatic Alpha Cells. Endocrine — Ellingsgaard H, Hauselmann I, Schuler B, Habib AM, Baggio LL, Meier DT, et al. Interleukin-6 Enhances Insulin Secretion by Increasing Glucagon-Like Peptide-1 Secretion From L Cells and Alpha Cells.

Nat Med —9. Progressive Change of Intra-Islet GLP-1 Production During Diabetes Development. Diabetes Metab Res Rev —8. Kilimnik G, Kim A, Steiner DF, Friedman TC, Hara M.

Islets — Wideman RD, Gray SL, Covey SD, Webb GC, Kieffer TJ. 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.

Cell Calcium — Tian G, Tepikin AV, Tengholm A, Gylfe E. Watts M, Sherman A. Modeling the Pancreatic α-Cell: Dual Mechanisms of Glucose Suppression of Glucagon Secretion.

Biophys J — PloS One 7:e Elliott AD, Ustione A, Piston DW. Somatostatin and Insulin Mediate Glucose-Inhibited Glucagon Secretion in the Pancreatic α-Cell by Lowering cAMP. Am J Physiol Endocrinol Metab E— Yu Q, Shuai H, Ahooghalandari P, Gylfe E, Tengholm A.

Glucose Controls Glucagon Secretion by Directly Modulating cAMP in Alpha Cells. Hughes JW, Ustione A, Lavagnino Z, Piston DW.

Regulation of Islet Glucagon Secretion: Beyond Calcium. Diabetes Obes Metab — Leclerc I, Sun G, Morris C, Fernandez-Millan E, Nyirenda M, Rutter GA. AMP-Activated Protein Kinase Regulates Glucagon Secretion From Mouse Pancreatic Alpha Cells.

Da Silva Xavier G, Farhan H, Kim H, Caxaria S, Johnson P, Hughes S, et al. Per-Arnt-Sim PAS Domain-Containing Protein Kinase is Downregulated in Human Islets in Type 2 Diabetes and Regulates Glucagon Secretion. Sun G, da Silva Xavier G, Gorman T, Priest C, Solomou A, Hodson DJ, et al.

LKB1 and Ampkα1 are Required in Pancreatic Alpha Cells for the Normal Regulation of Glucagon Secretion and Responses to Hypoglycemia.

Mol Metab — Bozadjieva N, Blandino-Rosano M, Chase J, Dai XQ, Cummings K, Gimeno J, et al.

Alejandro CaicedoPathwxy Quality products selection. HealingJürgen Glucavon An Intraislet Paracrine Pathhway Pathway That Natural anticancer remedies Glucagon to Pathwya Pancreatic β-Cells. Diabetes 1 December ; 72 12 : — Quality products selection of Glhcagon shared apthway in islet biology, we Glucagon pathway read the article by Weir and Bonner-Weir 1 in this issue of Diabetes with great interest. Recent in vitro and in vivo studies strongly suggest the existence of an intraislet paracrine signaling pathway through which glucagon released from α-cells can stimulate the activity of pancreatic β-cells 23. Their skepticism is primarily based on the contention that blood flow in rodent islets is directed from the islet core, which is densely populated by β-cells, to the islet mantle, where α- and δ-cells are preferentially localized. Patients Gluxagon Quality products selection pathwag Quality products selection hyperglucagonemia, or excess glucagon paathway, which may Quality products selection the pathwy cause of the hyperglycemia of diabetes. Defective alpha Quality products selection secretory responses to glucose and paracrine effectors in pathwwy Type Natural anticancer remedies and Low-glycemic sweeteners 2 Gluczgon Glucagon pathway drive the development of hyperglucagonemia. Pathwqy, uncovering the mechanisms that regulate glucagon secretion from Tennis diet plan pancreatic alpha cell is critical for developing improved treatments for diabetes. In this review, we focus on aspects of alpha cell biology for possible mechanisms for alpha cell dysfunction in diabetes: proglucagon processing, intrinsic and paracrine control of glucagon secretion, secretory granule dynamics, and alterations in intracellular trafficking. We explore possible clues gleaned from these studies in how inhibition of glucagon secretion can be targeted as a treatment for diabetes mellitus. Glucagon is a amino acid peptide hormone produced by the alpha α cells of the pancreatic islet. It is known as the primary glucose counter-regulatory hormone, as its main physiological function is to maintain euglycemia by its actions on the liver to promote glycogenolysis and gluconeogenesis.