Abstract
Glucagon is secreted by the pancreatic alpha cell and has long been known to oppose insulin action. A lyophilized form of the hormone has been available to treat episodes of insulin-induced hypoglycemia in insulin-treated people with diabetes for decades, but the difficulty of use was a barrier to widespread utilization. Newer formulations of glucagon are stable at room temperature in single-use devices that many caregivers find are easier to use than the original glucagon emergency kit. In this review , we will review what is known about the role of glucagon in normal physiology and diabetes and then discuss how the research in this area has been translated into treatment for metabolic conditions.
Introduction
Glucagon is a 29 amino acid pancreatic peptide hormone secreted by the pancreatic alpha cells. It is derived from the precursor hormone proglucagon, which is also a precursor for glucagon-like gut peptides (Sandoval & D’Alessio 2015) (Fig. 1). For almost 50 years, glucagon has been understood to be a hyperglycemic factor that opposes the effects of insulin and has been used pharmacologically to correct insulin-induced hypoglycemia. More recently, research has increased our understanding of the physiology of glucagon, its potential role in the causation of diabetes, and its synergistic effects with other gut hormones in regulating metabolism. In this review article, we aim to summarize the known effects of glucagon and its translational aspects. We will first review what is known about the role of glucagon in normal physiology and diabetes and then discuss how the research in this area has been translated into treatment for metabolic conditions.
Discovery of glucagon
In the last half of the 19th century, many researchers, including Paul Langerhans, Oskar Minkowski, and Joseph von Mering, focused on understanding the basic structure and function of the endocrine pancreas. When pancreatectomized dogs were found to develop diabetes, it became clear that pancreatic dysfunction was central to the pathogenesis of the disease. This led to the discovery of insulin by Banting and Best in 1921 and the subsequent translational work that developed insulin as a therapy for diabetes. In 1922, Kimball and Murlin isolated a pancreatic extract component that increased blood glucose levels in rabbits and dogs. They named this component ‘glucagon’ from ‘glucoseagonist’ (Von Mering & Minkowski 1889). It took until the 1950s for this hormone to be purified and crystallized at Eli Lilly and Co (Staub et al. 1955). The complete amino acid sequence of glucagon was reported shortly afterward (Bromer et al. 1957). The molecular structure of glucagon is illustrated in Fig. 2. Unger and colleagues developed the first radioimmunoassay for glucagon in 1959 (Unger et al. 1961). This landmark innovation provided investigators with the new toll to use in elucidating basic glucagon physiology.
Metabolic effects of glucagon.
Citation: Journal of Endocrinology 257, 1; 10.1530/JOE-22-0278
Chemical structures of glucagon and dasiglucagon. Amino acids circled in red represent changes from native glucagon
Citation: Journal of Endocrinology 257, 1; 10.1530/JOE-22-0278
Metabolic effects of glucagon
Glucagon action on tissues begins with the binding of the hormone to its G protein-coupled receptor located on the plasma membrane (Pierce et al. 2002). The impact of this hormone on organ function is shown in Fig. 3. Glucagon augments glucose-stimulated increases insulin secretion from the β-cells in the islets of the pancreas. In the liver, glucagon antagonizes the effects of insulin by stimulating glycogenolysis and gluconeogenesis, thereby increasing hepatic glucose output.
Posttranslational products of proglucagon.
Citation: Journal of Endocrinology 257, 1; 10.1530/JOE-22-0278
Besides its effects on glucose metabolism, glucagon has been shown to exert its effects on amino acid and lipid metabolism as well. The data on the effects of glucagon on lipid metabolism have been conflicting. In older mice model experiments, glucagon has been shown to antagonize insulin’s effects on lipolysis in white adipose tissue and liver leading to the mobilization of fat stores (Habegger et al. 2013). In addition, glucagon was noted to stimulate beta-oxidation of fatty acids, inhibit lipogenesis, and decrease triglyceride and very low-density lipoprotein levels (Galsgaard et al. 2019). Newer studies in mice models show on the effect of glucagon on lipolysis in white adipose tissue (Vasileva et al. 2022). An in vitro experiment on human adipocytes has shown a minor direct effect of the physiological level of glucagon on lipolysis (Pereira et al. 2020). A liver-α-cell axis has been postulated to exist where amino acids and glucagon are involved in mutual feedback interactions (Holst et al. 2017). Amino acids stimulate the α-cells to produce glucagon which in turn supports the conversion of the hepatic amino acids to glucose, in animal and human studies (WewerAlbrechtsen et al. 2018, Winther-Sorensen et al. 2020). Glucagon also regulates hepatic amino acid metabolism by induction of hepatic ureagenesis in mice models (Hamberg & Vilstrup 1994, Galsgaard et al. 2020). In the case of glucagon-producing tumors (glucagonoma), hypoaminoacidemia with accelerated ureagenesis is seen (Barazzoni et al. 1999, Holst et al. 2017). In patients with mutations in glucagon receptors (Mahvash disease) (Yu 2018) and in knockout mice (Galsgaard et al. 2018), hyperaminoacidemia is noted. More details about the metabolic effects of glucagon on lipid and amino acid metabolism can be found in several outstanding reviews (Galsgaard et al. 2019, Winther-Sorensen et al. 2020).
