What is glucagon

Glucagon is a hormone produced in the pancreas alpha cells in the islets of Langerhans and glucagon is secreted between meals when your blood glucose concentration falls below 100 mg/dL (5.6 mmol/L). The main physiological role of glucagon is to stimulate liver glucose output, thereby leading to increases in glycemia. This provides the major counterregulatory mechanism for insulin in maintaining glucose homeostasis 1). Glucagon exerts two primary actions on your liver: (1) glycogenolysis, the breakdown of glycogen into glucose; and (2) gluconeogenesis, the synthesis of glucose from fats and proteins. These effects lead to the release of glucose into circulation, thus raising the blood glucose level. In adipose tissue, glucagon stimulates fat catabolism (breakdown) and the release of free fatty acids. Glucagon is also secreted in response to rising amino acid levels in the blood after a high-protein meal. Glucagon promotes amino acid absorption and thereby provides cells with the raw material for gluconeogenesis. The secretion of glucagon is inhibited by hyperglycemia, insulin, somatostatin, and glucagon like-peptide-1 (GLP-1) 2).

Glucagon is also used in diagnostic testing of the stomach and other digestive organs. Glucagon function is to defend against decreases in glucose availability during fasting, stress, and exercise by stimulating liver glycogenolysis (glycogen breakdown) phasically and liver gluconeogenesis (glucose production) tonically 3).

Insulin vs glucagon

Insulin, “the hormone of nutrient abundance,” is secreted during and immediately following a meal when blood nutrient levels are rising. Insulin is a hormone that helps glucose get into the body’s cells where it can be used for energy. Without insulin around, glucose stays in the blood and blood sugar levels get too high. Insulin plays an important role to keep plasma glucose value within a relatively narrow range throughout the day (glucose homeostasis). Insulin’s main actions are (1) In the liver, insulin promotes glycolysis and storage of glucose as glycogen (glycogenesis), as well as conversion of glucose to triglycerides, (2) In muscle, insulin promotes the uptake of glucose and its storage as glycogen, and (3) in adipose tissue, insulin promotes uptake of glucose and its conversion to triglycerides for storage. Insulin is secreted by Beta (β) cells, or B cells of islets of the Langerhans in your pancreas.

The effects of glucagon are the opposite of the effects induced by insulin. The two hormones need to work in partnership with each other to keep blood glucose levels balanced.

In times of plenty, insulin stimulates cells to absorb glucose, fatty acids, and amino acids and to store or metabolize them; therefore, it lowers the level of blood glucose and other nutrients. It promotes the synthesis of glycogen, fat, and protein, thereby promoting the storage of excess nutrients for later use and enhancing cellular growth and differentiation. It also antagonizes glucagon, thus suppressing the use of already-stored fuels. The brain, liver, kidneys, and red blood cells absorb and use glucose without need of insulin, but insulin does promote glycogen synthesis in the liver. Insulin insufficiency or inaction is well known as the cause of diabetes. Osteocalcin, a hormone from the osteoblasts of bone, also stimulates multiplication of beta cells, insulin secretion, and insulin sensitivity of other body tissues. The principal targets of insulin are the liver, skeletal muscles, and adipose tissue.

Glucagon vs glycogen

Glycogen is a stored form of glucose. Glycogen is a large multi-branched polymer of glucose which is accumulated in response to insulin and broken down into glucose in response to glucagon.

Glycogen is mainly stored in the liver and the muscles and provides the body with a readily available source of energy if blood glucose levels decrease.

The role of glycogen

Energy can be stored by the body in different forms. One form of stored energy is fat and glycogen is another. Fatty acids are more energy rich but glucose is the preferred energy source for your brain and glucose also can provide energy for cells in the absence of oxygen, for instance during anaerobic exercise.

Glycogen is therefore useful for providing a readily available source of glucose for the body.

Glycogen storage in diabetes

In a healthy body, the pancreas will respond to higher levels of blood glucose, such as in response to eating, by releasing insulin which will lower blood glucose levels by prompting the liver and muscles to take up glucose from the blood and store it as glycogen.

People with diabetes either do not make enough of their own insulin and/or their insulin does not work effectively enough. As a result, the pancreas may not be able to respond effectively enough to rises in blood glucose.

Glycogen release

Glycogen may be released by the liver for a number of reasons, including:

  • In response to stressful situations
  • Upon waking (this process is known as the dawn phenomenon)
  • In response to low blood sugar
  • To aid digestion

In these situations, when the body feels extra glucose is needed in the blood, the pancreas will release the hormone glucagon which triggers the conversion of glycogen into glucose for release into the bloodstream.

Glycogen and exercise

Glycogen plays an important role in keeping your muscles fueled for exercise. When you exercise, your muscles will take advantage of their stored glycogen. Glucose in your blood and glycogen stored in the liver can also be used to keep your muscles fueled.

Once you complete your exercise session, your muscles will replenish their glycogen stores. The time it takes to fully replenish glycogen stores can depend on how hard and how long you exercise and can vary from a few hours to several days.

