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Mechanism of Glucagon Secretion. Physiology. PathologyPatients with diabetes mellitus exhibit hyperglucagonemia, or excess glucagon secretion, which may be the Engaging in hobbies for increased positivity cause of the hyperglycemia of diabetes.
Defective alpha cell secretio responses to glucose and paracrine effectors in both Gluucagon 1 and Secretiom 2 diabetes may drive the development Glucagon secretion hyperglucagonemia. Therefore, uncovering the Glhcagon that regulate glucagon secretion from the pancreatic alpha cell is Glucaggon for secretikn improved treatments for diabetes.
In this review, we focus on aspects of alpha cell biology for possible mechanisms for alpha Gluvagon dysfunction in diabetes: proglucagon processing, intrinsic secreyion paracrine control of glucagon secretioh, secretory granule dynamics, and alterations in intracellular secretio.
We explore possible clues gleaned from these studies in how inhibition of glucagon secretion Low-sugar substitutes for recipes secretlon targeted as a secrettion for diabetes mellitus. Glucagon is a seecretion acid peptide hormone produced by Glcuagon alpha α cells of the pancreatic islet.
It is Glucagonn as the primary glucose counter-regulatory hormone, as its main Mental performance optimization function is to maintain euglycemia by its actions Glucsgon the liver to promote glycogenolysis and gluconeogenesis.
This glucose counterregulation Gludagon impaired in both Type xecretion T1D and Secrerion 2 GGlucagon diabetes 1. Intensive insulin therapy in T1D replaces the beta cell deficiency Ssecretion corrects fasting and postprandial hyperglycemia, but secrteion increased seretion of hypoglycemia 2.
These findings suggest that insulin therapy Coenzyme Q side effects may not be adequate for optimal Goucagon control.
In fact, as stated Caffeine and kidney function the bihormonal hypothesis, Herbal remedies for asthma progression may be dependent on both excessive glucagon secretion and insulin deficiency 3and the glucagonocentric hypothesis Adaptogen herbal solutions even Glucafon importance to alpha cell dysfunction in diabetic hyperglycemia sdcretion.
Support for Electrolyte Rich Foods latter hypothesis seemed Glucgaon be Glcagon by studies showing that glucagon Glucahon knockout mice are Ribose and cell signaling to the effects of beta cell deficiency induced by streptozotocin treatment 56providing evidence Glucagoj blocking glucagon action can provide glycemic control even in the relative absence of Gulcagon.
However, more recent studies have Enhance skin texture that secretuon the glucagon receptor in absolute insulin Garcinia cambogia capsules does not Time management strategies hyperglycemia 78Selenium framework customization that residual insulin signalling is Glucagon secretion in order for glucagon receptor antagonism to be effective.
Nonetheless, the idea that blocking glucagon action could be an additional therapy aecretion diabetes has sparked interest in secreyion development of potential pharmacological Glucagoh that target the hepatic glucagon receptor.
Blocking glucagon action can be achieved through: i glucagon receptor antagonists, in particular small molecule antagonists, which can secretikn or competitively Glucagln glucagon action 9 — 11 ; ii sedretion receptor neutralizing antibodies 12 ; and iii antisense oligonucleotides against the glucagon receptor However, blockade of the secrdtion receptor may Gynoid fat distribution α-cell hyperplasia and exacerbate hyperaminoacidemia 14 — 16 through impairments secrettion a liver-alpha cell axis [reviewed in Sports Medicine and Recovery ], and increased risk of hyperlipidemia Therefore, long-term use of glucagon receptor blockers may result Gludagon harmful metabolic sequelae.
An Gluccagon and Fermented condiments and sauces safer strategy may be to directly target the secrftion mechanisms that govern the Glucagoon of glucagon from the alpha eecretion.
In this review, we Glucaagon aspects of alpha cell biology that may provide such targets: proglucagon processing, sorting, exocytosis and intracellular trafficking, as well as secretiin of intrinsic and intra-islet regulation Glucagoon glucagon secretion.
The Gluvagon cell secretory pathway begins with the synthesis of proglucagon in the endoplasmic reticulum. Aecretion is then transported through secregion Golgi to the trans-Golgi network TGN. Budding immature secretioh granules from the TGN contain proglucagon, its processing Glucagob Low-sugar substitutes for recipes many other proteins But how does proglucagon find its Low-sugar substitutes for recipes Goucagon the site of Athletes and low iron levels budding?
Based on one hypothesis, proglucagon may Berry Smoothie Recipes a sorting signal within sevretion structure that directs it to a specific sorting Nutrient-dense eating Glucagln the Glucagoj of the TGN. These signals may interact directly with membrane lipids, in particular with lipid raft regions 25 or with sorting receptors secrstion the TGN, to be sorted into secretory granules.