In mice, glucagon increases thermogenesis in the brown adipose tissue directly or indirectly through its stimulation of hepatic production of FGF 21 production along with an increase in circulating level (Kinoshita et al. 2014). Glucagon has been shown to exert an inhibitory effect on gastrointestinal motility in dogs and humans, explaining the common side effects of nausea and vomiting associated with glucagon administration (Patel et al. 1979, Mochiki et al. 1998). Radiographic studies in 15 male and female volunteers have shown a dose-dependent effect of i.m. administration on gastrointestinal motility, larger doses were associated with a longer duration of action (Miller et al. 1978). Glucagon has been shown to increase satiety leading to decrease food intake in both mice and humans (Habegger et al. 2010).
Glucagon and hypoglycemia
Glucagon plays a critical role in maintaining normoglycemia, particularly in the fasting state. In healthy individuals, beta cell secretion is inhibited when the plasma glucose falls below 80 mg/dL and alpha cell secretion is activated in response to a fall in plasma glucose to a value less than 70 mg/dL (Hawkes et al. 2019). Activation of the sympathetic nervous system, and cortisol and growth hormone secretion also occur as the glucose falls below 60–65 mg/dL (Hawkes et al. 2019). Together these actions prevent the development of hypoglycemia. This counterregulatory response to hypoglycemia becomes impaired in people with type diabetes soon after the onset of the disease and gradually diminishes over time (Cryer 2012). This loss of response is thought to be secondary to progressive β-cell failure, probably because hypoglycemia-induced inhibition of insulin secretion is an important paracrine signal leading to glucagon secretion in the setting of hypoglycemia. As a result, people with type 1 and advanced type 2 diabetes must rely on the catecholamine response to hypoglycemia to prevent progressive hypoglycemia and return blood sugar to normal. Over time, this response also becomes impaired and people with diabetes develop a great risk of developing severe hypoglycemia, which can lead to death. To mitigate this risk, glucagon has been used therapeutically to treat severe hypoglycemia since the 1950s.
Translational aspects of glucagon
Treatment of hypoglycemia
Glucagon was first developed as a treatment for severe hypoglycemia. The original glucagon emergency kit contains a lyophilized form of human glucagon that must be reconstituted into an acidic solution immediately before its immediate use. Each kit contains a vial of 1 mg sterile glucagon powder and a prefilled syringe of 1 mL acidic diluent that a bystander must combine before it can be given to a person with severe hypoglycemia. At this dose, s.c. administration resulted in a mean peak glucose concentration of 136 mg/dL at 30 min after injection and i.m. injection in a glucose concentration of 138 mg/dL at 26 min after injection in a comparative study. The two-step process for reconstituting lyophilized glucagon has proven to be a barrier to its administration because caregivers must prepare the product for use at the same time and in the same place a person with diabetes is recognized to have severe hypoglycemia. The stress of this experience reduces both the rate of successful administration and user satisfaction (Kedia 2011, Rylander 2015).
To overcome the limitations of the emergency glucagon kit, several companies have developed new glucagon products that are ready to use and do not require refrigeration (Table 1). Nasal glucagon (BAQSIMI, Eli Lilly) contains a human recombinant hormone in a powdered form and is packaged in a single-use container designed for intranasal administration. Liquid stable glucagon (GVOKE HypoPen, Xeris Pharmaceuticals, Chicago, IL, USA) is packaged as a single-use injectable pen and contains dimethyl sulfoxide as a solvent to keep the hormone in solution. Dasiglucagon is a glucagon analog composed of 29 amino acids (Fig. 2 B). The seven amino acid substitutions apparent in the figure result in enhanced stability by reducing the tendency for glucagon to form fibrils in aqueous solution (Hovelmann et al. 2018). It comes in a prefilled autoinjector and a prefilled syringe.