Where is glucagon produced

The main site of glucagon production is pancreatic Alpha (α) cells, or A cells of islets of the Langerhans in your pancreas, which secrete glucagon in response to hypoglycemia (low blood sugar), amino acids, gastric inhibitory peptide, and ghrelin. In humans, A-cells are scattered throughout the islets of Langerhans. The pancreatic content of glucagon varies considerably among species; human pancreas contains approximately 700 to 1000 µg of glucagon, roughly 1-2 x 1017 molecules 4). For reference, the normal human pancreas contains about ~150 U of insulin or ~5000 µg 5); this translates to ~6-8 x 1017 molecules. Thus the normal human pancreas has about 1/3 to 1/10 the number of glucagon molecules as insulin molecules 6).

Figure 1. Pancreas location

pancreas locationFigure 2. Pancreatic islets of Langerhans

pancreatic islets of LangerhansWhat does glucagon do

Glucagon is a single-chain polypeptide made up of 29 amino acids that are derived from a larger precursor peptide, which is cleaved upon secretion. Glucagon acts exclusively on the liver to antagonize insulin effects on hepatocytes (liver cells). Glucagon generally elevates the concentration of glucose in your blood by promoting gluconeogenesis and glycogenolysis by stimulating the cAMP pathway. Glucagon also promotes oxidation of fat (lipolysis), which can lead to the formation of ketone bodies. Glucagon also causes relaxation of the smooth muscle of the stomach, duodenum, small bowel, and colon. The effects of glucagon are the opposite of the effects induced by insulin. The two hormones need to work in partnership with each other to keep blood glucose levels balanced.

At concentrations that approximate those found in the portal vein in vivo, glucagon is a potent stimulator of hepatic glycogenolysis, gluconeogenesis, and ketogenesis in vitro. These actions of glucagon and the increases in plasma glucagon observed during hypoglycemia 7), exercise 8), trauma 9), infection (72), and other stress 10) provide considerable evidence that glucagon is important in the maintenance of euglycemia in the postabsorptive state and at times when there are increased demands for fuels and when the organism must rely on mobilization of endogenous substrate. Under these conditions, when B-cell function is normal, the major action of glucagon would be to counteract the actions of insulin on storage of glucose and other fuels. Conversely, when B-cell function is deficient, glucagon could accentuate the metabolic consequences of insulin deficiency and be an important determinant of the magnitude of hyperglycemia and hyperketonemia found in diabetes 11).

In addition to a role for glucagon in the maintenance of normal blood glucose by antagonizing the effects of postabsorptive (i.e. low) plasma insulin concentrations, there is considerable evidence that glucagon acts in the defense against hypoglycemia by antagonizing the effects of excess plasma insulin 12). When hypoglycemia is produced in humans by injection of insulin, release of glucagon is stimulated along with that of other counterregulatory hormones when the plasma glucose decreases below 3.8 mmol/L (~68 mg/dl). Restoration of normal blood glucose is due to a compensatory increase in hepatic glucose production. Although secretion of catecholamines, growth hormone, and cortisol are stimulated along with that of glucagon, only the increases in plasma glucagon and catecholamines coincide with or precede the compensatory increase in the glucose production rate 13). That glucagon is the major acute glucose counterregulatory hormone is suggested by the fact that inhibition of the plasma glucagon responses by somatostatin markedly attenuates the compensatory increase in the glucose production rate and impairs restoration of euglycemia following insulin administration. Prevention of cortisol secretion 14), adrenergic blockade 15), adrenalectomy 16), or acute growth hormone deficiency 17) does not appreciably affect immediate glucose counterregulation. The effects of glucagon during restoration of euglycemia involves both glycogenolysis and gluconeogenesis, predominantly the former 18).

Glucagon acts via the glucagon receptor, a seven transmembrane G protein-coupled receptor, located in the plasma membrane consisting of 485 amino acids 19). To date, glucagon-binding sites have been identified in multiple tissues, including liver, brain, pancreas, kidney, intestine, and adipose tissues 20). The conformation change in the receptor activates G proteins, a heterotrimeric protein with α, β, and γ subunits. When the G protein interacts with the receptor, it undergoes a conformational change that results in the replacement of the GDP molecule that was bound to the α subunit with a GTP molecule. This substitution results in the releasing of the α subunit from the β and γ subunits. The alpha subunit specifically activates the next enzyme in the cascade, adenylate cyclase.

Adenylate cyclase manufactures cyclic adenosine monophosphate (cyclic AMP or cAMP), which activates protein kinase A (cAMP-dependent protein kinase). This enzyme, in turn, activates phosphorylase kinase, which then phosphorylates glycogen phosphorylase b (PYG b), converting it into the active form called phosphorylase a (PYG a). Phosphorylase a is the enzyme responsible for the release of glucose-1-phosphate from glycogen polymers.