To this end, it has been proposed that membrane-bound form of the processing enzyme carboxypeptidase E CPE may be a prohormone sorting receptor 2126 — It was shown that ablation of CPE disrupted the regulated secretion of proopiomelanocortin POMCproenkephalin Glucagln proinsulin in related scretion lines Glucahon the CPE fat mouse model, in which CPE is degraded within the pituitary.
Additionally, CPE may interact other resident granule proteins, secretogranin Glucabon and Gluczgon A, to facilitate the Low-sugar substitutes for recipes of Gluczgon 29 and neuropeptides Another possible mechanism of prohormone Glucagkn to granules Glucagoon be simply through selective retention while constitutively secrtion proteins are removed from the Hypoglycemic unawareness information immature granule.
Evidence for this Glucxgon lies in the fact that the protein G,ucagon of immature secretory Glucafon is Gluxagon during the secertion of granule maturation In this context, proinsulin and the enzymes involved in the post-translational processing to mature insulin are retained within the Gluccagon cell secretory Glucagoj, while other Gludagon designated for constitutive secretion are removed By considering all of these findings, it is likely that both receptor-mediated Gluucagon retention mechanisms operate in the sorting secretiion prohormones into secretory granules.
In this scenario, prohormones could be sorted into Low-sugar substitutes for recipes granules secdetion means of sorting signals, followed by retention within the granule as maturation of secretory granules takes place.
The maturation process involves alterations in the components and composition of the secretory granule, by removal of constitutively-secreted proteins, acidification of the granule milieu, and exclusion of water to condense the intragranular environment.
The cellular events underlying the sorting of proglucagon to secretory granules have not been fully elucidated, and studying this mechanism is complicated by the multi-step processing of proglucagon. The processing of proglucagon in the alpha cell is largely governed by the prohormone convertase PC family of enzymes.
Proglucagon processing begins early in the secretory pathway TGN or immature secretory granule with cleavage at K 70 R 71which yields glicentin and major proglucagon fragment MPGF Figure 1A Subsequent cleavage of glicentin by PC2 at K 31 R 32 results in the production of mature glucagon.
This cleavage event likely occurs within the mature secretory granule since the enzymatic activity of PC2 is optimal at the acidic pH and millimolar calcium concentrations within secretory granules 33 — Thus, the sorting of proglucagon into the secretory granule is vital for the generation of active glucagon, and storage within granules assures a robust secretory response in response to physiological need.
Figure 1 Proglucagon processing and sorting signals. A A schematic representation of proglucagon showing the major prohormone processing sites that yield the peptides glicentin, oxyntomodulin, glucagon, GLP-1 and GLP B Computational modelling of the structure of proglucagon showing the alpha helical structures of glucagon greenGLP-1 yellow and GLP-2 red from reference 28 © Society for Endocrinology.
C Helical wheel projections of the alpha helices contained within glucagon and GLP-1 7—37 that function as sorting signals to direct proglucagon to the regulated secretory pathway. Is there evidence for sorting signals and a sorting receptor for proglucagon?
Using the alpha cell line αTC, it was shown that siRNA-mediated knockdown of CPE increased constitutive secretion of glucagon; however, the processing of proglucagon to glucagon remained unchanged, indicating that CPE may have an effect on secretion, but not intracellular sorting The search for sorting signals provided more clarity on the mechanisms of proglucagon sorting.
Computational modelling of proglucagon indicates a largely disordered structure comprising alpha helices, some of which correspond to glucagon, GLP-1 and GLP-2 Figure 1B.
Using Fc-tagged proglucagon-derived peptides that could be detected by immunoprecipitation and immunofluorescence microscopy, it was shown that two dipolar α-helices containing hydrophobic patches with three charged residues within the sequences play roles as sorting signals.
Interestingly, Fc-glicentin was sorted to secretory granules, but Fc-MPGF was not, suggesting that the sorting signal within GLP-1 is masked when contained within the MPGF sequence. These results indicate that the sorting of proglucagon into secretory granules occurs prior to the initial processing event, such that processing occurs exclusively within the granule.
Another possibility is that processing to glicentin and MPGF occurs first, with the prediction that glicentin is sorted into granules and processed to glucagon, while MPGF is not sorted, or very inefficiently sorted into granules. This proglucagon processing profile changes in diabetes; in human and rodent islets, there is a significant increase in the processing of proglucagon to GLP If both glucagon and GLP-1 are produced in a proportion of alpha cells, and are both sorted to secretory granules, the question arises: are they sorted to distinct granule populations, and released under different glucose conditions?