Currently available glucagon formulations.
| Traditional glucagon kits | Nasal glucagon | Liquid stable glucagon | Dasiglucagon | |
|---|---|---|---|---|
| Brand name | GlucaGen HypoKit Glucagon Emergency Kit |
BAQSIMI | GVOKE | ZEGALOGUE |
| Manufacturer | Novo Nordisk Eli Lilly |
Eli Lilly | Xeris Pharmaceuticals | Zealand Pharma (Søborg, Denmark) |
| Molecular formula of active ingredient | C153H225N43O49S (native glucagon) |
C153H225N43O49S (native glucagon) | C153H225N43O49S (native glucagon) | C152H222N38O50 (glucagon analog) |
| Adult dose | 1 mg | 3 mg | 1 mg | 0.6 mg |
| Pediatric dose | 1 mg (FDA 2010; FDA 2021a) | 4 years and older 3 mg (FDA 2019) | 12 years and older 1 mg 2–12 years <45 kg 0.5 mg 2–12 years >45 kg 1 mg (Gvoke 2021) |
6 years and older 0.6 mg ( FDA 2021b) |
| Delivery device | Kit containing a vial of sterile glucagon and a syringe of sterile diluent | Single-use, ready-to-use device | Single-dose pre-filled syringe/auto-injector | Single-dose pre-filled syringe/auto-injector |
| Route of administration | Subcutaneous, intramuscular | Intranasal | Subcutaneous | Subcutaneous |
| Adverse effects | Nausea, vomiting, headache | Nausea, vomiting, headache, upper respiratory tract irritation, watery eyes, redness of eyes, itchy nose, throat, and eyes | Nausea, vomiting, injection site reaction, headache | Nausea, vomiting, headache, diarrhea, and injection site reaction |
| Storage | GlucaGen HypoKit: At controlled room temperature 20–25°C (68–77°F) prior to reconstitution Glucagon Emergency Kit: At controlled room temperature, 15–30°C prior to reconstitution Both need to be discarded after reconstitution |
At temperatures up to 30°C (86°F) in the shrink-wrapped tube | At controlled room temperature, 20–25°C (68–77°F) | In a refrigerator between 2–8°C (36–46°F) |
Each of these novel glucagon products has been shown to be effective and increase plasma glucose to the same degree as the glucagon emergency kit. Nasal glucagon (3 mg) was studied in a randomized, multicenter, crossover study in 75 adult patients with type 1 diabetes where insulin was given to achieve nadir blood glucose levels to 50 mg/dL. Nasal glucagon was as effective as intramuscularly administered glucagon in reversing insulin-induced hypoglycemia with 100% of participants in both groups achieving treatment success (defined as an increase inplasma glucose to ≥70 mg/dL or an increase of ≥20 mg/dL from the plasma glucose nadir within 30 min of receiving glucagon) (Rickels et al. 2016). Liquid stable glucagon was compared to traditional glucagon kits in a multicenter cross over study involving 161 participants (Christiansen et al. 2021) subjected to insulin - induced hypoglycemia. The proportion of patients who achieved a primary outcome of a plasma glucose >70 mg/dL (from baseline glucose of <50 mg/dL) was 98.7% in the liquid stable glucagon group and 100% in the glucagon emergency kit group. The mean time to achieve the primary outcome was similar in both groups. Dasiglucagon was examined in a multicenter crossover student of 170 participants who also underwent experimental hypoglycemia (Pieber et al. 2021) where plasma glucose concentration was reduced to <60 mg/dL using an i.v. insulin infusion. The median time to plasma glucose recovery, defined as an increase in plasma glucose of ≥20 mg/dL from baseline without rescue i.v. glucose, was significantly shorter (P < 0.001) for dasiglucagon (10 min) vs placebo (40 min). The median time to plasma glucose recovery for reconstituted glucagon was 12 min. These agents all have side effects similar to the glucagon in the emergency kit (Table 1). These novel glucagon formulations have been approved for use in children as well (Deeb et al. 2018, Battelino et al. 2021), as is shown in Table 1.