Additionally, the coordinated control of glycolysis and gluconeogenesis in the liver is adjusted by the phosphorylation state of the enzymes that catalyze the formation of a potent activator of glycolysis called fructose-2,6-bisphosphate 21). The enzyme protein kinase A (PKA) that was stimulated by the cascade initiated by glucagon will also phosphorylate a single serine residue of the bifunctional polypeptide chain containing both the enzymes fructose-2,6-bisphosphatase and phosphofructokinase-2. This covalent phosphorylation initiated by glucagon activates the former and inhibits the latter. This regulates the reaction catalyzing fructose-2,6-bisphosphate (a potent activator of phosphofructokinase-1, the enzyme that is the primary regulatory step of glycolysis) 22) by slowing the rate of its formation, thereby inhibiting the flux of the glycolysis pathway and allowing gluconeogenesis to predominate. This process is reversible in the absence of glucagon (and thus, the presence of insulin).

Glucagon stimulation of protein kinase A also inactivates the glycolytic enzyme pyruvate kinase in hepatocytes 23).

Glucagon regulation

Glucagon secretion, similar to that of insulin, is tightly regulated and intimately tied to blood glucose levels (Figure 3) 24). Converse to the inhibition of insulin secretion by hypoglycemia, low levels of blood glucose directly stimulate the pancreatic alpha (α) cells to secrete glucagon 25). Hyperglycemia decreases glucagon secretion 26). In vitro studies, such as those using the isolated perfused pancreas in which most variables operative in vivo can be controlled, indicate that the alpha (α) cells is as exquisitely sensitive to changes in the ambient extracellular glucose concentration as is the beta-cell 27); thus, glucose suppresses basal and stimulated glucagon release at concentrations as low as 5 mmol/L glucose (90 mg/dl). To some extent the inhibition of glucagon secretion is dependent on concomitant stimulation of insulin release. In vivo, a decrease in plasma glucose of 1 to 2 mmol/L increases plasma glucagon 28).

The secretion of glucagon is promoted via the action of voltage-dependent sodium (Na+) and calcium (Ca 2+) channels, which maintain action potentials during times of low glucose. Depolarization increases the Ca 2+ influx and subsequent glucagon secretion 29), which is supported by the activity of ATP-sensitive potassium (KATP) channels 30). As glucose levels rise, secretion of glucagon is inhibited through the elevation of cytosolic ATP, blockade of KATP channels and termination of the Na+-induced and Ca2+-induced action potentials. This process inhibits Ca2+ influx and ends glucagon secretion. Although the cellular signals regulating glucagon secretion are fairly well-established, the role of glucose, whether directly, or indirectly via β-cell activation, is still a matter of debate. Studies in rats suggest that mediatory, paracrine signaling from the β cell is essential for the inhibition of glucagon secretion by elevated glucose levels 31). Investigations in mice and humans, however, suggest that glucose directly inhibits glucagon secretion at concentrations which are too low to stimulate insulin secretion 32). Furthermore, this inhibition has been demonstrated in vitro in both isolated α cells and in intact pancreatic islets 33). However, a study in individuals with type 1 diabetes mellitus suggests that insulin is the primary signal that inhibits glucagon secretion in humans 34). In addition to glucose, several other physiological parameters are known regulators of glucagon secretion, including GLP-1 35), GLP-2 36), fatty acids 37), the autonomic nervous system 38) and circulating amino acids 39).

Figure 3. Some controls of glucagon secretion

Some controls of glucagon secretion

Footnote: Nutrient, neural, endocrine, paracrine, and autocrine effects control glucagon secretion. The dynamic interactions among these controls are poorly understood. As the figure indicates, there are many possibilities for positive- and negative-feedback loops (e.g., glucagon stimulates both hepatic glucose production and insulin secretion, and both glucose and insulin inhibit glucagon secretion), for indirect effects (e.g., the incretin hormone glucagon-like peptide 1 [GLP-1] stimulates insulin and amylin secretion, both of which inhibit glucagon secretion, both by acting directly on the α-cells and by reducing gastric emptying), and for antagonistic effects (one example is that the incretin hormone GLP-1 inhibits glucagon secretion but the incretin hormone glucose-dependent insulinotropic polypeptide [GIP] stimulates it; another example is that mixed-nutrient meals increase both plasma glucose, which inhibits glucagon secretion, and plasma amino acids, which stimulates glucagon secretion, with the net result a brief stimulation of glucagon secretion). Somatostatin may contribute in situations in which insulin and glucagon secretion do not change in a simple inverse fashion, such as after mixed-nutrient meals. Finally, central and peripheral glucose-sensing neurons converge onto sympathetic and vagal efferents that drive insulin and glucagon secretion. α, pancreatic α-cell (glucagon); β, pancreatic β-cell (insulin); δ, pancreatic δ-cell (somatostatin); arrows, stimulatory inputs; T-ends, inhibitory inputs.

[Source 40) ]

Glucagon and lipid metabolism

Plasma lipid homeostasis

Studies in the early 1960s investigated glucagon’s action independent of glucose homeostasis. These studies described a lipid-mobilizing effect for glucagon in a range of species 41). The regulation of plasma lipids by glucagon was first highlighted in studies which suggested that glucagon acts to decrease plasma cholesterol, total esterified fatty acids and arachidonic acid levels 42). As epinephrine, insulin and exogenous glucose all failed to lower levels of plasma cholesterol, the investigators concluded that these effects were not an indirect result of altered carbohydrate metabolism 43). In both canines and humans, the researchers observed a total decrease in levels of plasma cholesterol, as well as plasma total lipid concentrations, within 30 min of intravenous glucagon administration. Intriguingly, this depression was not found for whole-blood total lipid levels, suggesting a repartitioning of lipids from serum to platelet-rich fractions. Incubation of the blood at 37 °C led to partial or full restoration of plasma cholesterol and total lipid levels, further supporting the hypothesis of repartitioning 44). Reports from other groups provided additional support for a role of glucagon in the regulation of plasma lipids 45).