These questions may have been answered in a very recent islet granule peptidomics study showing that both human and mouse islets produce times more glucagon than active GLP-1 46indicating that the processing of proglucagon to active GLP-1 in alpha cells is very inefficient.
Also in this study, analysis of secreted proglucagon-derived peptides showed that both glucagon and active GLP-1 were released in parallel in response to either low 1 mMmedium 6 mM or high Therefore, both glucagon and GLP-1 are likely stored in the same granules and secreted under the same conditions, with glucagon being the dominant peptide, and perhaps serving as the intra-islet GLP-1R agonist The control of hyperglucagonemia obviously targets glucagon secretion.
But what mechanism s are potentially druggable? Inhibition of glucagon secretion by glucose from alpha cells is a long-standing puzzle in islet biology. Unlike insulin secretion from beta cells which is primarily driven by prevailing glucose levels, there is no one single factor that governs glucagon secretion from the alpha cell.
Intrinsic glucose sensing, intra-islet paracrine secretion and factors from the alpha cell itself all interact to generate a complex network that regulates glucagon secretion. In order to examine the direct effects of glucose on glucagon secretion in the absence of paracrine inputs, isolated mouse pancreatic alpha cells, clonal hamster In-R1-G9 cells 4849clonal mouse αTC and -9 cells 395051 and dispersed alpha cells from human islets 52 have been used.
All of these preparations show a bimodal response to increasing glucose concentrations. In the range from 1 to ~7 mM, glucagon secretion is suppressed in a dose-dependent manner, and above 7 mM, glucagon secretion increases Figure 2A. This secretion profile suggests intrinsic mechanisms alone can operate in regulating glucagon secretion below 7 mM glucose, and that these mechanisms may be ineffective at higher glucose concentrations.
However, such conclusions must be interpreted with caution, as single dispersed alpha cells are in a highly abnormal environment, and alpha cell lines are not representative of the normal alpha cell phenotype, as discussed in more detail below.
Figure 2 Glucagon secretion from dispersed alpha cells and alpha cells in intact islets demonstrate the role of paracrine regulation at high glucose concentrations. A V-shape curve of glucagon exocytosis in response to glucose in dispersed non-diabetic black and T2D red human α-cells. B Glucagon secretion from intact islets in response to glucose.
Created with BioRender. The alpha cell secretory response to both glucose is likely more accurately captured in isolated, intact mouse and human islets, where the paracrine regulatory environment and cell-cell contacts are intact.
Similar to dispersed alpha cells, increasing the glucose concentration from 1 to 7 mM dose dependently decreases glucagon secretion from mouse alpha cells 53 and human alpha cells 52 within intact islets, and remains low as glucose levels increase beyond 7 mM, a concentration at which insulin secretion is stimulated Figure 2B.
Therefore, paracrine inputs are significant factors in the inhibition of glucagon secretion as glucose concentrations increase above euglycemia. One mechanism underlying the intrinsic response to glucose is the direct effect on alpha cell electrical activity.
At low 1 mM glucose concentrations, alpha cells in intact mouse and human islets exhibit low K ATP activity and are electrically active 54 — 56 and as glucose concentrations increase, K ATP activity is inhibited.
A recent review by Zhang et al. Therefore, the intrinsic regulation of glucagon secretion by glucose may be explained primarily by the unique electrical properties of the alpha cell, and secondarily by glucose metabolism.
In particular, cAMP signalling may play a key role in the alpha cell secretory response to insulin and somatostatin There is one report that cAMP may also mediate intrinsic glucose sensing within the alpha cell.
Using genetically encoded fluorescent cAMP biosensors, it was shown that high glucose suppressed subplasmalemmal cAMP levels in isolated mouse and human islets Conversely, sustained high cAMP levels abolished the suppression of glucagon secretion by high glucose concentrations.
Lastly, intrinsic glucose sensing by the alpha cell may also be mediated by the nutrient sensors AMP-activated protein kinase AMPK and its downstream target, mammalian target of rapamycin complex 1 mTORC1.
In a series of studies that manipulated alpha cell expression of AMPK itself 65 and its upstream effectors PASK 66 and LKB1 67it was shown that components of this nutrient-sensing pathway can mediate the low glucose-induced secretion of glucagon.
One of these proteins, PASK, is down-regulated in T2D human islets, thus indicating that components of the AMPK pathway may be potential targets for controlling hyperglucagonemia. Using innovative mouse models that selectively targeted activators and inhibitors of mTORC1, it was shown that loss of mTORC1 activity resulted in a loss of the glucose counter-regulatory response and reduction in response to alpha cell secretagogues Interestingly, depletion of the mTORC1 inhibitor TSC2 in alpha cells resulted in a mouse model of hyperglucagonemia and glucagon resistance 69which will be an excellent resource for studies on mechanisms of hyperglucagonemia.
