Impaired hypoglycaemia awareness: are we aware?

Diabetes and Primary Care, Summer, 2004 by Rajeev Kumar, Miles Fisher

Introduction

Recurrent episodes of hypoglycaemia lead to a shift of glycaemic thresholds for symptoms of hypoglycaemia to lower plasma glucose concentrations, which results in the syndrome of impaired hypoglycaemia awareness. This is a common problem in type I diabetes, which is experienced by as many as a quarter of all patients and is characterised by loss of autonomic warning symptoms before the development of neuroglycopaenia. Patients and healthcare workers should be made familiar with the potential dangers of frequent episodes of hypoglycaemia and hypoglycaemia unawareness.

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Hypoglycaemia is a well-known consequence of treatment of diabetes, particularly in patients with type I diabetes. The Diabetic Control and Complications Trial (DCCT, 1993) and the United Kingdom Prospective Diabetes Study (UKPDS, 1998) clearly showed that achieving near euglycaemia is of vital importance and is certainly in the best interest of all patients with diabetes. However, with intensive treatment of diabetes hypoglycaemia becomes almost inevitable. The dangers of recurrent hypoglycaemia are not always appreciated, and treatment and patient education is often focused on minimising hyperglycaemia. Recurrent hypoglycaemia (recognised or not) leads to impaired hypoglycaemia awareness and creates a vicious cycle of hypoglycaemia begetting further hypoglycaemia.

Symptoms of hypoglycaemia

Symptoms of hypoglycaemia can be divided into two broad categories: autonomic (or neurogenic) and neuroglycopaenic. Autonomic symptoms are the result of discharge of the autonomic nervous system triggered by hypoglycaemia while neuroglycopaenic symptoms are the direct result of glucose deprivation in the brain. (Figure 1). A major difference between these symptom responses is that, once triggered, the autonomic response quickly reaches a maximum intensity that gradually declines with time, whereas the neuroglycopaenic response becomes more profound the further the blood glucose level falls (Frier and Fisher, 1999).

Glycaemic thresholds

When plasma glucose levels fall, a typical and usually predictable, sequence of responses ensues (Figure 2). There is a distinct hierarchy of responses to falling plasma glucose that provides an opportunity to avoid dangerous hypoglycaemia. This natural system of glucose counter-regulation is normally extremely effective in preventing or quickly correcting hypoglycaemia. It is important to notice that falling insulin concentrations and rising glucagon and adrenaline provide the first three major defences against hypoglycaemia. Cortisol and growth hormone, even though they are involved in defence against hypoglycaemia, are not critical to recovery.

As shown by Amiel et al (1988) these glycaemic thresholds are not static and tend to shift upwards to higher plasma glucose concentration following prolonged hyperglycaemia (i.e. poorly controlled diabetes) and downwards to lower plasma glucose concentration following episodic hypoglycaemia (i.e. tightly controlled diabetes, insulinoma).

Impaired hypoglycaemia awareness

Hypoglycaemia unawareness is a common problem in type I diabetes that occurs in varying severity in approximately a quarter of all patients and becomes more common with increasing duration of insulin treatment (Hepburn et al, 1990). It is also seen in type 2 diabetes after treatment with insulin for several years, and becomes a more frequent clinical problem as the disease progresses and the patient approaches the insulin deficient end of the spectrum of type 2 diabetes (Segel et al, 2002). It is not entirely clear whether this phenomenon occurs in patients with type 2 diabetes who are treated with oral hypoglycaemic agents only.

Hypoglycaemia unawareness is characterised by loss of autonomic warning symptoms before the development of neuroglycopaenia. The patient is unable to take action (eat food) to abort the episode because of the absence of early warning symptoms, and the first clinical manifestation of hypoglycaemia is neuroglycopaenia. Hypoglycaemia unawareness is associated with intensive insulin therapy, prolonged duration of diabetes, frequent episodes of hypoglycaemia, and impaired glucose counter-regulation. Affected patients have a six-fold higher rate of hypoglycaemia than patients who retain normal awareness of hypoglycaemia (Gold et al, 1994).

Hypoglycaemia unawareness is mostly observed in patients with tightly controlled diabetes who, due to previous recognised or unrecognised episodes of recurrent hypoglycaemia, tend to have a shift of glycaemic threshold towards lower plasma glucose levels. The adrenaline response is therefore markedly attenuated or even absent in these patients and much lower plasma glucose concentrations are required to elicit it; a level at which patient may not be able to take action to abort the attack due to failing cognition and clouded sensorium (neuroglycopaenia). Heller and Cryer (1991) demonstrated that even a single episode of hypoglycaemia is sufficient to partially attenuate adrenaline secretion and the symptoms associated with hypoglycaemia. Patients with tightly controlled diabetes are able to 'tolerate' hypoglycaemia better (i.e. exhibit hypoglycaemia unawareness) mainly because of the shift of glycaemic threshold to lower plasma glucose levels.