In the context of triglyceride metabolism, several reports indicated that triglyceride production is decreased in perfused livers treated with glucagon 46). Although these studies suggest hepatic lipoprotein metabolism as the site of such regulation, the molecular mechanism by which glucagon achieved this result remained elusive. Building upon these observations, the role of glucagon on lipid suppression was investigated in a rat model of hyperlipidemia 47). This study demonstrated that glucagon sig nificantly decreased levels of serum triglycerides, cholesterol, and VLDL cholesterol in hyperlipidemic rats, as well as in control eulipidemic rats. Furthermore, a decrease in synthesis of hepatic lipoprotein apoproteins was observed 48), complementing earlier studies that described depression of triglyceride synthesis in livers treated with glucagon. A caveat of this study is that it involved supraphysiological concentrations of glucagon administered over a 4-day period. Thus, the relevance of acute signaling by endogenous glucagon remained uncertain. Guettet et al. 49) continued the investigation of chronic effects of glucagon signaling in the Wistar rat. Their initial studies described a decrease in concentrations of plasma cholesterol, phospholipids and tri glycerides. Interestingly, these reductions were not seen in the liver or in erythrocytes of these rats, which suggested another target tissue as the site of action. Continued investigation of cholesterol turnover revealed increased urinary secretion of cholesterol, as well as elevated transformation to bile acids. Of special importance was the reported observation that the chronic treatment of Wistar rats with twice-daily glucagon (20 μg per day) for 3 weeks reduced blood glucose and insulin concentrations. This report thus indicated that chronic glucagon pharmacology was neither transient nor detrimental to glucose homeostasis 50).

Further studies by Guettet et al. 51) evaluated the effect of chronic glucagon treatment on lipoprotein composition in fed and fasted rats, as well as rats fed a cholesterol-rich diet. Cholesterol, phospholipids and total protein levels were proportionally decreased in chylomicrons, VLDL cholesterol, LDL cholesterol and HDL cholesterol, which suggested a reduction in the number of lipoprotein particles. Triglycerides were reported to be decreased only in the chylomicron and VLDL fractions. Evaluation of the lipoproteins indicated a decline in levels of apolipoprotein E (ApoE) and an increase in ApoB 52). Collectively, these findings suggested glucagon-stimulated targeting of the ApoE-rich lipoproteins to limit the accumulation that typically occurs with high-cholesterol feeding 53). A follow-up study showed that glucagon treatment had no effect on secretion rates of triglyceride-rich particles in either fed or fasted conditions. Conversely, glucagon treatment accelerated the rate of triglyceride removal (fractional catabolic rate constant) from the plasma compartment 54). Taken together, the work of Guettet et al. 55) revealed that increased glucagon signaling may directly regulate lipid catabolism.

Rudling and Angelin 56) extended these findings by the direct study of glucagon’s effects on LDL receptors (LDLRs). The investigators found that glucagon administra tion to rats resulted in a dose-dependent increase in binding of LDL cholesterol to the receptor, with no apparent effect on receptor mRNA expression. Concomitant with this increased binding was a decrease in levels of cholesterol, ApoB, and ApoE. Furthermore, these effects were completely antagonized by insulin administration. Rudling and Angelin hypothesized a mechanism such as post-translational receptor modification, whereby glucagon increases LDLR activity without affecting expression levels 57). The findings in rodents were complemented by studies in dairy cattle which showed that subcutaneous injections of glucagon led to variable decreases, some of sizable magnitude, in circulating plasma concentrations of VLDL-triglycerides, HDL1-phospholipids and HDL2-free cholesterol 58). Improved glucose status with decreased nonesterified fatty acids and β-hydoxybutyrate was also reported 59).

Genetic manipulation of the glucagon receptor has led to inconclusive results regarding glucagon’s role in lipid metabolism. Conarello et al. 60) found that Gcgr−/− mice are resistant to high fat diet-induced liver steatosis; however, Longuet et al. 61) showed that Gcgr−/− mice have enhanced susceptibility to hepatic steatosis. Interestingly, these studies used genetically modified null mice generated in an identical manner and of the same background (C57B6). Furthermore, the effect was observed in mice fed a similar diet (45% fat). The length of diet differed between the two studies (8 versus 12 weeks); however, mice fed a high fat diet for the longer duration did not exhibit steatosis. Taken together, the contribution of glucagon receptor agonism to liver steatosis has yet to be conclusively described.