Therefore, the mechanisms underlying the intrinsic response to glucose may provide potential targets for the control of abnormally up-regulated glucagon secretion in diabetes. The beta cell secretory granule contains a number of agents that act directly or indirectly on the alpha cell to inhibit glucagon secretion, and also generally modulate mechanisms of alpha cell biology, such as proliferation.
Insulin, the primary cargo, is a potent suppressor of glucagon secretion and operates through several mechanisms. Mice lacking the insulin receptor on alpha cells αIRKO exhibit hyperglycemia and hyperglucagonemia, indicating that insulin receptor signalling is required for an appropriate alpha cell secretory response to glucose Alpha cell insulin resistance may underlie the abnormal up-regulation of glucagon secretion Type 2 diabetes Additionally, these results also indicate that insulin alone is not sufficient to regulate glycemia in the face of hyperglucagonemia.
Along with insulin, gamma amino butyric acid GABA is also released from the beta cell and is a potent suppressor of glucagon secretion from alpha cells 73 Activating the GABA A receptor in alpha cells results in Cl - influx into the cells which hyperpolarizes the membrane and reduces glucagon secretion As well, there is coordination between insulin and GABA A receptor activity, as insulin action leads to the translocation of GABA A receptor to the cell membrane 76thus augmenting the inhibitory effects of GABA.
In addition, GABA also inhibits mTOR activity to suppress alpha cell proliferation. In type 1 diabetes, the destruction of beta cells leads to a reduction in the amount of secreted GABA, resulting in the activation of mTOR and alpha cell proliferation In addition to effects on alpha cell proliferation, some studies have suggested that pharmacologic activation of GABA A receptor by artemisinins or GABA may alter alpha cell identity and trans-differentiate adult alpha cells to beta-like cells 78 — 80and have led to clinical trials investigating GABA receptor agonists as protection against the development of diabetes.
: Glucagon secretion| α-cell glucokinase suppresses glucose-regulated glucagon secretion | Page Range: 5—19 Online Publication Date: Oct Copyright: © Society for Endocrinology Free access. Download PDF. Check for updates. Abstract The secretion of glucagon by pancreatic α-cells plays a critical role in the regulation of glycaemia. Introduction The principal level of control on glycaemia by the islet of Langerhans depends largely on the coordinated secretion of glucagon and insulin by α- and β-cells respectively. Islet of Langerhans: cell architecture and function Glucagon-secreting α-cells are one of the main endocrine cell populations that coexist in the islet of Langerhans along with insulin-secreting β-cells. Figure 1 Schematic model for glucose-dependent regulation of glucagon secretion in the mouse α-cell. Regulation of α-cell function by glucose: direct or paracrine effect? Regulation of glucagon secretion by fatty acids and amino acids 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. Autocrine, paracrine, endocrine and neural regulation of glucagon secretion Autocrine, paracrine and endocrine signalling The spatial distribution of α-cells and the vascular organization within the islet sustain an important intercellular communication through autocrine and paracrine mechanisms Fig. Figure 3 Paracrine signalling in the α-cell. Insulin and zinc One of the most important paracrine mechanisms responsible for inhibiting glucagon release is conducted by insulin, acting via several pathways. Somatostatin and glucagon 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. GLP1 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. Other extracellular messengers The neurotransmitter γ-aminobutyric acid GABA is another α-cell modulator. Neural regulation 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 Glucagon physiological and pathophysiological actions and its role in diabetes Glucagon synthesis 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. Glucagon receptor 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. Figure 4 The role of glucagon and the glucagon receptor in the liver. Glucagon control of glucose homeostasis and metabolism 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. Modulation of glucagon secretion Sulphonylureas Sulphonylureas are efficient K ATP channel blockers that have been extensively used for the clinical treatment of diabetes. GLP1 mimetics and DPP4 inhibitors 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. Somatostatin analogues Because of the different expression of SSTR in the islet Kumar et al. Amylin and pramlintide 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 Modulation of glucagon action and glucagon receptor signalling Peptide-based glucagon receptor antagonists Several linear and cyclic glucagon analogues have been developed to work as glucagon receptor antagonists. Conclusions Pancreatic α-cells and glucagon secretion are fundamental components of the regulatory mechanisms that control glucose homeostasis. Declaration of interest The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. Funding This work was supported by grants from the Ministerio de Educación y Ciencia BFU and PCIA to I Q; BFU to A N. PubMed Ahloulay M Bouby N Machet F Kubrusly M Coutaud C Bankir L Effects of glucagon on glomerular filtration rate and urea and water excretion. 