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You must accept the terms and conditions. Read the terms and conditions. Thr phosphorylation occurs in a PDK1-dependent manner and is essential for AKT kinase activity. Ser is phosphorylated by the rapamycin-insensitive mTOR complex mTORC2 and is permissive for full kinase activity Importantly, the mechanisms of mTORC2 regulation remain uncertain.

AKT activation leads to subsequent phosphorylation of forkhead box—containing protein, O subfamily FOXO. FOXO proteins especially members 1 and 6 are transcription factors that induce GNG. AKT-dependent phosphorylation triggers nuclear exclusion and, thus, is inhibitory to this action Overview of INSR signaling pathways in the regulation of hepatic glucose homeostasis.

MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol 3-kinase; PLCγ, phospholipase Cγ. INSR activation stimulates phospholipase Cγ, generating inositol-1,4,5-triphosphate InsP 3.

Diabetes, whether type 1 T1D or type 2 T2D , is defined by hyperglycemia and is ultimately the result of insufficient insulin action. In the case of T1D, this deficiency is caused by destruction of the pancreatic β-cell and therefore a lack of the insulin hormone. In T2D, insulin resistance accumulates to a point where β-cell compensatory hypersecretion is insufficient to counteract the resistance In the liver, this insufficiency is manifested as a failure to suppress hepatic glucose output i.

Intriguingly, in T2D this resistance is often incomplete, resulting in a preservation of insulin-stimulated lipogenesis Consistent with its counterregulatory role, both fasting and postprandial plasma glucagon levels are elevated in diabetes However, these observations have been made in individuals with established cases of diabetes, and thus the causality of hyperglucagonemia is difficult to assign.

As a counterregulatory hormone with a role in maintaining fasting blood glucose, it is tempting to assume that glucagon opposes all actions of insulin. Consistent with this hypothesis, circulating glucagon levels are elevated in all known instances of T1D or T2D, including animal models of the disease Likewise, preclinical GCGR ablation or pharmacological GCGR inhibition including neutralizing antibodies against glucagon in individuals with diabetes is sufficient to reduce glycemia and HbA 1c.

However, many of these strategies have been slowed due to adverse effects on liver transaminases, liver fat, and dyslipidemia Conversely, the increased concentrations and action of glucagon in the fasting state are well suited to potentiate subsequent insulin-mediated glucose control.

To this point, glucagon acts in a paracrine manner to increase insulin secretion through activation of both β-cell GCGR and GLP-1R Likewise, postprandial elevations of glucagon and GLP-1 contribute to the improved postprandial glucose profile observed in Roux-en-Y gastric bypass patients and rodent models of this powerful intervention Importantly, these physiological conditions are all characterized by their heightened insulin sensitivity.

Regarding glucagon enhancement of insulin action, the use of the bionic pancreas glucagon and insulin must be mentioned This technology was hypothesized to prevent life-threatening hypoglycemic episodes in people with diabetes.

Beyond reducing hypoglycemic episodes, the bihormonal glucagon and insulin pump reduced average glycemia while requiring a similar total daily insulin dose in adolescents Likewise, h glucagon infusion increased both glucose appearance and disappearance in patients, suggesting that its regulation of human glucose metabolism is not restricted to increasing hepatic glucose output Together, these observations support the hypothesis that glucagon, released during fasting and the prandial response, acts to prime metabolic tissues for the subsequent nutrient challenge of feeding.

Moreover, it positions cooperative actions of glucagon and insulin as crucial to this physiology. INSR and GCGR signaling also converge at the hepatocyte.

This initial observation was followed by more detailed investigation of acute i. This work identified enhanced insulin-dependent signaling in the phosphorylation of AKT Ser in mice treated with IUB 60 min prior to insulin and was exclusive of PDK1-dependent phosphorylation Thr This single, acute IUB treatment increased insulin sensitivity, as defined by increased glucose infusion rate and improved insulin-stimulated suppression of hepatic glucose output during hyperinsulinemic-euglycemic clamps These observations suggest GCGR and INSR signaling intersect via a TORC2-dependent phosphorylation of AKT Ser Our observation was quickly followed by work by Besse-Patin et al.

