Potential use of glucagon agonism in diabetes
Insulin and glucagon are partner hormones in glucose metabolism, but the therapeutic potential of glucagon remains under-developed. Native glucagon is highly unstable and its only current therapeutic use is in “rescue kits” for treating severe hypoglycemia. The available kits are difficult to use because glucagon is not stable in solution and has to be reconstituted in a buffer just before injection. There is however large potential in developing glucagon receptor (GCG-R) agonists for improved versions of the rescue kits since these are highly underused and only a few people with diabetes carry these kits with them at all times. An alternative therapeutic use of glucagon would be in a dual hormone (insulin and glucagon) automated artificial pancreas (AP), or bionic pancreas. This has long been a dream, since a dual control system could permit much tighter control of blood glucose levels. Current automated systems only supply insulin and cannot respond directly to hypoglycaemia. Several companies, consortia and clinics are developing more or less automated APs using algorithms that balance insulin and glucagon infusion in response to continuous glucose monitoring.
Insulin and glucagon are reciprocally released by pancreatic islet cells to regulate glucose secretion by the liver, an interaction considered in more detail under Glucose metabolism and Glucagon . Insulin, however, has found widespread therapeutic application, whereas glucagon has found limited clinical application.
(see also Treatment and prevention of hypoglycaemia)
The need to reconstitute native glucagon in current rescue kits for severe hypoglycaemia presents a major challenge for for relatives, friends or other people without proper instruction to treat a person with severe hypoglycemia. This helps to explain why people with diabetes and their families are unenthusiastic about the current rescue kits, and why these are underused.
The quest for stable glucagon
For this reason, there appears to be a market for easy-to-use rescue kits which do not require reconstitution, prepared in a simple pen device for immediate use. Such devices could potentially be more widely used and could greatly simplify the management of severe hypoglycemia by members of the public.
This requires glucagon to be stable in solution. There are two possible routes to this:
More effective excipients: This line of development relies on use of native glucagon stabilized with more effective buffers (excipients). This would allow it to be formulated as a ready-made solution. In a novel approach researchers have tested nasal administration of native glucagon in a powder form with great success, providing better results than with current rescue kits.
Glucagon agonists: The alternative is to modify the glucagon molecule itself in order to render it more stable in solution without loss of biological function.
Recently a third option has emerged where native human glucagon is used in a nasal spray. This innovative idea has shown promising results in clinical trials. The native glucagon is in powder form and is sprayed directly into the nose of the hypoglycemic subject. Although the action of glucagon is slower than with direct injection, the effect is as good as the latter.
Another major use of glucagon (or a GCG-R agonist) would be as the second balancing hormone to insulin in a so called ‘Artificial Pancreas’ (AP). The concept is that access to both hormones would facilitate near-physiological control of blood glucose. Researchers agree that algorithms which aim for a given level of blood glucose are difficult to construct, and that hypoglycaemia cannot currently be completely avoided with insulin alone. Many patients therefore prefer not to use closed-loop systems (automated glucose monitoring coupled to automated insulin infusion) but measure glucose themselves and inject insulin based on this and on their experience.
A GCG-R agonist that is readily soluble, stable and have the same receptor activation properties as the native peptide should serve as the balancing hormone to insulin. This could either be a novel formulation of glucagon or an analogue, just as for the rescue pen (see above).
With a little luck the same formulation or analogue may serve both functions, though different requirements may apply to the two GCG-R agonists in terms of stability. Some consortia and groups of physicians are exploring the benefits of having glucagon available for dual-hormone blood glucose control. They are using the glucagon from the rescue kits with the available buffer, though the stability is low. However, even with this limitation the dual hormone approach appears to be superior to the single-hormone (insulin) currently in use. The dual-hormone approach appears to eliminate severe hypoglycaemia and reduce all hypoglycaemic events (severity and number). Furthermore, it appears also to allow for more rigorous use of insulin making hyperglycemic events lower in magnitude and shorter (1).
Hypoglycaemia remains a major concern for all those with diabetes, as for those who treat them. Most people with diabetes share this concern, which may increase with time and experience to the point at which it affects quality of life. Parents of young people with type 1 diabetes are particularly concerned with nocturnal hypoglycaemia since they may not be alerted to severe episodes at night. Many parents get up several times per night to measure the blood glucose of the diabetic, and this affects the life of the family for years. An automated dual-hormone closed loop AP could help resolve these problems, avoiding any hypoglycaemia and also ensuring a tighter control of the blood glucose levels at all time, leading to fewer and less severe diabetic complications, such as diabetic nephropathy, blindness, diabetic foot and cardiovascular complications.