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Introduction Islet of Langerhans: cell architecture and function Glucagon secretion by pancreatic α-cells Stimulus-secretion coupling in α-cells: from ion channel activity to exocytosis Regulation of α-cell function by glucose: direct or paracrine effect? Regulation of glucagon secretion by fatty acids and amino acids Autocrine, paracrine, endocrine and neural regulation of glucagon secretion Glucagon physiological and pathophysiological actions and its role in diabetes Glucagon synthesis Glucagon receptor Glucagon control of glucose homeostasis and metabolism The role of α-cell function in diabetes Molecular pharmacology of glucagon release and action: therapeutic potential in diabetes treatment Modulation of glucagon secretion Modulation of glucagon action and glucagon receptor signalling Conclusions Declaration of interest Funding. Copyright: © Society for Endocrinology Page s : 15 Article Type: Research Article Rev-recd: 30 Jul Accepted Date: 31 Jul Print Publication Date: 01 Oct Online Publication Date: Oct Get Permissions. Export Figures. Close View raw image Schematic model for glucose-dependent regulation of glucagon secretion in the mouse α-cell. View raw image Paracrine signalling in the α-cell. View raw image The role of glucagon and the glucagon receptor in the liver. Export References. ris ProCite. bib BibTeX. In rat pancreatic preparations perfused with an SSTR2 antagonist, the suppression of glucagon secretion by 3. However, in isolated human islets, blockade of SSTR2 did not affect suppression of glucagon secretion at 6 mM glucose 55 , perhaps reflecting species-specific differences or differences in the models perfused pancreas vs static islet culture. Interestingly, insulin secretion was also elevated, indicating that both insulin and somatostatin are required for the suppression of glucagon secretion at high glucose concentrations. In intact human islets, high glucose 10 mM inhibition of glucagon exocytosis was lost after administration of the SSTR2 antagonist CYN In diabetes, circulating and pancreatic somatostatin, together with SST mRNA, are elevated. However, expression of SSTR2 on alpha cells is decreased in T2D due to increased receptor internalization 52 , indicating alpha cell somatostatin resistance. Together with alpha cell insulin resistance, this could be another mechanism in the hyperglucagonemia of diabetes. Alternatively, somatostatin resistance may be a dominant and direct mechanism of hyperglucagonemia, as eliminating the insulin receptor on delta cells completely abolishes the glucagonostatic effect of insulin, indicating an indirect glucagonostatic effect for insulin The emerging role of somatostatin in the regulation of alpha cell function and glucagon secretion has been further highlighted by one study in which mice were engineered for optogenetic activation of beta cells to study the paracrine regulation of alpha cells By this approach, opto-activation of beta cells both suppressed alpha cell electrical activity and stimulated action potentials in delta cells mediated by gap junction currents. The suppressive effect of beta cell activation was lost in the presence of the SSTR2 antagonist CYN 99 , indicating that somatostatin secretion stimulated by beta cell electrical activity is critical for the suppression of glucagon secretion. Subsequent modelling predicted that a reduction in gap junction connections between beta and delta cells, perhaps caused by disruptions in islet architecture in T2D , may contribute to the hyperglucagonemia of diabetes. Thus these findings highlight a central role for delta cells in the context of intra-islet regulation of glucagon secretion, and may have implications for designing drugs for the treatment of hyperglucagonemia of diabetes. The alpha cell itself displays plasticity during the progression of diabetes. In addition to the mechanisms above that describe changes in responses to glucose and paracrine effectors, there are alterations within the alpha cell, including proglucagon processing and secretion of proglucagon-derived peptides, and remodelling of the secretory granules themselves in terms of exocytotic behavior and contents, and alterations in intracellular trafficking pathways. Secreted glucagon from alpha cells can stimulate its secretion through an autocrine effect. It has been shown that glucagon stimulates glucagon secretion from the rat and mouse isolated alpha cells in an autocrine manner through glucagon receptor-stimulated cAMP signaling In αTC cells and mouse islets, exogenous glucagon administration, as well as secreted glucagon stimulated by 1 mM glucose, increased glucagon secretion and proglucagon gene transcription through the PKA-cAMP-CREB signalling pathway in a glucagon receptor-dependent manner The apparent interplay between glucagon and its receptor on the alpha cell appears to be of a positive feedback loop, controlled by the pulsatile nature of glucagon secretion. In addition to glucagon, a novel proglucagon-derived peptide, proglucagon PG comprised of GRPP and glucagon, was identified as a major molecular