Glucagon dynamics during exercise with type 1 diabetes
by Adam Burrack, PhD
Previously in our series, we have described the exercise science of maximal performance in terms of oxygen consumption (basically 2-mile race pace) and how imperfect, artificial, control of insulin levels during exercise may negatively affect exercise performance. Too much insulin in the circulation during intense exercise could lead to low blood sugar levels, which can be dangerous in fast-moving sports. Too little insulin in the circulation can lead to high blood sugars – and potentially diabetic ketoacidosis – in long-duration endurance events.
But what about the other side of the blood sugar level thermostat? Glucagon is the antagonist and mirror image of insulin. Since insulin levels can be so out-of-whack in the exercising T1D, how does this effect glucagon levels and the efficacy of glucagon that is produced? Since the main function of glucagon is to increase blood sugar levels, during prolonged high-intensity exercise (think 5k, 10k, or half marathon running races), it would be useful to have a little boost from our internal glucagon to ‘make sure’ our blood sugar levels don’t crash. That is, in fact, the normal sequence of events in non-diabetic individuals in these situations: levels of insulin in the plasma go way down, and levels of glucagon to up. At running paces approaching 75% of VO2 max (approximate half marathon pace for most of us), or faster, this relationship between insulin and glucagon is key for mobilizing fuel to get us to finish line without bonking. In other words, in this situation glucagon is your friend, big time.
It is known that some people with type 1 diabetes will eventually develop hypoglycemia unawareness, a potentially life-threatening condition. This condition is the current clinical prerequisite to go onto the pancreas transplant waiting list. We also know that at least some of the autonomic nerves going into pancreatic islets are destroyed as part of the disease process of type 1 diabetes. These nerves – which likely carry signals both from the pancreatic islets to the brain stem and back from the brain stem to the islets – do not appear to be destroyed during the development of type 2 diabetes. This is one of several key differences between type 1 and type2 diabetes. Today, we will delve into the biology of glucose metabolism during exercise in the individual with type 1 diabetes through the lens of glucagon, the antagonist of insulin.
The lab of Ananda and Rita at the Mayo Clinic in Rochester MN has been studying glucose metabolism for >10 years. This husband-and-wife team have published on a range of topics, including glucagon dynamics in individuals with type 1 diabetes during exercise. Long story short, type 1 diabetic athletes have more insulin and less glucagon in their circulation during steady-state exercise (60% VO2 max for 60-75 minutes) than do non-diabetic individuals. This represents a sort of “double jeopardy” for the T1D athlete at low-to-moderate exercise intensity. Due to injections of insulin (reminder that normally insulin goes essentially straight from the pancreas to the liver, where it directly promotes glycogen production and energy storage), they have way more insulin in their blood during exercise and also significantly less glucagon, creating a situation where they are at very high risk for hypoglycemia. This mirrors empirical results referenced in the JDRF exercise guidelines for T1D athletes. One method around this situation is to consume 30 grams of carbohydrate (or more) per hour of moderate intensity exercise. Another option is to tend toward higher-intensity exercise – with the attendant risk of low blood sugar levels after high-intensity exercise. Regardless of approach, the athlete with T1D being aware of the fundamental problem – and not blaming themselves for poorly managing their during-exercise blood glucose levels – is the point.
Another clinically applicable area the Basu lab is engaged in is development better methods to track glucagon levels and to deliver glucagon in tandem with insulin, in a stable form. To track glucagon this research group is using of labeled-water methods to track metabolism over the course of an in-hospital study. This group is one of several working – in collaboration with industry partners – to determine more stable formulations of glucagon that would be remain useable for up to 5 days in an insulin pump-type device. Finally, the Basu lab is exploring methods of glucagon delivery (ie subcutaneous as insulin is currently delivered via pumps compared to intravenous delivery) that was optimize its physiologic function. Overall, the field has much more experience with making and delivering insulin than glucagon. There is some homework to be done to get glucagon up to speed for a widely applicable dual-hormone replacement system. And there are some clever, hard-working folks working on these challenges.