Impaired awareness of hypoglycaemia: a reviewAltération de la perception des hypoglycémies. Revue générale
Section snippets
Definitions of hypoglycaemia
Hypoglycaemia is a major barrier to the implementation of intensive glycaemic control to treat diabetes. In the Diabetes Control and Complications Trial (DCCT) severe events were three-fold greater in the group with strict glycaemic control compared to those with conventional treatment [1]. In clinical practice, hypoglycaemia is defined by the ability of an individual to self-treat. Self-treated events are classified as “mild”, while “severe” hypoglycaemia is any episode that requires external
Frequency of hypoglycaemia
People with type 1 diabetes mellitus (T1DM) experience an average of one to two episodes of mild hypoglycaemia per week; one third experience an episode of severe hypoglycaemia annually [6]. Retrospective recall of severe hypoglycaemia is robust for up to one year in people with both types of diabetes [7,8], but recall of mild hypoglycaemia is limited to one week [9]. Relatives report significantly more annual episodes of severe hypoglycaemia than people with T1DM do themselves [10]. The
Symptomatology of hypoglycaemia
The application of statistical methodology has enabled classification of the symptoms of hypoglycaemia in patients with T1DM; those generated by the activation of the sympathoadrenal system are termed autonomic and those occurring as a consequence of cerebral glucose deprivation are termed neuroglycopenic. Young adults also express a non-specific or malaise group of symptoms. These three groups of symptoms can be measured using the Edinburgh Hypoglycaemia Symptom Scale [12]. Although it has
Impaired Awareness of Hypoglycaemia (IAH)
In 1922, very shortly after insulin was first used to treat diabetes, Elliot Joslin observed that hypoglycaemia could occur without warning symptoms [21]. More than one third of episodes of severe hypoglycaemia that occur during waking hours are not accompanied by warning symptoms [22], and many people with insulin-treated diabetes develop a syndrome with a spectrum of severity in which their ability to identify the onset of hypoglycaemia becomes progressively impaired. “Impaired awareness of
Impaired defences against hypoglycaemia in T1DM
In normal health, when blood glucose falls to a level which may compromise the integrity of cognitive function, glucose counter-regulation is initiated (Fig. 1). This is triggered when blood glucose declines below the lower end of the normal range and is preceded by suppression of endogenous insulin secretion. Glucagon and adrenaline (epinephrine) are the most important counter-regulatory hormones to acute hypoglycaemia. In people with T1DM the glucagon response to hypoglycaemia rapidly
Glucose sensing
The ventromedial thalamus (VMH) is a key glucose-sensing region involved in the detection of hypoglycaemia [37]. The counter-regulatory response is ameliorated to a large extent by maintaining cerebral euglycaemia in the presence of systemic hypoglycaemia [38]. Local perfusion of the VMH with glucose to maintain localised euglycaemia markedly suppressed the counter-regulatory response despite the presence of systemic hypoglycaemia [39]. Glucose sensing also occurs outside of the brain and
Variable susceptibility to hypoglycaemia in people with T2DM
People with T2DM comprise a heterogeneous population with abnormalities ranging from pronounced insulin resistance to advanced insulin deficiency, and with variable residual endogenous insulin-secretory capacity. In contrast with early T1DM, residual beta cell function is usual and glucagon secretion is preserved in people with T2DM on oral therapies, so limiting the development of severe hypoglycaemia [43,44]. Increased insulin resistance associated with central obesity may also limit the
Definition and prevalence of IAH
The lack of an acceptable clinical definition of IAH has hindered accurate ascertainment of the prevalence of IAH and research into this condition. “Awareness” of hypoglycaemia and its progressive impairment represent a continuum ranging from normal perception of the onset of hypoglycaemia to complete inability to detect its onset [31]. For the purposes of developing a clinical scoring system, awareness of hypoglycaemia was arbitrarily divided into normal, “partial” and “absent” awareness,
Risk factors for IAH
Factors that influence the normal awareness of hypoglycaemia are shown in table 1. Many episodes of severe hypoglycaemia are under-reported by people with IAH. Furthermore, if blood glucose monitoring is infrequent, many episodes of asymptomatic (or biochemical) hypoglycaemia are not detected. Major risk factors that are associated with the development of IAH in T1DM include increasing age and duration of diabetes and strict glycaemic control [7,52]. Behavioural factors are important with
Clinical assessment of IAH
Glucose clamp studies have been used to determine awareness of hypoglycaemia [62] and to demonstrate the hierarchy of responses that occur as blood glucose declines. Autonomic symptoms occur before neuroglycopenic symptoms, with a difference of around 0.5 mmol/l between the thresholds at which they are generated [63,64]. However, this artificial and controlled experimental setting bears little relationship to everyday life with its myriad distractions, and this small threshold difference cannot
Morbidity and mortality associated with IAH
People who have impaired awareness of hypoglycaemia have a much greater risk of severe hypoglycaemia, up to six fold, with its attendant morbidity [33,70]. Severe hypoglycaemia may result in many serious forms of morbidity including seizure, coma, fractures and joint dislocation and cardiac arrhythmias, and is occasionally fatal. However, although these problems are more frequent in people with IAH the frequencies of these morbidities associated with severe hypoglycaemia have not been formally
Effect of alcohol, sleep and distraction on awareness of hypoglycaemia
Alcohol is an important risk factor for hypoglycaemia [72]. The clinical features of hypoglycaemia can be mistaken for those of alcohol intoxication which can delay correct treatment of the hypoglycaemic episode. Despite increased counter-regulatory responses in those who had consumed alcohol compared with those who had not, during experimental hypoglycaemia they were less likely to recognise that they were hypoglycaemic (2 out of 15 versus 11 out of 15) [73].