form of glucagon in plasma from human patients with hyperglucagonemia-associated conditions: Type 2 diabetes and renal dysfunction, morbid obesity or gastric bypass surgery, and only after oral ingestion of macronutrients This N-terminally extended form of immunoreactive glucagon was not found in healthy controls, leading the authors to speculate that PG , and molecular heterogeneity of glucagon in general, could be a biomarker for alpha cell dysfunction. Administration of PG decreased glucagon secretion in healthy rats, diverging from the positive feedback observed with glucagon administration. Interestingly, this effect was not observed in diabetic rats, suggesting an impairment in this distinct feedback loop in the alpha cell. The interplay between glucagon, insulin and somatostatin in the regulation of glucagon secretion at various levels of glucose is illustrated in Figure 3. In diabetes, beta cell deficiency, together with alpha cell insulin and somatostatin resistance, all contribute to alpha cell dysfunction and a loss of the regulation of glucagon secretion, resulting in hyperglucagonemia. Figure 3 Cross-talk among α, β, and δ-cells in the paracrine regulation of glucagon secretion. Under low glucose mM conditions, secreted glucagon may act in an autocrine feed-forward loop. Additionally, electrical coupling of the beta and delta cells through gap junctions contributes to somatostatin release. Somatostatin binds to SST receptor 2 SSTR2 on the α cell membrane, where signalling through G i inhibits glucagon secretion. The glucose-dependent insulinotropic actions of intestinal GLP-1 on the beta cell are well known. GLP-1 also suppresses glucagon secretion in both healthy people and people with type 2 diabetes , and poorly-controlled type 1 diabetes The emerging evidence of GLP-1 being produced and secreted by the pancreatic alpha cell has led to a debate on which source of GLP-1 suppresses glucagon secretion from pancreatic alpha cells. To investigate this question, Chambers et al. The gut-derived GLP-1 binds to its receptor on local afferent vagal nerve terminals, which ultimately signals for satiety, delaying gastric emptying and suppression of hepatic glucose release , However, this model may not translate well to human islets due to differences in islet architecture, and in light of the recent findings that glucagon is the dominant peptide hormone secreted from human alpha cells The search for a GLP-1 receptor on alpha cells has been hampered by a lack of a reliable GLP-1 receptor antibody , GLP-1 appears to mildly reduce action potentials in the alpha cell membrane at 1 mM glucose in isolated mouse alpha cells, and this effect is blocked by the GLP-1R antagonist exendin , therefore suggesting the presence of GLP-1R, perhaps at a very low density, on a small proportion of alpha cells. The development of near infra-red and fluorescent analogues of GLP-1R ligands has enabled both in vivo , and high-resolution tissue imaging , of GLP-1R with high specificity, sensitivity, and reproducibility. Given the already small proportion of alpha cells in the mouse islet, the contribution of direct alpha cell action to the glucagonostatic effect of GLP-1 is likely very small. Islet GLP-1 may also exert its effects through receptors on delta cells , resulting in stimulation of somatostatin secretion and inhibition of glucagon secretion via SSTR2 on alpha cells , This paracrine effect could not be detected in isolated normal human islets ; nonetheless, this mechanism may be clinically relevant in the treatment of T2D, as experiments in human islets showed that the GLP-1R agonist liraglutide enhanced somatostatin secretion to reduce hyperglucagonemia induced by the SGLT2 inhibitor dapagliflozin As drugs targeted to the control of glucagon secretion are now being developed for the treatment of hyperglucagonemia, a deeper understanding of the dynamics of the alpha cell secretory granule is critical for identifying effective targets. However, the study of glucagon granule trafficking and exocytosis presents several technological challenges. Commonly used cell lines such as InR1-G9, αTC and αTC, while useful for preliminary studies on trafficking and secretion, as a rule do not exhibit robust secretory responses to glucose or other secretagogues. The αTC cell line in particular differs from primary alpha cells in their complement of transcriptional, epigenetic and metabolic factors , which may explain the blunted secretory response to glucose. Dispersed primary alpha cells may offer a slightly better alternative, but as discussed above, both cell lines and dispersed primary alpha cells exhibit aberrant glucagon exocytosis patterns at high glucose levels, likely due to the absence of paracrine inputs and juxtamembrane contacts. 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. 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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. 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. Turn recording back on. National Library of Medicine Rockville Pike Bethesda, MD Web Policies FOIA HHS Vulnerability Disclosure. Help Accessibility Careers. Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation. Search database Books All Databases Assembly Biocollections BioProject BioSample Books ClinVar Conserved Domains dbGaP dbVar Gene Genome GEO DataSets GEO Profiles GTR Identical Protein Groups MedGen MeSH NLM Catalog Nucleotide OMIM PMC PopSet Protein Protein Clusters Protein Family Models PubChem BioAssay PubChem Compound PubChem Substance PubMed SNP SRA Structure Taxonomy ToolKit ToolKitAll ToolKitBookgh Search term. 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. Evidence for a physiologic role of pancreatic glucagon in human glucose homeostasis: studies with somatostatin. Gromada J, Franklin I, Wollheim CB. Alpha-cells of the endocrine pancreas: 35 years of research but the enigma remains. Müller TD, Finan B, Clemmensen C, DiMarchi RD, Tschöp MH. The New Biology and Pharmacology of Glucagon. Physiological Reviews. |