Longuet et al. 62) also demonstrated the importance of glucagon signaling in the adaptive response to fasting. Following exposure to a prolonged fasting period, Gcgr−/− mice showed increased levels of plasma triglycerides and free fatty acids 63). During either glucagon treatment or a prolonged fast, wild-type mice had an increased expression of genes involved in fatty acid oxidation, including Decr2, carnitine O-palmitoyltransferase (Cpt) 1a, Cpt2 and Acadm. These changes in expression were correlated with an increased capacity of the liver to oxidize free fatty acids. By contrast, this increased gene expression was not observed in Gcgr−/− mice, which displayed a reduced oxidation of free fatty acids in both the fed and the fasted state. These data highlight the essential physiological role of glucagon-receptor signaling in the regulation of gene expression during prolonged fasting.

Glucagon-mediated lipolysis and ketogenesis

Glucagon-mediated regulation of lipid metabolism is not limited to plasma triglycerides and cholesterol. Glucagon treatments as low as 10−8 mol/l have been implicated in promoting lipolysis in white adipose tissue 64). This lipolytic effect appears to be independent of sympathetic nervous system innervation 65), as denervation of white adipose tissue does not block glucagon-induced glycerol release, whereas it decreases the release of nonesterified fatty acids. The latter, however, is reported to be the result of re-esterification 66), not a blockade of glucagon’s lipolytic effects. Mechanistically, glucagon is known to stimulate the activity of hormone-sensitive lipase in adipocytes, resulting in an increase of nonesterified fatty acids in the circulation 67). These fatty acids, usually bound to albumin, are transported to the heart, skeletal muscle, kidney and liver, where they are catabolyzed or, in the case of the liver, alternatively converted to ketone bodies.

Ketone bodies provide up to two-thirds of the energy for the brain during times of glucose deficiency, thus sparing glucose utilization and reducing proteolysis 68). Supporting a role for glucagon in the regulation of keto-genesis, suppression of glucagon secretion via somatostatin prevented the development of ketoacidosis in patients with type 1 diabetes mellitus 69). Pegorier et al. 70) elucidated the regulation of fatty acid oxidation and keto-genesis by glucagon in rabbit hepatocytes. The researchers reported increased ketone-body production in the presence of either glucagon or dibutyryl cAMP. Oxidation of exogenous oleate was increased by both glucagon and cAMP, effects which were reduced in the presence of insulin. Furthermore, exposure to glucagon or cAMP completely inhibited lipogenesis and decreased malonyl-CoA concentration and stimulated fatty acid oxidation. These effects were suggested to be driven by a fall in the sensitivity of CPT1 to malonyl-CoA, releasing the inhibition of this rate-limiting enzyme in the transport of fatty acids across the mitochondrial membranes 71). The relevance of these studies was confirmed by the observation that glucagon directly controls ketone-body production in primary human hepatocytes 72). Specifically, glucagon increased ketone-body production and fatty acid oxidation, whereas it decreased fatty acid esterification, similar to the effects of cAMP 73).

Lipid-induced glucagon resistance

In addition to glucagon’s regulation of lipid metabolism, previous studies suggest that lipids may also regulate glucagon signaling. Studies by Charbonneau et al. 74) show that rats fed a high fat diet display hepatic steatosis that is associated with glucagon resistance. Specifically, exercise training in rats was used to increase plasma glucagon levels and improve fatty liver. In trained rats, a negative correlation between liver adiposity and density of the glucagon receptors in the plasma membrane was observed. Additional studies described a reduction in both hepatic glucagon-receptor density and Gsα protein content at the plasma membrane 75). The mechanism for this decrease in receptor density was explored in a study which proposed that high fat diet promoted glucagon receptor proteolysis 76). A reduction in glucagon receptors at the plasma membrane was notable, accompanied by a marked increase in the number of endosomal and lysosomal compartments. These effects were correlated with an increase of protein kinase Cα (PKCα) on the plasma membrane, which is known to phosphorylate G-protein-related kinases. Such action, in turn, is known to inhibit receptor internalization which leads to receptor desensitiza tion 77). The same association seems to be conserved in humans, as glucagon resistance is associated with pathological hyperlipidemia in humans 78).

Glucagon and bile acid metabolism

Although the canonical role of bile acids is associated with the absorption of dietary lipids and cholesterol homeostasis, new studies suggest that these acids have additional signaling roles in glucose homeostasis. This emerging function was highlighted in a study by Song and Chiang 79), who investigated cholesterol 7-alpha-monooxygenase (CYP7A1) as a possible target of glucagon signaling. Their study demonstrated that glucagon, as well as cAMP, represses CYP7A1 expression in human primary hepatocytes. CYP7A1 is the rate-limiting enzyme in bile acid synthesis, and its expression is tightly regulated as a means to control flux through the pathway 80). Song and Chiang86 further showed that glucagon’s regulation of CYP7A1 expression is mediated via PKA signaling to HNF-4α. Given that no direct measure of bile acid synthesis or secretion was available, the direct result on bile acid metabolism remains unknown. The findings of their earlier study 81), however, were complemented by work from Hylemon et al., 82) who showed similar decreases in CYP7A1 expression in response to glucagon or cAMP exposure in rat hepatocytes. These in vitro studies support initial observations that suggest a role for glucagon in the regulation of bile acid metabolism and provide a plausible mechanism for the glucagon-induced decrease in plasma cholesterol levels.