The usability of nasal glucagon and the glucagon autoinjector by caregivers compared to the emergency kits has been tested in situations of simulated hypoglycemia. In both, more caregivers were successful in administering the novel product than were caregivers asked to administer the glucagon in the emergency kit (Seaquist et al. 2018, Valentine et al. 2019, Settles et al. 2020, Christiansen et al. 2021).
Future uses of glucagon currently under study
Bihormonal pumps for management of diabetes
Bihormonal pumps that contain both insulin and glucagon and are coupled to a continuous glucose monitor have been proposed as a new method to treat type 1 diabetes. In theory, such pumps would use an algorithm to administer both insulin and glucagon to achieve target glycemia. Glucagon delivery would occur to prevent hypoglycemia in a situation where reducing the basal rate of insulin was deemed to be insufficient. Small, randomized trials with human glucagon have shown these pumps perform as well as closed loop pumps that contain insulin alone with respect to reducing the time spent less than 70–72 mg/d L, but glucagon need s to be replaced on a daily basis because of its instability in solution (Haidar et al. 2017, Castle et al. 2018). More recent trials have demonstrated that the use of bihormonal pumps increased the time in thenormoglycemic range and reduced the time in thehypoglycemia range in patients following total pancreatectomy (van Veldhuisen et al. 2022) and that they could be safely used by persons with type 1 diabetes in the outpatient setting (El-Khatib et al. 2017, Blauw et al. 2021). The glucagon solution in these pumps had to be reconstituted every 24 h in these pumps (Haidar et al. 2017). With the development of glucagon analogs that are stable in solution at room temperature for prolonged periods of time, these suggestions now appear feasible. Short trials that were days in length of small numbers of subjects have shown liquid stable glucagon and dasiglucagon can be feasibly used to manage glycemic control in type 1 diabetes (Russell et al. 2016, El-Khatib et al. 2017, Castellanos et al. 2021). Larger trials are now planned.
Exercise-induced hypoglycemia
Activity-induced hypoglycemia is common in people with type 1 diabetes and can prevent people from engaging in aerobic exercises. The use of glucagon therapy for the prevention of exercise-associated hypoglycemia in pump users with type 1 diabetes has recently been examined by Rickels and colleagues. They performed a randomized controlled study in 15 adults with type 1 diabetes, where subjects were exercised in the fasted state in the morning at ∼55% VO2max for 45 min under conditions of no intervention (control), 50% basal insulin reduction, 40 g oral glucose tablets, or 150 μg liquid stable glucagon (Rickels et al. 2018). All interventions were administered 5 min before the exercise session. Plasma glucose levels were measured at t= 5, 10, 15, 25, 35, and 45 min during exercise and at t= 50, 55, 60, and 75 min during early recovery from exercise. Both glucagon and glucose ingestion led to slightly higher plasma glucose levels during the exercise and the control condition, while the reduction in insulin had no effect. There was a greater increase in plasma with glucose ingestion compared to glucagon in the early recovery phase after exercise (P < 0.001). Hypoglycemia(plasma glucose <70 mg/dL) was experienced by six subjects following the control intervention, five subjects during insulin reduction, and none with glucose tablets or glucagon administration. Five subjects developed post-intervention hyperglycemia (plasma glucose ≥250 mg/dL) following ingestion of glucose tablets but only one subject did so following glucagon administration.
Post-bariatric hypoglycemia
Post-bariatric hypoglycemia (PBH) occurs in approximately 0.2–1% of patients undergoing the procedure and sometimes can be challenging to treat (Marsk et al.2010, Patti & Goldfine2016, Salehi et al. 2018). In a recent randomized controlled trial, the efficacy of dasiglucagon in preventing postprandial hypoglycemia in ten participants with Roux-en-Y gastric bypass–associated post PBH was examined (Nielsen et al. 2022). Each subject underwent a mixed meal challenge on three separate occasions: once after placebo, once after administration of 80 µg dasiglucagon, and once after administration of 200 µg of dasiglucagon. The nadir plasma glucose was raised by 0.9 mmol/L (16.2 mg/dL) (95% CI 0.35–1.35 mmol/L; P = 0.002) and 1.4 mmol/L (25.2 mg/dL) (95% CI 0.81–2.05 mmol/L; P = 0.0002) compared to placebo following administration of 80 and 200 µg dasiglucagon, respectively. Time in hypoglycemia (plasma glucose <70 mg/dL) was significantly reduced to 0.0 min (0.0; 58.8) (P = 0.03) (median (interquartile range) after 80 µg and 0.0 min (0.0; 11.3) (P = 0.008) after 200 µg dasiglucagon administration compared to 70.0 min (38.8; 80.0) in the placebo condition. Five participants experienced severe hypoglycemia (<54 mg/dL) in the placebo group, while only one of ten participants treated with 80 µg of dasiglucagon experienced severe hypoglycemia (P = 0.066). None of the participants experienced severe hypoglycemia following the administration of 200 µg of dasiglucagon (P < 0.05).