| You and Your Hormones | The mice received a bolus of 14 Cdeoxy-D-glucose Perkin-Elmer; dil. Glutamate is a positive autocrine signal for glucagon release. The GLP1R Agonist Liraglutide Reduces Hyperglucagonemia Induced by the SGLT2 Inhibitor Dapagliflozin via Somatostatin Release. When glucagon binds to the glucagon receptors, the liver cells convert the glycogen into individual glucose molecules and release them into the bloodstream, in a process known as glycogenolysis. Intra-islet somatostatin regulates glucagon release via type 2 somatostatin receptors in rats. |
| Top bar navigation | Paracrine signalling in the α-cell. Intracellular ATP did not change in α-cells from these mice when exposed to 0. Baukrowitz, T. Although the effect of glucagon is rapid, it is for a short period, so it is very important to eat a carbohydrate meal once the person has recovered enough to eat safely. McCALL MS, Madison LL. Hatton, T. However, as with the previous measurements of ATP, these experiments were performed with glucose as the only substrate. |
Glucagon secretion -
Measurements of insulin secretion were also performed on islets isolated from week-old mice. At the end of each static incubation, the islets were collected and lysed in acid ethanol to assess insulin and glucagon content.
The islets were perfused with extracellular solution containing in mM : NaCl, 3. Glucose, methyl-succinate, and FCCP have been added as indicated in Fig. Images were acquired at a frequency of 0. Electrical activity, transmembrane currents, and cell capacitance were recorded from randomly chosen cells on the peripheral of the islets.
α-cells were identified by the expression of fluorescent protein tdtomato see Mouse Validation. α-cells were identified by their electrical activity in response to glucose and lack of tdtomato fluorescence. Electrical activity and K ATP conductance were recorded using perforated patch-clamping technique.
Perforating reagent gramicidin 0. Extracellular solution contains in mM : NaCl, 3. After the experiments, the membrane potential recordings were exported as ASCII files and converted to ABF files axon binary file using ABF utility software version 2.
The resultant ABF files were then imported into Clampfit software version 9. Depolarization-triggered cell exocytosis was monitored as increase in membrane capacitance. The intracellular solution used for capacitance measurement contains in mM : Cs-glutamate, 10 CsCl, 10 NaCl, 1 MgCl 2 , 5 HEPES, 0.
The extracellular solution contains in mM : NaCl, 5. Plasma glucagon levels were quantitated by radioimmunoassay Merck Millipore and by ELISA Mercodia.
Plasma insulin levels were assessed by ultra-sensitive ELISA Mercodia. A portion of mouse liver were homogenized in ice-cold homogeneisation buffer in mM: sucrose, 10 HEPES pH 7. Proteins from nuclear fractions were extracted, and the protein content was determined by bicinchoninic acid assay Pierce, Thermo Scientific.
Transfer to nitrocellulose membranes was performed using the Mini Trans-Blot apparatus from Bio-Rad. Bands corresponding to the specific proteins were visualized using enhanced chemiluminescence reagent Advansta. Digital images were acquired with Fusion FX7 system Vilber Lourmat and Bio-1D software Vilber Lourmat for quantification and normalization.
The same membranes were reprobed with anti-β-actin antibodies to confirm the equal loading of proteins for each sample. Real-time PCR was performed using Power SYBR Green Master Mix Applied Biosystems. All reactions were normalized to β-actin levels. Specific mouse primers for each gene are listed in Supplementary Table 1.
The animals were processed in the morning in the random-fed state. The mice received a bolus of 14 Cdeoxy-D-glucose Perkin-Elmer; dil. The mice were then placed in cages without water or food. After the last blood sampling, the mice were killed by cervical dislocation under isoflurane anesthesia.
Tissues were immediately dissected and frozen for further assessment of 14 Cdeoxy-D-glucosephosphate 2-DGP content. The Plasma radioactivity was determined at each time point by liquid scintillation counting, in order to calculate the area under the curve of the plasma tracer decay.
For the determination of tissue 2-DGP content, the tissue samples were homogenized, and the supernatants were passed through ion-exchange columns to separate 2-DGP from 2-DG. Tissue 2DG uptake was calculated by normalizing the tissue 2DG-6P content as disintegrations per minute to the tissue weight and to the AUC of the plasma tracer decay.