Glucagon and energy expenditure

In addition to regulating glucose and lipid metabolism, glucagon participates in the control of energy expenditure and thermogenesis. Early studies by Davidson et al. 83) showed that pharmacological infusion of glucagon increased oxygen consumption in rats. This effect was mirrored by a report in human study participants, in whom infusion of a pharmacological dose of glucagon increased resting energy expenditure during acute insulin deficiency produced by the additional infusion of somatostatin 84). Moreover, a physiological dose of glucagon increased energy expenditure in humans during euinsulinemia, and hyperinsulinemia blunted glucagon’s thermogenic activity 85). Studies conducted in vitro showed that hyperglucagonemia may increase energy expenditure via stimulation of oxygen consumption and heat production in brown adipose tissue 86). Studies in rats confirmed that glucagon administration increased whole-body oxygen consumption, core body temperature, blood flow 87), as well as temperature and mass of brown adipose tissue 88). Furthermore, cold exposure was found to increase plasma glucagon levels 89), which implicates glucagon in nonshivering thermogenesis. The stimulation of thermogenic activity in brown adipose tissue by glucagon 90) has become even more relevant, as novel findings suggest a renewed importance for brown adipose tissue in human energy metabolism 91).

The mechanism by which glucagon-induced thermogenesis is regulated is probably complex and may involve the sympathetic nervous system. Supporting this hypothesis, glucagon-induced increases in oxygen consumption, blood flow and thermogenesis in brown adipose tissue were blocked by the nonselective β adrenergic receptor blocker, propranolol 92), whereas denervation of brown adipose tissue blunted the thermogenic action of glucagon 93). Furthermore, although glucagon injection in ducklings was associated with an increase in norepinephrine, blockade of catecholamines via guanethidine sympathectomy (the interruption of the transmission of sympathetic nerve impulses by a chemical agent that blocks the secretion of epinephrine and norepinephrine at postganglionic nerve endings) decreased metabolic rate compared to nonsympathectomized birds treated with glucagon or saline 94). Glucagon might also have a direct effect on thermogenesis, as glucagon incubation of brown adipocytes of rat and mice, but not those of Syrian hamsters, markedly increased oxygen consumption 95). However, the concentration of glucagon required for such in vitro effects has been speculated to be supraphysiological 96).

The role of glucagon in mediating cold-induced thermogenic responses has been further questioned by a report that denervated interscapular brown adipose tissue decreased the number of glucagon receptors as compared to the contralateral adipose tissue pad that served as an internal (within animal) control 97). Given that cold exposure is a well-known stimulator of the sympathetic nervous system in brown adipose tissue 98), a decrease in glucagon receptor protein or gene expression mitigates the role for glucagon in cold-triggered brown adipose tissue thermogenesis via innervation of the sympathetic nervous system. Taken together, these data suggest a pivotal role for the sympathetic nervous system in glucagon-induced thermogenesis and suggest a thermogenic basis for anti-obesity effects of glucagon.

Glucagon on body weight

Recent studies have suggested that glucagon may have role in body weight regulation 99). Mice with the whole body glucagon receptor knockout have higher lean body mass despite similar to wild type animal growth pattern, food intake and energy expenditure 100). How the loss of glucagon action affects body composition remains to be determined but possible explanations may include effects on leptin, sympathetic nervous system, and brown adipose tissue thermogenesis and white adipose tissue lipolysis 101).

A study by Geary, N. & Smith, G. P. 102), found that selective hepatic vagotomy blocks glucagon’s satiety effect. This suggests a critical action of glucagon being conducted via the hepatic branch of the abdominal vagus. Although current evidence indicates that the inhibitory effect of glucagon on feeding probably arises, at least in part, from a hepatic metabolic action of the hormone, novel studies in animals suggest that additional effects of glucagon acting directly in the central nervous system to inhibit food intake are also possible 103).

Glucagon and regulation of food intake

Early studies indicated that glucagon administration diminishes the sense of hunger and decreases food intake in humans 104) and rats 105). Additional studies in rats confirmed that glucagon specifically decreases meal size owing to increased satiation rather than illness or aversion. Intravenous infusions similarly produced a dose-related decrease in eating 106). Evidence for an endogenous role of glucagon in satiation was provided by demonstrations that glucagon concentration increases physiologically during meals, in many situations 107), and that antagonism of glucagon by preprandial administration of glucagon antibodies increases the amount of food consumed in one meal (meal size) 108). Finally, intravenous infusion of a physiological dose of glucagon during meals was shown to reduce meal size in humans 109).

A study in rats with both hepatic portal vein and vena cava infusion catheters indicated that both exogenous and endogenous glucagon act in the liver to limit meal size 110). Furthermore, as for several other peripheral signals that control eating, vagal afferents relay the signal to the brain 111). In the case of glucagon, the hepatic branch of the abdominal vagus is critical 112), consistent with the hepatic site of action. Although the inhibitory effect of glucagon on feeding probably arises, at least in part, from a hepatic metabolic action of the hormone, novel studies in sheep suggest that glucagon acts directly in the central nervous system to inhibit food intake 113).

