Impaired Hypoglycaemia awareness in type 1 diabetes: can CSII help?

Journal of Diabetes Nursing, March, 2008 by Gill Morrison, Philip Weston

Hypoglycaemia occurs once plasma glucose concentrations are below 3.5 mmol/l (Pampanelli, et al 1996; Bolli et al, 1993). The fall in plasma glucose levels causes the central hypothalamic autonomic centres in the brain to trigger the activation of the peripheral autonomic nervous system and stimulate the sympathoadrenal system (Bolli, 2003). This response is responsible for many classical autonomic reactions such as sweating and tremor and, as a result of an increase in rate and contractibility, the sensation of a 'pounding heart' (Bolli, 2003). The magnitude of this response is further heightened by the secretion of large quantities of adrenaline from the adrenal medullae (Frier and Fisher, 2000). Thus, the warning signs and symptoms that occur in response to an abnormally low blood glucose level provide a useful defence mechanism for the brain by alerting it to impending neuroglycopaenia. Unlike other tissues, such as muscle and liver, the brain is totally dependent on the oxidation ofglucose for its 'fuel' (Bolli, 2003). As the brain is unable to store or synthesise glucose, an inadequate supply of glucose will cause it to malfunction, with cognitive impairment rapidly becoming evident as an overt manifestation of neuroglycopaenia (Bolli, 1999).

Hypoglycaemia in type 1 diabetes

Inappropriate hyperinsulinaemia is the obvious cause of hypoglycaemia in people with type 1 diabetes, with episodes tending to be more prolonged and severe than in people without diabetes (Bolli et al, 1984).

For people with type 1 diabetes, the defence mechanisms against hypoglycaemia are impaired (Bolli, 1990). As a result of the irreversible loss of the glucagon response within 3-5 years of diagnosis (White, 1994) adrenaline becomes the main influence that provides a counter-regulatory response to hypoglycaemia (Bolli, 1990). However, many individuals have a reduced response to adrenaline, particularly those with a long duration of diabetes (Bolli et al, 1984; Bolli, 1990; Fanelli et al, 1994); thus, these individuals are at risk of episodes of severe hypoglycaemia.

Hypoglycaemic unawareness

As defined by Vignesh and Mohan (2004) hypoglycaemic unawareness is 'the reduced ability or failure to recognise hypoglycaemia at the physiological plasma glucose concentrations at which warning symptoms normally occur'.

The exact underlying mechanisms behind impaired awareness of hypoglycaemia are unknown and, in all probability, the key factors are multifactorial and often interlinked (Frier and Fisher, 2000). Possible causes are listed in Box 1.

Box 1. Potential causes of hypoglycaemia unawareness.

Chronic exposure to low blood glucose levels.

Recurrent transient exposure to low blood glucose values.

Central nervous system glucoregulatory failure.

Peripheral nervous system dysfunction.

Certain medications.

Use of human insulin.

Alcohol.

Compromised glucose counter-regulation

People with type 1 diabetes with combined glucagon and adrenaline defects are at greatest risk of severe hypoglycaemia (Bolli, 1990). This hazard is further heightened for certain groups such as those with autonomic neuropathy. Evidence suggests that such individuals will exhibit an additional defect in adrenaline release during hypoglycaemia (Bottini et al, 1997). Paraplegic individuals, who as a result of a high cervical cord transection lose adrenaline secretion, also lose autonomic response to hypoglycaemia (Mathias et al, 1980).

Glycaemic thresholds

The blood glucose level at which symptomatic hypoglycaemia occurs varies between individuals, with the glycaemic threshold for the onset of symptoms higher in people with a long duration of type 1 diabetes (Vea et al, 1992).

A key factor that will affect the threshold for hypoglycaemic symptoms in insulin-treated diabetes is exposure to prolonged hypoglycaemia (Boyle et al, 1994). Recent studies have demonstrated that the brain adapts to chronic exposure to low blood glucose by increasing glucose transporters localised in the microvessels of the blood-brain barrier (such as GLUT-1), as well as the neuron-specific glucose transporter GLUT-3 (Simpson et al, 1999). The implication for clinical practice is that people with insulin-treated diabetes with on-going sub-optimal control will experience symptoms of hypogiycaemia when their blood glucose declines within a hyperglycaemic range (Boyle et al, 1988). Conversely, chronic exposure to 'tight' glycaemic control will modify the glycaemic threshold for the onset of symptoms so that they do not occur until the blood glucose value has declined to a much lower level than that required in the less well-controlled individual. Therefore, during subsequent hypoglycaemic events, the brain is less neuroglycopaenic than normal and does not need to generate autonomic warning symptoms of impending hypoglycaemia. This is a maladaptive response that may not be beneficial to the individual with diabetes.

Antecedent hypoglycaemia

Antecedent exposure to hypoglycaemia can temporarily induce defective counter-regulation as a response to glucose sensing neurones altering their hypoglycaemic sensitivity in reaction to a recent previous glucose experience (Levin et al, 1999). Indeed, a single hypoglycaemic episode can reduce counter-regulation responses for the next 24-72 hours (Cryer, 1992).