All collected data were included without data exclusion. Statistical analysis was performed using GraphPad Prism 5. The data distribution was assumed to be normal.
p -values less than 0. Other statistical methods were mentioned and indicated where they were used. No statistical methods were used to pre-determine sample sizes, but sample sizes are similar to those used in our previous studies.
The data that support the findings of this study are available from the corresponding author upon reasonable request. Unger, R. Glucagon and the A cells. Physiology and Pathophysiology.
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Diabetes Res. Download references. This work was supported by grants to B. from the Swiss National Science Foundation A0B and the European Research Council Advanced grants INSIGHT and INTEGRATE.
was supported by a Diabetes UK RD Lawrence Fellowship. PR was supported by the Wellcome Trust and the Swedish Research Council. PLH was funded by Fondation privée of the University Hospitals of Geneva and the NIDDK grant DK We thank the Mouse Metabolic Evaluation Facility MEF from the Center for Integrative Genomics for performing tissue glucose uptake measurements.
Center for Integrative Genomics, University of Lausanne, , Lausanne, Switzerland. Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Churchill Hospital, Oxford, OX3 7LE, UK. Department of Clinical Science, UMAS, Division of Islet Cell Physiology, Lund, Sweden.
Department of Genetic Medicine and Development, , Geneva, Switzerland. You can also search for this author in PubMed Google Scholar.
secured funding. performed the experiments. provided the the Gcg-Cre mice. provided expertise and assisted with the editing of the manuscripts. Correspondence to Bernard Thorens.
Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution 4. Reprints and permissions. Basco, D. α-cell glucokinase suppresses glucose-regulated glucagon secretion.
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Subjects Islets of Langerhans Nutrient signalling Pre-diabetes. Abstract Glucagon secretion by pancreatic α-cells is triggered by hypoglycemia and suppressed by high glucose levels; impaired suppression of glucagon secretion is a hallmark of both type 1 and type 2 diabetes.
Introduction Glucagon secretion by pancreatic α-cells is rapidly increased when the blood glucose concentration falls below the normoglycemic level to increase hepatic glucose production, and is suppressed by hyperglycemia 1 , 2.
Full size image. Discussion Here, we show that inactivation of Gck in α-cells results in hyperglucagonemia in the fed state and increased hepatic glucose production.
Pancreatic islet isolation Before removal of the pancreas, a solution of Liberase TL 0. Hormone release measurements Measurements of insulin and glucagon secretion were performed using the static incubations of islets isolated from week-old mice.
In vivo biochemical measurements Plasma glucagon levels were quantitated by radioimmunoassay Merck Millipore and by ELISA Mercodia. Western blotting analysis A portion of mouse liver were homogenized in ice-cold homogeneisation buffer in mM: sucrose, 10 HEPES pH 7.
Radioactive 2-deoxy-glucose 2-DG uptake assay The animals were processed in the morning in the random-fed state. Data representation and statistics All collected data were included without data exclusion.
Data availability The data that support the findings of this study are available from the corresponding author upon reasonable request. The glucagon-secreting alpha cells surround the insulin -secreting beta cells , which reflects the close relationship between the two hormones.
To do this, it acts on the liver in several ways:. Glucagon also acts on adipose tissue to stimulate the breakdown of fat stores into the bloodstream. Glucagon works along with the hormone insulin to control blood sugar levels and keep them within set levels.
Glucagon is released to stop blood sugar levels dropping too low hypoglycaemia , while insulin is released to stop blood sugar levels rising too high hyperglycaemia. It works in totally opposite way to insulin.
The release of glucagon is stimulated by low blood glucose, protein -rich meals and adrenaline another important hormone for combating low glucose. The release of glucagon is prevented by raised blood glucose and carbohydrate in meals, detected by cells in the pancreas.
For example, it encourages the use of stored fat for energy in order to preserve the limited supply of glucose. A rare tumour of the pancreas called a glucagonoma can secrete excessive quantities of glucagon.
This can cause diabetes mellitus, weight loss, venous thrombosis and a characteristic skin rash. Unusual cases of deficiency of glucagon secretion have been reported in babies.
This results in severely low blood glucose which cannot be controlled without administering glucagon. Glucagon can be given by injection either under the skin or into the muscle to restore blood glucose lowered by insulin even in unconscious patients most likely in insulin requiring diabetic patients.
It can increase glucose release from glycogen stores. Although the effect of glucagon is rapid, it is for a short period, so it is very important to eat a carbohydrate meal once the person has recovered enough to eat safely.
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Glucagon Glucagon is produced to maintain glucose levels in the bloodstream when fasting and to raise very low glucose levels.
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