While preparing for a recent Diabetes Manager University (DMU) training program in Saskatoon, Saskatchewan my colleague was reflecting on insulin options and hypoglycemia management. She asked me if I could remind her why people living with Type 1 Diabetes did not have a glucagon response to low blood sugars aka hypoglycemia. While insulin’s main job is to move sugar from the blood stream into the cells, glucagon’s job is to mobilize sugar from the liver and muscle into the blood stream to raise blood sugars up when the body’s blood sugar levels get too low. In Type 1 Diabetes (T1D), the glucagon response to low blood sugars is lost shortly after diagnosis and without external sources of glucose/sugar, places the individual living with Type 1 Diabetes in a hypoglycemic medical emergency. Her question had me reflecting on the factors that influence the body’s glucagon response, and that’s what I’ll dive into in this blog post.

Factors that Influence Glucagon in the Body

The literature reveals that glucagon secretion occurs in response to several body mechanisms. These include cessation of insulin (known as insulin withdrawal, which persists for up to 14 hours after discontinuing external insulin), ingestion of amino acids (the building blocks of protein, triggering a response upon ingestion), exposure to lipopolysaccharides (commonly found in grains and vegetables, prompting a response upon ingestion), engagement in physical activity (where the body demands sugar for energy), and even the consumption of a meal, which elicits a significant glucagon response in individuals with Type 1 Diabetes. However, despite these responses to food and exercise, why is it that individuals with T1D do not experience a sufficient rise in blood sugar when faced with hypoglycemia, when glucagon is needed most?

Impaired Glucagon Response in Type 1 Diabetes

There are several theories about why the glucagon response is impaired in people living with Type 1 Diabetes. Each of them is a clue into the lack of response while no one theory explains the lack of glucagon response in full.

Theory 1: Duration of Diabetes

It has been hypothesized that the impaired response of glucagon in Type 1 Diabetes (T1D) has to do with the duration of living with T1D. Evidence and real-world cases show that for many people living with T1D, their glucagon response is fully dysfunctional in addressing hypoglycemia within weeks or months of their diagnosis, yet is responsive in other aspects of physiology.

Theory 2: High Circulating Insulin Levels (Hyperinsulinemia)

It is also hypothesized that the dysfunction could be caused by high circulating insulin levels related to Type 1 Diabetes treatment preventing the opposing response of glucagon release.

Theory 3: Frequent Hypoglycemia (Low Blood Sugar Levels)

Repeated hypoglycemic episodes impairs the body’s autonomic nervous system (ANS) response, while also decreasing body signs and symptoms of hypoglycemia in future hypoglycemia episodes. The ANS is responsible for much of the covert or less obvious signalling inside our body. Is your heart pumping? Thank your autonomic nervous system!  Do you jump back and recoil your hand when you touch a hot stove? Thank your autonomic nervous system.

Although the autonomic nervous system’s (ANS) responsiveness to hypoglycemia may be compromised in T1D, certain aspects of the ANS do show improvement when hypoglycemic episodes are avoided. For instance, there’s a notable enhancement in the epinephrine response, a hormone integral to the fight-or-flight reaction, which raises blood sugar levels. Additionally, individuals with Type 1 Diabetes experience a return of hypoglycemic signs and symptoms. While these improvements suggest a dynamic response within the ANS, it’s clear that challenges in the system extend beyond this factor for those living with Type 1 Diabetes.

So, if it is not duration of diabetes, hyperinsulinemia, nor an impaired autonomic nervous system, then what could be happening?

The Intraislet Insulin Hypothesis

With the human body, things are never as straightforward as we may like. If the lack of glucagon response was as basic as cells that have died off or shut down due to overwork, researchers might be able to focus their efforts to develop a drug or hormone to correct the issue. This would be just like how the semaglutide hormone (aka Ozempic) can stimulate defunct beta cells or help the body make new beta cells, allowing the individual to eventually produce their own insulin again.

The Intraislet theory is a hypothesis that states there is a direct and local stimulation of the alpha cells by insulin only when that insulin is produced in the beta cells. The proximity of the insulin to the alpha cell is a key part of the theory. This happens all within the Islets of Langerhans, an area of the pancreas that contains alpha cells (which make glucagon), beta cells (which make insulin), delta cells (which make somatostatin), and P cells (that secrete pancreatic polypeptides). It is known that exogenous or injected insulin does not have the same effect on glucagon response as the insulin produced within the Islets of Langerhans. As already mentioned, there are also other factors influencing glucagon response in Type 1 Diabetes including somatostatin, incretin (gut) hormones, neurons, mixed meals, inflammation, and exercise.

While islet cell transplantation shows partial restoration of the glucagon response, pancreatic transplant fully restores the glucagon response. This is an area that needs further study as there is limited literature to inform practice. Additionally, there are a limited number of pancreas donors available, plus there are risks and long-term management needed with transplantation.

Summary

It appears that the lack of glucagon response to hypoglycemia in Type 1 Diabetes is due to an assortment of body systems and cells that are not working optimally with the key factor likely being the loss of endogenous insulin production. The loss of endogenous insulin production precipitates the lack of localized stimulation of the glucagon response within the pancreas, preventing the body’s glucose stores from mobilizing and raising blood sugars in response to hypoglycemia. This places the person living with Type 1 Diabetes, who must manage their condition with insulin injections everyday, in constant danger of severe hypoglycemia. Thus, highlighting the importance of discussing hypoglycemia during each visit with a health care professional. Persons living with diabetes need to have a clear plan to address hypoglycemia, both in the moment it strikes and afterwards, to adjust any diabetes treatment factors that may be contributing to the issue.

Have ideas for diabetes-related topics that you would like to know more about?  Send us an email or post in our Diabetes Training 101 Community of Learning and let us know what you think.

Until next time,
Michelle

 

References

  1. Bisgaard Bengtsen M, Møller N. Mini-review: Glucagon responses in type 1 diabetes – a matter of complexity. Physiol Rep. 2021 Aug;9(16):e15009. doi: 10.14814/phy2.15009. PMID: 34405569; PMCID: PMC8371343. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371343/
  2. Diabetes Canada Clinical Practice Guidelines Expert Committee. Diabetes Canada 2018 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Senior Peter A. MBBS, PhD, FRCP, AlMehthel Mohammed MD, FRCPC, Miller Andrea RN, Paty Breay W. MD, FRCPC. Chapter 20: Diabetes and Transplantation. Can J Diabetes. 2018;42(Suppl 1):S1-S325.  https://guidelines.diabetes.ca/cpg/chapter20