Treatment of diabetes
Several oral glucagon receptor antagonists have been developed for the treatment of diabetes over the last few decades based on the hypothesis that hyperglucagonemia and α-cell hyperplasia may play a role in the development of diabetes. LY2409021 and RVT-1502 have been studied in phase 2 clinical trials and showed modest glucose lowering with reversible elevations in transaminases. In a 12-week randomized trial, RVT-1502 significantly reduced HbA1c relative to placebo by 0.74, 0.76, and 1.05% in the 5-, 10-, and 15 mg groups (P < 0.001), respectively) (Pettus et al. 2020). Only modest elevations but reversible in serum transaminases were noted. The rate of hypoglycemia was low. LY2409021 also demonstrated increases in hepatic fat (Guzman et al. 2017). Interestingly, an increase in GLP-1 levels was noted in some studies, likely due to the upregulation of proglucagon by glucagon receptor antagonism. Whether this increase in GLP-1 level also helps with glycemic control needs to be determined by future studies.
A monoclonal antibody antagonist of the glucagon receptor has also been developed as a potential treatment for type 2 diabetes. RN909 is given subcutaneously each month and was used in a dose escalation trial in 84 type 2 diabetic subjects for 12 weeks (Gumbiner et al. 2018). This drug produced significant dose-dependent decreases in fasting glucose levels and HbA1c levels. This medication was well tolerated , but the incidence of antidrug antibodies was 33% after single doses and 50% after multiple doses.
The use of incretin hormones, GLP 1 and GIP, in the management of type 2 diabetes and obesity has gained significant momentum in the last few years. Most of these hormones are derived from the posttranslational processing of preproglucagon in different tissues and they have been shown to lead to substantial weight loss. Recently, investigators have begun to test drugs that act on both the receptors of glucagon and incretin hormones. One such drug is mazdutide (IBI362), a GLP 1/glucagon receptor dual agonist that is given weekly. It was recently tested in a 12 week phase 1b trial (Ji et al. 2021) in 12 participants with overweight (body mass index (BMI) ≥24 kg/m2) accompanied by hyperphagia and/or at least one comorbidity or obesity (BMI ≥28 kg/m2). Between the baseline and 12 weeks, the participants lost −6.05% (−7.91 to −4.18) of their mean bodyweight on the highest dose of 6 mg compared with 0.60% (−0.86 to 2.07) for those receiving placebo. The most common adverse events were gastrointestinal. Another GLP 1/glucagon receptor dual agonist, cotadutide (MEDI0382), was recently compared to liraglutide 1.8 mg a week in a 54 week phase 2b trial (Nahra et al. 2021) of 834 subjects with overweight/obesity and type 2 diabetes. Cotadutide, administered subcutaneously daily, led to a significant decrease in bodyweight and HbA1c compared to placebo. The weight loss was also greater than liraglutide at the highest dose. Improvements in lipid profile, AST and ALT levels, propeptide of type III collagen level, fibrosis-4 index, and nonalcoholic fatty liver disease fibrosis score were observed with the highest dose of cotadutide compared to liraglutide and placebo.
Conclusions
Glucagon is a pancreatic hormone that has been used most widely to treat severe hypoglycemia in people with diabetes who are treated with insulin or sulfonylureas. Recent improvements in the formulations of available products have made glucagon easier to use for caregivers. Glucagon is also being developed as a treatment for post - bariatric surgery hypoglycemia and for use in bihormonal pumps. In the future, glucagon-related products may become useful for the management of type 2 diabetes and obesity.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the review reported.
Funding
This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.
Author contribution statement
JK drafted the review and ERS revised the draft.
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