100 years of glucagon
While the recent 100th anniversary of the discovery of insulin was widely acknowledged in the diabetes community, much less attention has been paid to the centenary of its vital counter-regulatory hormone, glucagon. To redress the balance, a new review in Diabetologia looks at the biology and clinical aspects of glucagon, and at the promise of glucagon-based therapies. Dr Susan Aldridge reports.
The discovery of insulin in 1921 was accompanied by the observation that pancreatic extracts and crude insulin preparations induce a brief episode of hyperglycaemia before glucose levels decrease. During experiments with insulin in 1922, Charles Kimball and John Murlin isolated a pancreatic factor that elevates blood glucose in rabbits and dogs. They called this ‘glucose agonist’ – later known as glucagon – for its ability to oppose the hypoglycaemic effect of insulin. Today, glucagon is used as a treatment for severe hypoglycaemia, although this has only come into general use relatively recently.
In the years that followed the initial discovery, several groups looked into the mechanisms underlying glucagon’s hyperglycaemic effect, although its status as a hormone was not yet generally accepted. Glucagon was finally purified and crystallised in 1953 and its 29-amino acid sequence determined in 1957.
Meanwhile, Christian de Duve, Earl Sutherland and colleagues identified the secretory origin of glucagon as the pancreatic alpha cells and discovered that the gastric mucosa are another source of glucagon. And with the introduction of the first glucagon radioimmunoassay by Roger Unger and colleagues in 1959, it became possible to measure plasma concentrations of glucagon and therefore study its physiology and role in pathophysiological processes. This led to the discovery that people with diabetes have increased plasma glucagon concentrations.
Since then, efforts have been made to understand the regulation of glucagon, but many gaps in our knowledge remain. There have also been challenges in developing methods for the accurate measurement of glucagon levels, which have added to difficulties in fully understanding its biology. In this review, Nicolai Albrechtsen of Copenhagen University Hospital and colleagues elsewhere took a detailed look at what we now know about glucagon, including its role in diabetes and promise as a therapeutic.
Glucagon in diabetes
The historic finding of hyperglucagonaemia in type 2 diabetes has now been replicated in numerous studies and it is found in both fasting and feeding conditions. Glucagon receptor (GRCR) antagonists lower glucose and HbA1c in rodent models of type 2 diabetes and in people who have the condition. These findings suggest that hyperglucagonaemia contributes to the raised glucose levels that are a hallmark of type 2 diabetes. However, postprandial hyperglucagonaemia in response to an oral glucose tolerance test (OGTT) is not always observed in experiments.
This suggests that lack of glucagon suppression may not be a central feature of type 2 diabetes. Instead, fasting hyperglucagonaemia appears to be more associated with hepatic insulin resistance or with hepatic steatosis. So when hyperglucagonaemia is seen in type 2 diabetes, it may arise from concurrent liver disease, specifically hepatic steatosis. In the authors’ opinion, a mixed meal as a test stimulus – rather than the OGTT – may better reflect changes in plasma glucagon in a real-world setting. After a mixed meal, glucagon secretion might increase in response to the protein and lipid content of the meal.
Meanwhile, hyperglucagonaemia has also been reported in people newly diagnosed with type 1 diabetes and in animal models. When type 1 diabetes is well controlled, hyperglucagonaemia may not be evident and may only be seen where there is inadequate insulin therapy. This may explain why a recent study of people with type 1 diabetes treated with a glucagon receptor (GCGR) antagonist showed little effect of this potential therapy on blood glucose levels.
Glucagon in liver disease
People with liver cirrhosis sometimes have hyperglucagonaemia, which may be linked with the co-existence of kidney disease. It is also, more consistently, found in people with non-alcoholic fatty liver disease (NAFLD), independent of type 2 diabetes. A major confounding factor here is the close association between obesity and NAFLD. So a key question is whether it is obesity or NAFLD that drives hyperglucagonaemia. Preliminary data from the authors’ laboratories suggest that both are involved, though via different mechanisms. People with NAFLD have a disrupted liver-alpha cell axis, suggesting that elevated amino acid levels (and maybe fatty acids too), rather than dysfunctional glucose sensing by alpha cells, are behind the hyperglucaconaemia.
Agonism, antagonism or co-agonism
Hepatic glucose production of glucagon is increased in people with type 2 diabetes, compared with those without diabetes of similar age and BMI. This is consistent with the importance of hyperglucagonaemia in type 2 as mentioned above. Also, somatostatin-induced inhibition of glucagon lowers blood glucose in both insulin-deficient dogs and people with type 1 diabetes.
Meanwhile, mice that are deficient in the glucagon receptor show improved glucose tolerance and enhanced insulin sensitivity. The authors note that such mice are also resistant to beta cell destruction and hyperglycaemia that is induced by streptozotocin. This suggests that perhaps the presence of glucagon may play a more important role in the development of type 1 diabetes than lack of insulin. Ongoing experiments are exploring this idea.
In light of glucagon’s ability to increase glucose production and the beneficial effects of glucagon signal inhibition for the treatment of type 2 diabetes, it seems counterintuitive that glucagon could be used with GLP-1 receptor agonists to treat obesity and type 2 diabetes. The rationale for the first GLP-1/glucagon receptor co-agonist came from the observation that a water-soluble form of glucagon not only decreased body weight in mice with diet-induced obesity but also improved glucose tolerance.
Consistent with the non-glycaemic effects of glucagon, which inhibit food intake, enhance lipid metabolism and accelerate energy expenditure, a single molecule GLP-1/GCGR co-agonist improved body weight and glucose control in mice with diet-induced obesity beyond that which could be achieved with GLP-1 receptor agonism alone. That the co-agonist can improve glucose, lipid and energy metabolism has now also been demonstrated in human studies. A series of co-agonists is now progressing in clinical development for the treatment of type 2 diabetes, non-alcoholic steatohepatitis (NASH) and obesity.
Based on these findings, the addition of glucagon action has also been shown to enhance the effects of the GIP/GLP-1 receptor co-agonism exemplified by tirzepatide. And a series of GLP-1/GIP/GCGR tri-agonists are in clinical development, showing promising efficacy and safety. With the current buzz around anti-obesity drugs such as semaglutide, it will be fascinating to see what a tri-agonist might achieve.
Although glucagon, like insulin, has been studied for more than 100 years, some its physiological actions are still under debate and investigation. Its role in hepatic glucose metabolism and the regulation of alpha cell glucagon secretion by glucose have been the subject of intense study, but other aspects of glucagon biology have received less attention so far. Key areas for study include the role of glucagon in the kidney, its effect in the heart and the importance of GCGR signalling for brain-associated metabolism and function, including appetite and food intake.
Of special interest is the development of therapeutics based on glucagon’s metabolic actions, particularly in combination with GLP-1 receptor agonists, which may have special application in the metabolic liver diseases that often accompany obesity and/or type 2 diabetes. In this context, knowledge about the cardiovascular consequences of glucagon agonism will be essential. It is safe to say that the future use of glucagon and GCGR agonism will probably not be limited to the treatment of severe hypoglycaemia.
To read this paper, go to: Albrechtsen NJW, Holst JJ, Cherrington AD, Finan B, Gluud LL, Dean ED, Campbell JE, Bloom SR, Tan TM, Knop FK, Müller TD. 100 years of glucagon and 100 more. Diabetologia 27 June 2023. https://doi.org/10.1007/s00125-023-05947-y
To learn more about NAFLD, enrol on the EASD e-Learning course ‘Non-alcoholic fatty liver disease’.
Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.