By just writing the title "Another Perspective on Dead in Bed Syndrome " increases anxiety for both me and my patients with type 1 diabetes. I was the worried diabetologist quoted in Dr. Quick's thoughtful and well-documented blog posted earlier this week. At the conclusion of his discussion, Dr.Quick made a modification to the statement that "One in 20 people with type 1 diabetes will die in their sleep from a sudden drop of blood sugar," to "One in 20 apparently healthy people under age 40 or 50 with type 1 diabetes die in their sleep from unknown causes that might be hypoglycemia."
Last week, one of my pediatric cardiology colleagues alerted me to a recent publication in the New England Journal of Medicine by Dr. Philip Cryer: "Mechanisms of Hypoglycemia- Associated Autonomic Failure in Diabetes." (N Engl J Med 369:4, July 25, 2013, 362-372.) also known as HAAF. The paper was a review article discussing the mechanisms of disease and attempted to explain the various biological pathways leading to hypoglycemia and the potential avenues for amelioration.
This blog is an attempt to have a rigorous, somewhat technical discussion about the very serious problem of hypoglycemia and hypoglycemia unawareness. I have attempted to be as clear as possible in an effort to explain the various pathways.
In order to do so, a brief discussion of biology is appropriate. The nervous system has two components: the voluntary nervous system in which you control movement, and the autonomic in which you have no conscious control. Today we are talking about the autonomic nervous system.
Essentially, according to Dr.Cryer, the normal response to falling blood sugar levels would be:
1. Decreased secretion of insulin from functioning _ beta_ cells
2. Increased secretion of glucagon from the alpha cells (which serves to increase glucose levels)
3. Increase of epinephrine (glucose raising adrenomedullary hormone) in the absence of an increase in glucagon ( the medulla of the adrenal gland produces epinephrine)
The normal behavioral response is to ingest carbohydrate due to autonomic symptoms of shakiness and dizziness that result from a sympathetic neural response (release of epinephrine and norepinephrine by the autonomic nervous system). This defense ensures a continuous supply of glucose to the brain.
In people with diabetes, as the blood glucose level falls, in the absence of endogenous insulin due to beta cell failure, the insulin levels do not diminish as the insulin levels are a function of injected insulin. In addition, in patients with long standing diabetes, there is also a loss in glucagon response from the alpha cells along with a decreased secretion of epinephrine. Thus, the combination of the inability to decrease insulin levels or increase glucagon secretion and weak responses from the adrenal gland in the production of epinephrine causes the clinical syndrome of "defective glucose counterregulation," which increases the risk of recurrent severe hypoglycemia by a factor of 25 or more." (Cryer)
The compromised behavioral response as glucose levels fall is, of course, due to the failure to ingest rapid-acting carbohydrates because the symptoms of hypoglycemia are absent (due to the weakened adrenal response- sympathoadrenal or sympathetic neural response). This weakened behavioral response results in hypoglycemic unawareness syndrome which increases the risk of recurrent severe hypoglycemia by a six- fold.
Unfortunately, continued hypoglycemia weakens epinephrine and sympathetic defenses against subsequent hypoglycemia in both people with and without type 1 diabetes- leading to the concept of hypoglycemic-associated autonomic failure (HAAF) in diabetes.
Dr. Cryer goes on to further explain that "recent hypoglycemia secondary to sleep or prior exercise can effect glucose counterregulation by further weakening the epinephrine response, in the context of an insulin concentration that is not reduced and glucagon secretion that is not increased and hypoglycemic unawareness (due to the weakened sympathetic neural response), thus leading to a vicious cycle of recurrent hypoglycemia."
In regard to HAAF (hypoglycemic-associated autonomic failure) , a key finding is that the loss of the glucagon response is NOT related to the strict avoidance of all hypoglycemia. As Dr. Cryer further explains" in type 1 diabetes, the lack of a decrease in beta cell insulin secretion causes the loss of an increase in alpha cell glucagon secretion as glucose levels fall in response to therapeutic hyperinsulinemia. The lack of a decrease in insulin and the lack of an increase in glucagon are prerequisites for glucose counterregulation, but do not cause defective glucose counterregulation or hypoglycemia unawareness. Those two components of HAAF in diabetes develop only when the sympathoadrenal and symptomatic responses to hypoglycemia become weakened."
Therefore, unlike the loss of insulin and glucagon responses at the islet level, the alteration resulting in weakened sympathoadrenal responses must reside within the central nervous system (CNS)or it's incoming and outgoing connections.
There are several hypotheses that attempt to explain these Central Nervous system mediated mechanisms of the weakened sympathoadrenal responses that cause HAAF syndrome; however, the precise mechanisms are not known. There are, however, clues that that available drugs might lower the risk of hypoglycemia and that lactate can affect brain metabolism that can possibly alter cerebral mechanisms in the cause of Hypoglycemia associated autonomic failure.
Perhaps medication (putative examples include adrenergic antagonists such as propranolol, SSRI's, and opiate antagonists such as nalaxone), based on the above explanations and possible etiology of hypoglycemia unawareness, along with the currently available continuous glucose monitoring systems, may someday mitigate or eliminate "Dead in Bed Syndrome." My colleagues and I will continue to keep you posted as new information and potential treatments become available.