This elegant study confirmed glucagon-enhanced AKT Ser phosphorylation and identified glucagon-dependent induction of Ppargc1a as a transcriptional regulator of relative levels of hepatocyte IRS1:IRS2 ratios This shift toward IRS2 favors insulin-dependent suppression of hepatic glucose output and is consistent with our observations in hyperinsulinemic-euglycemic clamps Congruous with our study and interpretation, Besse-Patin et al.

concluded that glucagon via PGCα primes the liver for subsequent insulin action. However, an importation caveat to these studies is that the observations of Besse-Patin et al. were made 4 h after glucagon treatment.

Subsequent observations in cultured hepatocytes suggest GCGR signaling transiently stimulates protein synthesis via an mTORC1-dependent action This effect was also observed to be convergent with insulin signaling and dependent on EPAC activity Additionally, work by Perry et al.

This work supported a role for inositol triphosphate receptor 1 INSP3R1 -mediated calcium signaling downstream of GCGR activation. In this model, the benefits of GCGR signaling on glucose metabolism are related to hepatic mitochondrial oxidation In summary, emerging data support a beneficial role for GCGR signaling in hepatic insulin glucose metabolism.

While the precise mechanisms have yet to be elucidated, data support roles for mTORC1, mTORC2, and PCG1a-IRS2 as potential points for cross talk with hepatic insulin signaling Fig.

INSP3R1 may also represent a mechanism by which hepatic GCGR signaling benefits glucose metabolism secondary to its regulation of mitochondrial oxidation.

Potential and reported cross talk in hepatic glucagon GCG and INSR signaling. PI3K, phosphatidylinositol 3-kinase. Of note, treating mice with the INSR antagonist S induces severe insulin resistance, hyperglycemia, and ketonemia, yet the GCGR-blocking antibody REGN was sufficient to normalize blood glucose and β-hydroxybutyrate levels in these mice Subsequent clinical investigation uncovered reductions in fasting plasma glucose and HbA 1c in REGNtreated T2D patients Similar benefits in mice have been reported for the monoclonal antibody and competitive GCGR antagonist REMD 2.

Moreover, GCGR antagonism, when combined with GLP-1R agonism, stimulates cell regeneration in STZ-treated mice However, enthusiasm for GCGR antagonism is offset by observations of dose-dependent increases in hepatic aminotransferases and induction of profound dyslipidemia Conversely, the benefits of GCGR agonism on energy expenditure, hepatic steatosis, and lipid homeostasis are of great therapeutic interest.

Intriguingly, coupling of the antidiabetic properties of GLP-1R agonism with GCGR agonism profoundly enhances the therapeutic action of both receptors 17 , 18 , The mechanisms underlying these benefits are still the focus of intense investigation.

This weight loss is likely due to GCGR stimulation of energy expenditure and GLP-1R inhibition of gastric emptying , the latter also contributing to slower glucose uptake into the circulation. It is also likely that these compounds increase glucose-stimulated insulin secretion via activation of GCGR and GLP-1R at the β-cell while concomitantly enhancing insulin action via GCGR agonism at the liver.

Based on this hypothesis, coupling GCGR agonism with other known insulin secretagogues should have similar effects. This hypothesis is supported by the observation in mice that tolbutamide enhanced glucagon-stimulated decreases in glycemia In summary, the glucagon peptide was discovered a century ago, yet our understanding of its metabolic actions is still evolving.

The original view that GCGR signaling is antagonistic to insulin action is certainly true in some contexts yet is clearly incomplete.

Studies currently underway will continue to refine the role of this long-known hormone and its therapeutic utility in metabolic diseases. See accompanying articles, pp. I thank Dr. Teayoun Kim, Dr. Shelly Nason, and Jessica Antipenko Comprehensive Diabetes Center and Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL for helpful discussion.

The project described in this work was supported by National Institutes of Health grant 1R01DK K. Duality of Interest. No potential conflicts of interest relevant to this article were reported.

Prior Presentation. Parts of this work were presented at the 82nd Scientific Sessions of the American Diabetes Association, New Orleans, LA, 3—7 June Sign In or Create an Account.

Search Dropdown Menu. header search search input Search input auto suggest. filter your search All Content All Journals Diabetes. Advanced Search. User Tools Dropdown. Sign In. Skip Nav Destination Close navigation menu Article navigation. Volume 71, Issue 9. Previous Article Next Article.

The Discovery of Glucagon and Insulin. Glucagon Secretion. GCGR Tissue Distribution and Hepatic Signaling. Metabolic Actions of Hepatic GCGR Signaling. Insulin, Insulin Action, and Hepatic INSR Signaling.