Sleep is a physiological state
Effect of IAH on cognitive function
People with IAH often state that they do not experience any cognitive impairment during hypoglycaemia and are capable of carrying out the usual activities of daily living even though they may be exposed to frequent asymptomatic hypoglycaemia. To some extent this is true, as cognitive function is less affected during moderate hypoglycaemia and recovery is quicker compared than in people with T1DM who have normal awareness [81]. The glycaemic threshold for cognitive dysfunction is re-set at a
Neuroimaging studies
The effect of hypoglycaemia on the brain can be directly visualised with neuroimaging techniques such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). During euglycaemia, glucose is the obligate metabolic substrate required to maintain cerebral function, and this is unchanged during hypoglycaemia [88]. The likely contribution of other energy sources (e.g. lactate) remains small although there is some evidence that people with T1DM may be better able to
Management of IAH
The mainstay of treatment of IAH is the complete avoidance of hypoglycaemia, which is of course very difficult to achieve. Reducing the frequency of hypoglycaemia can be attempted by various measures as shown in table 2. Hypoglycaemia awareness can be restored by scrupulous avoidance of hypoglycaemia, although this may be at the cost of jeopardising glycaemic control [96,97]. Hypoglycaemia avoidance can lead to a significant improvement in hypoglycaemia symptom scores during exposure to
Conclusion
Impaired awareness of hypoglycaemia is an acquired syndrome associated with the use of insulin and exposure to hypoglycaemia that is common in people with T1DM and is observed less frequently in insulin-treated T2DM. It should be defined by the loss of ability to perceive the onset of hypoglycaemia, which is usually manifested by a reduced intensity and number of symptoms and a change in symptom profile. Asymptomatic biochemical hypoglycaemia occurs more frequently and people with established
Conflicts of interest
No potential conflict of interest relevant to this article was reported.
References (110)
- et al.
Factors affecting hypoglycemia awareness in insulin-treated type 2 diabetes: The Diabetes Outcomes in Veterans Study (DOVES)
Diabetes Res Clin Pract
(2004) - et al.
Hypoglycaemic counter-regulation at normal blood glucose concentrations in patients with well controlled type-2 diabetes
Lancet
(2000) - et al.
Prevalence of impaired awareness of hypoglycaemia and frequency of hypoglycaemia in insulin-treated type 2 diabetes
Diabetes Res Clin Pract
(2010) - et al.
Warning symptoms of hypoglycaemia during treatment with human and porcine insulin in diabetes mellitus
Lancet
(1989) - et al.
Classification of hypoglycemia awareness in people with type 1 diabetes in clinical practice
J Diabetes Complications
(2010) - et al.
Hypoglycemia-induced cognitive dysfunction in diabetes mellitus: effect of hypoglycemia unawareness
Physiol Behav
(1995) - et al.
Restoration of hypoglycaemia awareness in patients with long-duration insulindependent diabetes
Lancet
(1994) The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group
N Engl J Med
(1993)Preventing hypoglycaemia: what is the appropriate glucose alert value?
Diabetologia
(2009)Defining hypoglycaemia: what level has clinical relevance?
Diabetologia
(2009)