The consequences of hypoglycaemia

Hypoglycaemia elicits a stress response, which acts to correct the glucose fall. In health, cessation of insulin secretion and stimulation of pancreatic glucagon, driven by both local and central neuroendocrine signalling, abort a plasma glucose fall through stimulation of hepatic endogenous glucose production. In insulin-deficient diabetes, where exogenous insulin or an insulin secretagogue is being taken, circulating insulin levels remain elevated and pancreatic alpha cells, unable to detect a signal from falling beta cell stimulation, do not secrete glucagon [5, 6]. Correction of the falling glucose is, therefore, dependent on hyperglycaemic sympathetic nerve stimulation, catecholamine secretion and, critically, the person recognising the hypoglycaemia and ingesting carbohydrate. The plasma glucose concentration at which these responses are triggered is influenced by prior glycaemic experience: people with poorly controlled type 2 diabetes and no previous experience of hypoglycaemia may experience some elements of the stress response, and certainly symptoms, at higher plasma glucose concentration than occurs in health [7], and people with previous experience of hypoglycaemia may downregulate the glucose concentration at which sympathetic and hormonal responses to a falling glucose occur, sometimes to a value below that at which cognitive deterioration starts [8, 9]. This creates a syndrome of impaired awareness of hypoglycaemia, in which failure of subjective awareness of hypoglycaemia increases risk of severe hypoglycaemia sixfold in people with type 1 diabetes (in whom severe hypoglycaemia is more common) and 17-fold in individuals with type 2 diabetes who are taking insulin [10, 11]. Parenthetically, we should note that other factors can affect the hierarchy of responses to hypoglycaemia. For example, age can have an impact on response to hypoglycaemia, with findings showing that older people have a lower glucose concentration for subjective awareness and hormonal responses, while the deterioration of cognitive function is preserved in these individuals at an arterialised plasma glucose of 3 mmol/l [12]. Furthermore, in children and in elderly people with diabetes, cognitive and behavioural signs and symptoms may be more prominent in the clinical presentation [13, 14].

We have thus described the first two important acute consequences of hypoglycaemia: the symptomatic stress response and the impairment of responses to subsequent episodes. In addition, we have implied a third: impairment of cognitive function during an acute episode.

The impairment of cognitive function associated with hypoglycaemia ranges from slowing of cerebration and performance, confusion, irrational behaviour and drowsiness, to coma and seizures. Other outcomes include inconvenience, embarrassment, and physical injury to the patient or to others, with possible employment, social and legal implications. There is evidence that the threshold for cognitive impairment changes less in response to antecedent hypoglycaemia than does the threshold for subjective awareness and neurohumoral responses, which provides a potential mechanism for the increased risk of severe hypoglycaemia, as the person becomes unable to self-treat [15, 16].

Other neurological consequences of a hypoglycaemic episode include temporary focal deficits, including Todd’s paresis, in which the person wakes after an undetected nocturnal hypoglycaemia with symptoms and signs mimicking a stroke [17]. Complete recovery occurs within hours and there is no prognostic implication to these episodes. We will discuss below whether residual cognitive deficit results from hypoglycaemia from which an apparently complete recovery is made at the time. Here we note only that in animal studies of extreme hypoglycaemia, the hippocampus seems particularly vulnerable. Anecdotally, memory deficits are reported by people with type 1 diabetes and problematic hypoglycaemia, with some evidence to support an association [18], but hypoglycaemia impairs formation and consolidation of memory in type 1 diabetes acutely [19, 20] and whether the memory deficits are resolved by hypoglycaemia avoidance remains to be determined.

Hypoglycaemia is associated with changes in regional brain activation, not just in the region of the hypothalamic–pituitary axis, but also in brain regions involved in interoception (relevant to symptom generation and perception) and in regions involved in emotional salience, aversion, executive function and memory [21]. Long duration type 1 diabetes can alter these regional brain responses and it has been postulated that enhanced thalamic activity in hypoglycaemia in type 1 diabetes may support subjective awareness in the face of reduced catecholamine responses [22].

Other potential acute consequences of hypoglycaemic episodes include cardiovascular effects, both as a result of the stress response (tachycardia, widened arterial pulse pressure) and arrythmias [23, 24], including lengthening of the QT interval (QTc) on an electrocardiogram and bradycardia. Such arrythmias are associated with the adrenergic responses and the fall in plasma potassium associated with hypoglycaemia [25]. Hypoglycaemia produces endothelial dysfunction (as does hyperglycaemia) [26], an inflammatory response [27], and creates a coagulopathy, which can last for several days [28].

