Curly question regarding beta cell failure effect on alpha cells and glucagon

Hi Allan, I am an adolescent diabetes educator at the Mater in Brisbane and spoke with you a while ago about your website.

I just wanted to let you know that I have spent quite a time, not as much as I would like, on the website and I think it is extremely good. I have recommended it to a number of patients recently and will continue to recommend it.

I think it will cater to all types of people, parents and kids, and depending on how much they want to know and understand it is all there.

I think you have done a great job with a difficult subject and given there is so little information on exercise out there. I think it is very cleverly put together with quizzes, graphics and your real life experiences.

I did have one question for you, well many, but one for now. I understand that after a few years of T1D the alpha cells stop secreting glucagon, as you need functioning beta cells for them to work properly would just like your thoughts about that - Jane.

Thanks Jane, I had a similar question from Robyn who is also a Diabetes Educator. I wish my response could be as simple as the question, after reviewing the literature, this topic could be the basis for a PhD thesis. So a detailed response is well beyond the scope of this newsletter. But rather than shy away, here’s my take:

In type 1 diabetes there is almost complete destruction of insulin producing  beta-cells, yet the glucagon producing  alpha-cells are present in normal numbers. Although several glucose raising counter-regulatory hormones exist, glucagon is considered to be most important.

In the absence of functioning beta-cells, as is the case with T1D, insulin levels do not auto-adjust up or down at the hepatic portal (i.e. central) level as they do in people without diabetes. Rather, insulin has to be delivered peripherally from outside the body (i.e. exogenously) by injection or insulin pump.

Normally, portal insulin levels decrease immediately in response to exercise, this is not the case when you have T1D where each individual has to make manual adjustments. This inevitably causes insulin excess relative to the normal exercise induced reduction in portal insulin. This is where I think  the root of your question lies. Normally when portal insulin levels drop in response to low blood glucose levels, glucagon producing alpha-cells are signalled to secrete glucagon to release glucose from the liver to stop BGLs dropping further. This signal for counter-regulation takes place via functioning beta-cell microcirculation, but with T1D this signalling is lost as beta-cell function is progressively lost. Resulting in a concurrent loss of the normal counterregulatory glucagon response to hypoglycaemia from normal to impaired to non-existent. Continue reading >>>

Several hypotheses exist explaining the loss of glucagon response to hypoglycemia in type 1 diabetes but none provide a complete explanation. One strongly supported explanation for abnormalities in alpha-cell glycogen production in response to hypoglycaemia is the intra-islet insulin hypothesis, this relates to the beta-cell micro-vascularity mentioned above.

The impairment of glucagon secretion described herein is in response to excess insulin induced hypoglycaemia – common in T1D. The literature indicates glucagon responses to stimuli other than hypoglycaemia, like those related to exercise, are largely, if not entirely, intact in type 1 diabetes.

During exercise the net insulin to glucagon ratio is the main the main regulator of hepatic (i.e. liver) glucose production, which serves to help support BGLs during exercise. Although delivered peripherally, optimal-low levels of plasma insulin are required for the breaking-down and release of liver glucose and free fatty acids (that’s another story). In addition a low, not absent, insulin level increases the liver’s sensitivity to the action of glucagon.

I could write about other factors like the effects of stress hormones but this response is getting way too long for a newsletter Q&A.

If all this has left you confused and thinking – give it a rest Coach!

Here’s the key take-home:  Achieving an ideal insulin-glucagon ratio through smart exercise timing and/or insulin adjustment is a key factor to exercise success. Aim to achieve optimal insulin levels, not too little, not too much – see the e-coach for the plain English version.

Background reading:
Cryer P. Hypoglycaemia: The limiting factor in the glycaemic management of Type I and Type II Diabetes. Diabetologia. 2002;45(7):937-948.
Gosmanov NR, Szoke E, Israelian Z, et al. Role of the Decrement in Intraislet Insulin for the Glucagon Response to Hypoglycemia in Humans. Diabetes Care. 2005;28(5):1124 -1131.
Petersen, K. F., Price, T. B., & Bergeron, R. Regulation of Net Hepatic Glycogenolysis and Gluconeogenesis during Exercise: Impact of Type 1 Diabetes. J Clin Endocrinol Metab. 2004; 89(9), 4656-4664.
Quesada I, Tuduri E, Ripoll C, Nadal A. Physiology of the pancreatic {alpha}-cell and glucagon secretion: role in glucose homeostasis and diabetes. J Endocrinol. 2008;199(1):5-19.
Sigal RJ, Fisher SJ, Halter JB, Vranic M, Marliss EB. Glucoregulation during and after Intense Exercise: Effects of {beta}-Adrenergic Blockade in Subjects with Type 1 Diabetes Mellitus. J Clin Endocrinol Metab. 1999;84(11):3961-3971.
Taborsky GJ, Ahrén B, Havel PJ. Autonomic mediation of glucagon secretion during hypoglycemia: implications for impaired alpha-cell responses in type 1 diabetes. Diabetes. 1998;47(7):995 -1005.