The importance of glucagon for blood glucose level maintenance
by Adam Burrack, PhD
As any diabetic who has suffered a severe hypoglycemic event will tell you, glucagon is central to energy metabolism. In contrast to what many of us with diabetes may believe, due to lack of beta cells we have dysregulated energy metabolism in general, not just an inability to produce insulin. Beta cells produce hormones other than insulin, some of which (eg, amylin) regulate the production of counter-regulatory hormones (like glucagon) which act in opposition to insulin. There is normally a delicate balance between these sets of hormones. The concentration of not only sugar levels but also amino acids, stress hormone levels, and growth hormone levels regulates production of these counter-regulatory hormones. In particular, increased levels of amino acids – from digestion of proteins in food – or enhanced levels of stress hormones promote glucagon release.
As one might imagine, standing at the starting line of a race promotes one heck of a fight-or-flight stress hormone response. It will probably not surprise our readers that races under 10 kilometers running distance promote a whopping stress hormone (cortisol) response. As such, I and many other T1D athletes tend to gravitate toward longer-distance aerobic endurance events, where these responses are less acute, or at least over time are blunted by the significant number of calories burned by completing races lasting over 60 minutes. Also as one might imagine, knocking one or more of these hormones completely out (by autoimmune destruction of beta cells) leads to dysregulation of the entire set of hormones. Replacing only insulin is life-sustaining, and one of the key medical advances of the 20th century, but is a very blunt tool for a situation which is normally finely balanced. Today I will describe some of the consequences of dysregulated glucagon production.
I’ve described in a previous blog that there is some published evidence that over time T cell responses against glucagon can develop. As described previously, this work from Teresa DiLorenzo is important for two reasons. First, insulin over-dosing due to inaccurate carbohydrate counts or skipped meals can lead to significant needs for glucagon production, leading to recurrent metabolic stress on alpha cells. Second, if autoimmunity against alpha cells develops and plays a role in decreased counter-regulatory responses, a cell-replacement therapy for T1D would have to include alpha cells, not only beta cells. So, glucagon is important for energy metabolism, might be a target of autoreactive T cells in long-term T1D, and so we – as scientists – may need to consider alpha cell replacement therapy for people with hypoglycemia unawareness.
As a stunning proof-of-principle, a 2011 Diabetes manuscript demonstrated that glucagon-receptor-deficient mice do not become diabetic following treatment with a beta cell toxin. Meaning, in the absence of the key counter-regulatory hormone insulin, the additional absence of glucagon signaling essentially cancels out effects on blood sugar levels. While having neither side of the “blood sugar level thermostat” in operation is obviously not an ideal situation – and is probably not a clinically viable approach – it appears that having one arm of the thermostat leaves one worse off, in terms of actual blood sugar levels, than having neither arm of the thermostat in operation. A follow-up paper from this group – led by – Roger Unger at UT Southwestern’s Touchstone Diabetes Center demonstrated that in the absence of glucagon signaling (tested in the same type of genetically engineered glucagon receptor knock-out mice) many of the ‘typical’ metabolic abnormalities associated with type 1 diabetes (and derangement in insulin:glucagon ratio) do not occur. The authors suggest in the discussion section of this paper that suppression of glucagon production would be a very useful adjunct to clinical T1D therapy.
Toward that end, a 2014 paper in Diabetes Care from Kevan Herold’s group at Yale demonstrated that treatment with the hormone glucagon-like peptide 1 (GLP-1) blunted glucagon production in T1D patients who had residual beta cell mass following a mixed (carbs, fat, and protein) meal. GLP-1 and glucose-dependent insulinotropic peptide (GIP) are two hormones in a class called incretins. Incretins play a central role in blood sugar control by promoting insulin secretion from beta cells as well as inhibiting glucagon production by alpha cells. As such, treatment with these hormones (or pharmaceutical mimics) is a key component of clinical therapy for type 2 diabetes, but would be rather useless to treat type 1 diabetes given the near-deficit of endogenous beta cells. However, incretin therapy may be of use for T1D as inhibiters of glucagon production – especially in patients with long-term T1D who have volatile blood sugar level control. This is an area of active research, and has potential to preserve alpha cell mass in patients with long-term T1D. This is worth pursuing, because preserving alpha cell mass over decades of T1D has the potential to prevent development of hypoglycemia unawareness, sparing T1D patients the rigamarole of current islet transplantation and lifelong immune suppression treatments.