Although one expects hypoglycemic episodes to be accompanied by the typical symptoms (e.g., tremor, sweating, palpitations, etc.), this is not always the case. When hypoglycemia occurs in the absence of such symptoms it is called ''hypoglycemic unawareness''. Especially in people with long-standing type 1 diabetes and those who attempt to maintain glucose levels which are closer to normal, hypoglycemic unawareness is common.
In patients with type 1 diabetes mellitus, as plasma glucose levels fall, insulin levels do not decrease - they are simply a passive reflection of the absorption of exogenous insulin. Also, glucagon levels do not increase. Therefore, the first and second defenses against hypoglycemia are already lost in established type 1 diabetes mellitus. Further, the epinephrine response is typically attenuated, i.e., the glycemic threshold for the epinephrine response is shifted to lower plasma glucose concentrations, which can be aggravated by previous incidents of hypoglycemia.
To further complicate matters, there may also be other contributing factors which contribute to hypoglycemic unawareness:
a) there may be autonomic neuropathy
b) the brain may have become desensitized to hypoglycemia
c) the person may be using medicines which mask the hypoglycemic symptoms
d) unexpected pharmacokinetics of the insulin being dosed
a) Autonomic neuropathy: During hypoglycemia, the body normally releases epinephrine commonly known as adrenalin and related substances. This serves two purposes: The β-effect of epinephrine is responsible for the palpitations and tremors, giving the patient warning that hypoglycemia is present. The β-effect of epinephrine also stimulates the liver to release glucose (gluconeogenesis and glycogenolysis). The epinephrine warns the patient that hypoglycemia is present and signals the liver to release glucose to reverse it. In the absence of epinephrine release, or when it is attenuated (reduced) during hypoglycemia, then patient may not be aware that his/her glucose level is low, therefore, the usual responses of glycogenolysis and gluconeogenesis may also lost or blunted.
Since epinephrine release is a function of the autonomic nervous system, the presence of autonomic neuropathy (i.e., a damaged autonomic nervous system) will cause the epinephrine release in response to hypoglycemia to be lost or blunted. Unfortunately, damage to the autonomic nervous system in the form of autonomic neuropathy is a common complication of long-standing diabetes (especially type 1 diabetes), so the presence of hypoglycemic unawareness may be a sign of autonomic neuropathy, although the autonomic response to hypoglycemia is already impaired in patients with type 1 diabetes mellitus even in the absence of autonomic neuropathy.
Because the autonomic response is, in effect, the body's backup system for responding to hypoglycemia, patients with type 1 diabetes are forced to rely almost exclusively on a backup system for protection, which can unfortunately, deteriorate over time. The reduced autonomic response (including the sympathetic neural norepinephrine and acetylcholine as well as the adrenomedullary epinephrine response) causes the clinical syndrome of hypoglycemia unawareness — loss of the largely neurogenic warning symptoms of developing hypoglycemia.
b) Brain desensitization to hypoglycemia: If a person has frequent episodes of hypoglycemia (even mild ones), the brain becomes "used to" the low glucose and no longer signals for adrenalin to be released during such times. More specifically, there are glucose transporters located in the brain cells (neurons). These transporters increase in number in response to repeated hypoglycemia (this permits the brain to receive a steady supply of glucose even during hypoglycemia). As a result, what was once the hypoglycemic threshold for the brain to signal adrenalin release becomes lower. Epinephrine is not released, if at all, until the blood glucose level has dropped to even lower levels. Clinically, the result is hypoglycemic unawareness.
Since repeated hypoglycemia is common in people with diabetes who strive to keep their glucose levels near normal, and they have impaired glucose counterregulation, the incidence of hypoglycemic unawareness becomes more prevalent in patients who follow prescribed treatment protocols.
The most common treatment for this condition is to liberalize the patient's target glucose levels, in an attempt to decrease the frequency of hypoglycemic episodes. Hypoglycemic unawareness will sometimes disappear when the frequency of hypoglycemic episodes has declined, but this is not always the case.
Blood Glucose Awareness Training (BGAT)
Researchers at University of Virginia Health Sciences Center have developed a psychoeducational program that helps patients identify their blood glucose symptoms more accurately, better predict when hypoglycemia is more likely to occur, and then treat hypoglycemia earlier than they might if they were relying exclusively on blunted autonomic symptoms alone. The program, called Blood glucose awareness training (BGAT), is designed to improve the accuracy of patients' detection and interpretation of relevant BG symptoms and other cues. Unfortunately, awareness of these treatments among certified diabetes educators is surprisingly low, and awareness of the program is not even required to attain certification. The reasons for this are multi-faceted, but a frequent criticism is the fact that a disproportionate share of the certification training is dedicated to issues related to the more common type 2 diabetes. Also, BGAT training is more complex, and requires considerable effort on the part of educators, and many may not view it as justified given the proportion of patients who have type 1 diabetes.
An online version of BGAT has been developed and was being tested, but is expected to be functional in the not-too-distant future. It is called BGAThome, and may bring this useful training program to more people in the future.
c) Beta blocker drugs: These medicines are designed to blunt the β-effect of adrenalin and related substances. Hence, if hypoglycemia occurs in someone who is using this type of drug, he/she may not experience the typical adrenergic warning symptoms such as tremor and palpitations. Again, the result is hypoglycemic unawareness. As noted above, beta blockers will also prevent adrenalin from stimulating the liver to make glucose. Although this phenomenon does not contribute to hypoglycemic awareness, it will make the hypoglycemia more severe and/or more protracted.
d) Unexpected pharmacokinetics of the insulin being dosed. Unlike endogenously produced insulin which is secreted directly into the bloodstream, insulin given as a medication is typically dosed subcutaneously. The time-activity profile of insulin administered this way can vary widely depending on the site the injection given, the angle of the injection and the relative size of the dosage. Thus, while clinical trials may provide ranges, the reality is that the time-activity profiles of artificially dosed insulin often vary considerably and may not be absorbed, distributed into the bloodstream, metabolized or excreted the same way regardless of how consistent the other variables may be, which may lead to unexpected incidents of hypoglycemia.
Further Reading
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"Diabetic hypoglycemia"
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