Genetically modified animal models also demonstrate that glucagon signaling is involved in regulating food intake and body composition. Gcgr−/− mice display a decreased adipose tissue mass and an increased lean mass despite similar food intake and body weight compared to their wild-type littermates 114). Furthermore, Gcgr−/− mice on a high fat diet are resistant to diet-induced obesity 115), which can be primarily attributed to a lower food intake compared with controls.

Glucagon injection

Glucagon injection is an emergency medicine used to treat severe hypoglycemia (low blood sugar) in diabetes patients treated with insulin who have passed out or cannot take some form of sugar by mouth or or treatment by mouth has not been successful. Glucagon emergency kit is available only with your doctor’s prescription. Glucagon is a hormone which helps to raise blood glucose levels. When injected, glucagon is absorbed into the blood stream and travels to the liver where it signals the liver to release glucose into the blood. Glucagon can be expected to take about 10-15 minutes to raise blood glucose back to safer levels.

Always read the instructions of the kit carefully when using glucagon.

Glucagon injection is also used as a diagnostic aid during X-ray tests of the stomach and bowels. This is to improve test results by relaxing the muscles of the stomach and bowels.

Glucagon emergency kit is available only with your doctor’s prescription. is available in the following dosage forms:

  • Powder for Solution

The glucagon emergency kit will usually consist of a syringe, a vial of powder and a vial of liquid. The instructions in the kit will give details of how to mix these for injection.

  • Glucagon can be injected into the arm, thigh or buttocks.
  • There is no danger of overdose with glucagon.
  • Glucagon can cause vomiting so make sure the patient remains in the recovery position to prevent the chances of choking.

The main symptoms associated with hypoglycemia are:

  • Sweating
  • Fatigue
  • Feeling dizzy

Symptoms of hypoglycemia can also include:

  • Being pale
  • Feeling weak
  • Feeling hungry
  • A higher heart rate than usual
  • Blurred vision
  • Confusion
  • Convulsions
  • Loss of consciousness
  • And in extreme cases, coma

Whilst medication is the main factor involved in hypoglycemia within people with diabetes, a number of other factors can increase the risk of hypos occurring.

Factors linked to a greater risk of hypos include:

  • Too high a dose of medication (insulin or hypo causing tablets)
  • Delayed meals
  • Exercise
  • Alcohol

Figure 4. Glucagon emergency kit

Glucagon emergency kit

Glucagon is usually given by injection beneath the skin, in the muscle, or in the vein. It comes as a powder and liquid that will need to be mixed just before administering the dose. Instructions for mixing and giving the injection are in the package. Glucagon should be administered as soon as possible after discovering that the patient is unconscious from low blood sugar. After the injection, the patient should be turned onto the side to prevent choking if they vomit. Once the glucagon has been given, contact your doctor. It is very important that all patients have a household member who knows the symptoms of low blood sugar and how to administer glucagon.

If you have low blood sugar often, keep a glucagon kit with you at all times. You should be able to recognize some of the signs and symptoms of low blood sugar (i.e., shakiness, dizziness or lightheadedness, sweating, confusion, nervousness or irritability, sudden changes in behavior or mood, headache, numbness or tingling around the mouth, weakness, pale skin, sudden hunger, clumsy or jerky movements). Try to eat or drink a food or beverage with sugar in it, such as hard candy or fruit juice, before it is necessary to administer glucagon.

Follow the directions on your prescription label carefully, and ask your pharmacist or doctor to explain any part you or your household members do not understand. Use glucagon exactly as directed. Do not use more or less of it or use it more often than prescribed by your doctor.

Glucagon injection is an emergency medicine and must be used only as directed by your doctor. Make sure that you and a member of your family or a friend understand exactly when and how to use this medicine before it is needed.

This medicine comes with patient instructions together with the kit provided with the package. Read and follow the instructions carefully and ask your doctor if you have any questions.

Do not use this medicine if a gel has formed, or if you see particles in the mixed solution.

Call for emergency medical help right after receiving glucagon injection.

Drink a fast-acting source of sugar such as a regular soft drink or fruit juice, and eat a long-acting source of sugar (such as crackers and cheese or a meat sandwich) as soon as you are able to swallow.

Special precautions

Before using glucagon:

  • tell your doctor and pharmacist if you are allergic to glucagon, any other drugs, or beef or pork products.
  • tell your doctor and pharmacist what prescription and nonprescription medications you are taking, including vitamins.
  • tell your doctor if you have ever had adrenal gland problems, blood vessel disease, malnutrition, pancreatic tumors, insulinoma, or pheochromocytoma.
  • tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding.

Patients with diabetes should be aware of the symptoms of hypoglycemia (low blood sugar). These symptoms may develop in a very short time and may result from:

  • using too much insulin (“insulin reaction”) or as a side effect from oral antidiabetic medicines
  • delaying or missing a scheduled snack or meal
  • sickness (especially with vomiting or diarrhea)
  • exercising more than usual.