Death during an acute hypoglycaemic episode is rare but does occur, accounting for up to 10% of deaths in people with type 1 diabetes under the age of 40 years, in whom other causes of death are, happily, rare [29].

There is a psychological impact from hypoglycaemia experiences. Any episode can be unpleasant: non-severe episodes can be associated with unpleasant symptoms, which may be distressing to the person experiencing them to the extent that the individual will describe the episode as ‘very severe’. One person with diabetes described multiple negative experiences of hypoglycaemia including interruption of activities, sleep disruption and a ‘horrible force feeding one has to endure if not remotely hungry’ (personal communication with author). Fear of hypoglycaemia may develop and lead to behaviours that are unhelpful either to diabetes control or to normal social interaction [36]. One recent study described 40–50% of a clinic population of adults with type 1 diabetes as expressing fear of hypoglycaemia [37] and, in people with type 2 diabetes, non-severe hypoglycaemia may have as big an impact on fear of hypoglycaemia as severe episodes, with negative impact on quality of life and on glucose management strategies [38, 39]. Other family members, perhaps particularly parents of children with diabetes, are also affected by fear of hypoglycaemia [40], with partners of people with problematic hypoglycaemia (impaired awareness of hypoglycaemia and recurrent severe episodes) expressing very high distress [41]. The societal impact may include loss of driving privileges, restricted employment, and breakdown of family relationships, with restricted access to children. There are potential economic impacts beyond the costs to healthcare providers (who are involved in a tiny minority of cases), including time lost from work, that have still to be fully understood [42].

Impaired awareness of hypoglycaemia is believed to arise as a result of recurrent exposure to hypoglycaemic episodes (under 3 mmol/l), with evidence that avoidance of such exposure can restore awareness, both in mechanistic studies (e.g. [43]), and clinically [44]. McCrimmon’s group has described this as a conditioning response [45]. A small but highly vulnerable group of patients seem resistant to interventions for hypoglycaemia avoidance [46]. Some may have unhelpful cognitions around hypoglycaemia, which may act as barriers to future hypoglycaemia avoidance [47, 48]. One clinic-based study of people with type 1 diabetes found that one-third of people at high risk for severe hypoglycaemia expressed low concern about their hypoglycaemia [49]. Neuroimaging studies offer a potential explanation, with altered activation of brain regions involved in appetite control, emotional salience, aversion, recall, arousal and decision making in response to hypoglycaemia in people with established impaired awareness and recurrent severe hypoglycaemia [50, 51]. Interventions that target cognitions around hypoglycaemia may be helpful in this group [52].

There is a growing body of evidence linking severe hypoglycaemia to future mortality both in hospital and in the community, with estimates of increased risk ranging from 50% to 600% [53]. Some of the responses to acute hypoglycaemia, particularly the proinflammatory and coagulopathy effects, have been implicated as underlying mechanisms, but the data remain compatible with hypoglycaemia being a marker of frailty and high risk of death [53]. Severe hypoglycaemia has been associated with approximately a doubling in risk of subsequent cardiovascular events, including death, but the relationship is bi-directional [54].

Meanwhile, concern remains that recurrent hypoglycaemia may have a lasting impact on cognitive function. There is some evidence that recurrent severe hypoglycaemia in children at an age when the brain is still developing may result in subtle impairment of performance on cognitive function testing in adolescence, especially when seizures have accompanied the hypoglycaemia [55, 56]. In adults data remain controversial, with consistently reassuring data coming from long-term follow-up of the DCCT/Epidemiology of Diabetes Interventions and Complications (EDIC) cohort of type 1 diabetes patients and from the Outcome Reduction With Initial Glargine Intervention (ORIGIN) trial in people with type 2 diabetes [57, 58]. However, a recent large study in older adults with type 1 diabetes demonstrated an association between patient-reported history of severe hypoglycaemia events (episodes resulting in emergency department or inpatient admission), either recent (any) or life-time exposure, and impaired performance in global cognition, language and executive function and recent episodic memory, with evidence for a dose effect [59]. An earlier meta-analysis also found a bi-directional relationship between dementia and hypoglycaemia in older adults [60].