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Glucagon and insulin to manage glucose control: Mimicking normal physiology

Type 1 diabetes – November 2020 digest

Daniel Flanagan discusses whether a new formulation of liquid glucagon will pave the way for effective dual-hormone artificial pancreas devices.

Clinicians and people with type 1 diabetes are anticipating the day when closed-loop glucose management systems are routinely available for the management of diabetes. Most will now be familiar with the concept of using a subcutaneous glucose sensor linked with an insulin pump to automate the control of glucose within the body. The first commercial product, the Minimed 670G, was launched last year and the 780G has now been approved for use in Europe. Both of these systems use insulin alone to manage glucose control, as is the case for all current insulin pump regimens.

These commercial products are the result of an accelerating research output relating to automated closed-loop glucose control. In 2000 there were eight publications relating to closed-loop systems. By 2010, this had risen to 49; this year, so far we have seen 169 publications. A proportion of these studies describe what have been called bihormonal systems, in which insulin and glucagon are used in concert to maintain a normal blood glucose level. These systems potentially have a significant advantage over using insulin alone, where the only response to falling glucose is to turn off insulin and eat more.

In the normal physiology of glucose control, the Islets of Langerhans within the pancreas act as the glucose sensor. When blood glucose rises this results in the release of insulin and allows glucose to enter cells. As blood glucose falls, so too does insulin, allowing other sources of fuel to be used. A second hormone, glucagon, is then released. This primarily acts on the liver, promoting the production of glucose from glycogen. If blood glucose continues to fall then stress hormones, such as cortisol and adrenaline, become important, but the normal day-to-day balance of glucose in response to meals and fasting are primarily controlled by insulin and glucagon.

Since the discovery of insulin, we have tended to ignore the role of glucagon in glucose homeostasis. Glucagon has had a role in the emergency treatment of hypoglycaemia but its use has been limited by the need to reconstitute the dried powder with water before use, as the solution would only be stable for 24 hours. We have had a number of papers previously describing systems using both insulin and glucagon, but they have all had to replace the glucagon every 24 hours. The novelty of this paper is that it describes a glucagon product that is stable for a long period in liquid form. This product is already licensed for clinical use by the US Food and Drug Administration. A significant barrier to mimicking the normal physiology of glucose control has now been removed.

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