Overlapping Hepatic GCGR and INSR Actions. GCGR and INSR Cross Talk in Emerging Therapeutics. Article Information. Article Navigation. Diabetes Symposium June 03 Cross Talk Between Insulin and Glucagon Receptor Signaling in the Hepatocyte Kirk M.

Habegger Corresponding author: Kirk M. Habegger, kirkhabegger uabmc. This Site. Google Scholar. Diabetes ;71 9 — Article history Received:. Get Permissions. toolbar search Search Dropdown Menu. toolbar search search input Search input auto suggest. Figure 1. Effects of glucagon on lipolysis and ketogenesis in normal and diabetic men.

Lindgren, O. Incretin hormone and insulin responses to oral versus intravenous lipid administration in humans. Livingston, J. Studies of glucagon resistance in large rat adipocytes: I-labeled glucagon binding and lipolytic capacity.

Longuet, C. The glucagon receptor is required for the adaptive metabolic response to fasting. Luyckx, A. Arguments for a regulation of pancreatic glucagon secretion by circulating plasma free fatty acids. Madison, L.

Effect on plasma free fatty acids on plasma glucagon and serum insulin concentrations. Metabolism 17, — Mandoe, M. The 2-monoacylglycerol moiety of dietary fat appears to be responsible for the fat-induced release of GLP-1 in humans.

Manganiello, V. Selective loss of adipose cell responsiveness to glucagon with growth in the rat. Mitchell, M. Growth-hormone release by glucagon. Lancet 1, — More, V. PLoS One e Mosinger, B.

Action of adipokinetic hormones on human adipose tissue in vitro. Müller, T. The new biology and pharmacology of glucagon. Niederwanger, A.

Postprandial lipemia induces pancreatic alpha cell dysfunction characteristic of type 2 diabetes: studies in healthy subjects, mouse pancreatic islets, and cultured pancreatic alpha cells. Olofsson, C. Palmitate stimulation of glucagon secretion in mouse pancreatic alpha-cells results from activation of L-type calcium channels and elevation of cytoplasmic calcium.

Parrilla, R. Effect of glucagon: insulin ratios on hepatic metabolism. Diabetes 23, — Paschoalini, M. Participation of the CNS in the control of FFA mobilization during fasting in rabbits. Patsouris, D. Peroxisome proliferator-activated receptor alpha mediates the effects of high-fat diet on hepatic gene expression.

Pegorier, J. Induction of ketogenesis and fatty acid oxidation by glucagon and cyclic AMP in cultured hepatocytes from rabbit fetuses. Evidence for a decreased sensitivity of carnitine palmitoyltransferase I to malonyl-CoA inhibition after glucagon or cyclic AMP treatment.

Peng, I. Penhos, J. Effect of glucagon on the metabolism of lipids and on urea formation by the perfused rat liver. Diabetes 15, — Perea, A. Physiological effect of glucagon in human isolated adipocytes. Perry, R. Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes.

Cell , — Pettus, J. Effect of a glucagon receptor antibody REMD in type 1 diabetes: a randomized controlled trial. Pocai, A. Diabetes 58, — Pozefsky, T. Metabolism of forearm tissues in man. Studies with glucagon.

Diabetes 25, — Pozza, G. Lipolytic effect of intra-arterial injection of glucagon in man. Prigge, W. Effects of glucagon, epinephrine and insulin on in vitro lipolysis of adipose tissue from mammals and birds.

B 39, 69— Prip-Buus, C. Evidence that the sensitivity of carnitine palmitoyltransferase I to inhibition by malonyl-CoA is an important site of regulation of hepatic fatty acid oxidation in the fetal and newborn rabbit.

Perinatal development and effects of pancreatic hormones in cultured rabbit hepatocytes. Raben, A. Diurnal metabolic profiles after 14 d of an ad libitum high-starch, high-sucrose, or high-fat diet in normal-weight never-obese and postobese women.

Radulescu, A. The effect on glucagon, glucagon-like peptide-1, total and acyl-ghrelin of dietary fats ingested with and without potato. Ramnanan, C. Physiologic action of glucagon on liver glucose metabolism. Richter, W. Human glucagon and vasoactive intestinal polypeptide VIP stimulate free fatty acid release from human adipose tissue in vitro.

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Rouille, Y. Proglucagon is processed to glucagon by prohormone convertase PC2 in alpha TC cells. Ryan, A. Effects of intraduodenal lipid and protein on gut motility and hormone release, glycemia, appetite, and energy intake in lean men. Sadry, S. Emerging combinatorial hormone therapies for the treatment of obesity and T2DM.