Unless corrected, hypoglycemia will lead to unconsciousness, convulsions (seizures), and possibly death. Early symptoms of hypoglycemia include: anxious feeling, behavior change similar to being drunk, blurred vision, cold sweats, confusion, cool pale skin, difficulty in concentrating, drowsiness, excessive hunger, fast heartbeat, headache, nausea, nervousness, nightmares, restless sleep, shakiness, slurred speech, and unusual tiredness or weakness.

Symptoms of hypoglycemia can differ from person to person. It is important that you learn your own signs of low blood sugar so that you can treat it quickly. It is a good idea also to check your blood sugar to confirm that it is low.

You should know what to do if symptoms of low blood sugar occur. Eating or drinking something containing sugar when symptoms of low blood sugar first appear will usually prevent them from getting worse, and will probably make the use of glucagon unnecessary. Good sources of sugar include glucose tablets or gel, corn syrup, honey, sugar cubes or table sugar (dissolved in water), fruit juice, or non-diet soft drinks. If a meal is not scheduled soon (1 hour or less), you should also eat a light snack, such as crackers and cheese or half a sandwich or drink a glass of milk to keep your blood sugar from going down again.

You should not eat hard candy or mints because the sugar will not get into your blood stream quickly enough. You also should not eat foods high in fat such as chocolate because the fat slows down the sugar entering the blood stream. After 10 to 20 minutes, check your blood sugar again to make sure it is not still too low.

Tell someone to take you to your doctor or to a hospital right away if the symptoms do not improve after eating or drinking a sweet food. Do not try to drive, use machines, or do anything dangerous until you have eaten a sweet food.

If severe symptoms such as convulsions (seizures) or unconsciousness occur, the patient with diabetes should not be given anything to eat or drink. There is a chance that he or she could choke from not swallowing correctly. Glucagon should be administered and the patient’s doctor should be called at once.

When to use glucagon injection

Glucagon is for use when someone is suffering severe hypoglycemia and is unable to treat themselves.

Glucagon may be given if the patient is:

  • unconscious
  • having a seizure
  • unable to take anything sweet to raise their blood glucose
  • or the patient has taken glucose by mouth which has not produced a raise in their blood glucose levels

Glucagon dosage

The dose of glucagon will be different for different patients. Follow your doctor’s orders or the directions on the label. The following information includes only the average doses of glucagon. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of glucagon that you take depends on the strength of glucagon. Also, the number of glucagon doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using glucagon injection.

For glucagon injection dosage form:

  • As an emergency treatment for severe hypoglycemia:
    • Adults and children 6 years and older and weighing 25 kilograms (kg) or more: 1 milliliter (mL) injected under your skin, into a muscle, or into a vein. The dose may be repeated while waiting for emergency assistance.
    • Children younger than 6 years of age and weighing less than 25 kg: 0.5 mL injected under your skin, into a muscle, or into a vein.

If it becomes necessary to inject glucagon, a family member or friend should know the following:

  • After the glucagon injection, turn the patient on his or her left side. Glucagon may cause some patients to vomit and this position will reduce the possibility of choking.
  • The patient should become conscious in less than 15 minutes after glucagon is injected, but if not, a second dose may be given. Get the patient to a doctor or to hospital emergency care as soon as possible because being unconscious too long can be harmful.
  • When the patient is conscious and can swallow, give him or her some form of sugar. Glucagon is not effective for much longer than 1½ hours and is used only until the patient is able to swallow. Fruit juice, corn syrup, honey, and sugar cubes or table sugar (dissolved in water) all work quickly. Then, if a snack or meal is not scheduled for an hour or more, the patient should also eat some crackers and cheese or half a sandwich, or drink a glass of milk. This will prevent hypoglycemia from occurring again before the next meal or snack.
  • The patient or caregiver should continue to monitor the patient’s blood sugar. For about 3 to 4 hours after the patient regains consciousness, the blood sugar should be checked every hour.
  • If nausea and vomiting prevent the patient from swallowing some form of sugar for an hour after glucagon is given, medical help should be obtained.

Keep your doctor informed of any hypoglycemic episodes or use of glucagon even if the symptoms are successfully controlled and there seem to be no continuing problems. Complete information is necessary for the doctor to provide the best possible treatment of any condition.

Replace your supply of glucagon as soon as possible, in case another hypoglycemic episode occurs.

You should wear a medical identification (ID) bracelet or chain at all times. In addition, you should carry an ID card that lists your medical condition and medicines.

Glucagon side effects

Glucagon may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

  • nausea
  • vomiting
  • rash
  • itching

If you experience any of the following symptoms, call your doctor immediately:

  • difficulty breathing
  • loss of consciousness

Rare side effects:

  • anxiety
  • blurred vision
  • chills
  • cold sweats
  • coma
  • confusion
  • cool, pale skin
  • depression
  • dizziness
  • fast heartbeat
  • headache
  • increased hunger
  • nausea
  • nervousness
  • nightmares
  • seizures
  • shakiness
  • slurred speech
  • unusual tiredness or weakness

Incidence not known:

  • difficulty with swallowing
  • dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
  • fast, pounding, or irregular heartbeat or pulse
  • hives, itching, or skin rash
  • pounding in the ears
  • puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
  • slow or fast heartbeat
  • sweating
  • tightness in the chest

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

References   [ + ]

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