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PLoS One 6:e Zhou, J. Citation: Galsgaard KD, Pedersen J, Knop FK, Holst JJ and Wewer Albrechtsen NJ Glucagon Receptor Signaling and Lipid Metabolism.

Received: 21 October ; Accepted: 26 March ; Published: 24 April

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.

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Proteopedia is hosted by the ISPC at the Weizmann Institute of Science in Israel. Structure of the Class B Human Glucagon G Protein Coupled Receptor- PDB 4L6R Show: Asymmetric Unit Biological Assembly.

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Luyckx, A. Arguments for a regulation of pancreatic glucagon secretion by circulating plasma free fatty acids. Madison, L. Effect on plasma free fatty acids on plasma glucagon and serum insulin concentrations.

Metabolism 17, — Mandoe, M. The 2-monoacylglycerol moiety of dietary fat appears to be responsible for the fat-induced release of GLP-1 in humans. Manganiello, V. Selective loss of adipose cell responsiveness to glucagon with growth in the rat. Mitchell, M. Growth-hormone release by glucagon.

Lancet 1, — More, V. PLoS One e Mosinger, B. Action of adipokinetic hormones on human adipose tissue in vitro. Müller, T. The new biology and pharmacology of glucagon.

Niederwanger, A. Postprandial lipemia induces pancreatic alpha cell dysfunction characteristic of type 2 diabetes: studies in healthy subjects, mouse pancreatic islets, and cultured pancreatic alpha cells.

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

Parrilla, R. Effect of glucagon: insulin ratios on hepatic metabolism. Diabetes 23, — Paschoalini, M. Participation of the CNS in the control of FFA mobilization during fasting in rabbits.

Patsouris, D. Peroxisome proliferator-activated receptor alpha mediates the effects of high-fat diet on hepatic gene expression. Pegorier, J. Induction of ketogenesis and fatty acid oxidation by glucagon and cyclic AMP in cultured hepatocytes from rabbit fetuses.

Evidence for a decreased sensitivity of carnitine palmitoyltransferase I to malonyl-CoA inhibition after glucagon or cyclic AMP treatment. Peng, I. Penhos, J. Effect of glucagon on the metabolism of lipids and on urea formation by the perfused rat liver.

Diabetes 15, — Perea, A. Physiological effect of glucagon in human isolated adipocytes. Perry, R. Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes.

Cell , — Pettus, J. Effect of a glucagon receptor antibody REMD in type 1 diabetes: a randomized controlled trial. Pocai, A. Diabetes 58, — Pozefsky, T. Metabolism of forearm tissues in man.

Studies with glucagon. Diabetes 25, — Pozza, G. Lipolytic effect of intra-arterial injection of glucagon in man. Prigge, W. Effects of glucagon, epinephrine and insulin on in vitro lipolysis of adipose tissue from mammals and birds.

B 39, 69— Prip-Buus, C. Evidence that the sensitivity of carnitine palmitoyltransferase I to inhibition by malonyl-CoA is an important site of regulation of hepatic fatty acid oxidation in the fetal and newborn rabbit.

Perinatal development and effects of pancreatic hormones in cultured rabbit hepatocytes. Raben, A. Diurnal metabolic profiles after 14 d of an ad libitum high-starch, high-sucrose, or high-fat diet in normal-weight never-obese and postobese women.

Radulescu, A. The effect on glucagon, glucagon-like peptide-1, total and acyl-ghrelin of dietary fats ingested with and without potato.

Ramnanan, C. Physiologic action of glucagon on liver glucose metabolism. Richter, W. Human glucagon and vasoactive intestinal polypeptide VIP stimulate free fatty acid release from human adipose tissue in vitro. Peptides 10, — Rodbell, M. Metabolism of isolated fat cells. The similar inhibitory action of phospholipase C Clostridium perfringens alpha toxin and of insulin on lipolysis stimulated by lipolytic hormones and theophylline.

Rouille, Y. Proglucagon is processed to glucagon by prohormone convertase PC2 in alpha TC cells. Ryan, A. Effects of intraduodenal lipid and protein on gut motility and hormone release, glycemia, appetite, and energy intake in lean men.

Sadry, S. Emerging combinatorial hormone therapies for the treatment of obesity and T2DM. Samols, E. Promotion of insulin secretion by glucogen. Lancet 2, — Sanchez-Garrido, M.

Diabetologia 60, —