Accepted Manuscript

Managing Hypoglycaemia

Ahmed Iqbal, BSc (Hons) MBBS (Hons) MRCP, Dr., Professor Simon Heller, BA MB
BChir DM FRCP, Professor of Clinical Diabetes & Honorary Consultant Physician

PII: S1521-690X(16)30021-5
DOI: 10.1016/j.beem.2016.06.004
Reference: YBEEM 1097

To appear in: Best Practice & Research Clinical Endocrinology & Metabolism

Please cite this article as: Iqbal A, Heller S, Managing Hypoglycaemia, Best Practice & Research
Clinical Endocrinology & Metabolism (2016), doi: 10.1016/j.beem.2016.06.004.

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 ACCEPTED MANUSCRIPT

Title: Managing Hypoglycaemia

Dr Ahmed Iqbal BSc (Hons) MBBS (Hons) MRCP

Medical Research Council Clinical Research Training Fellow and Specialty

Registrar in Diabetes and Endocrinology

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Academic Unit of Diabetes, Endocrinology and Metabolism

University of Sheffield

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School of Medicine and Biomedical Sciences

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Beech Hill Road

Sheffield

S10 2RX
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Tel: +44 (0)114 271 3204

Fax: +44 (0)114 271 2475 Email: [email protected]

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Professor Simon Heller BA MB BChir DM FRCP (corresponding author)

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Professor of Clinical Diabetes & Honorary Consultant Physician

Department of Human Metabolism and Oncology

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University of Sheffield

Room EU38, E Floor

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School of Medicine and Biomedical Sciences

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Beech Hill Road

Sheffield

S10 2RX

Tel: +44 (0)114 271 3204

Fax: +44 (0)114 271 2475 Email: [email protected]

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Abstract (No. words = 147)

Intensive glycaemic control reduces the diabetic microvascular disease

burden but iatrogenic hypoglycaemia is a major barrier preventing tight

glycaemic control because of the limitations of subcutaneous insulin

preparations and insulin secretagogues. Severe hypoglycaemia is

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uncommon early in the disease as robust physiological defences, particularly

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glucagon and adrenaline release, limit falls in blood glucose whilst associated

autonomic symptoms drive patients to take action by ingesting oral

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carbohydrate. With increasing diabetes duration, glucagon release is

progressively impaired and sympatho-adrenal responses are activated at

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lower glucose levels. Repeated hypoglycaemic episodes contribute to
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impaired defences, increasing the risk of severe hypoglycaemia in a vicious
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downward spiral. Managing hypoglycaemia requires a systematic clinical

approach with structured insulin self-management training and support of

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experienced diabetes educators. Judicious use of technologies includes

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insulin analogues, insulin pump therapy, continuous glucose monitoring, and

in a few cases islet cell transplantation. Some individuals require specialist

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psychological support.
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Keywords: Hypoglycaemia, counter-regulation, impaired hypoglycaemia

awareness, adrenaline, cardiovascular risk

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Introduction

Since the earliest description by Banting, the clinical challenges of

hypoglycaemia have been recognised as a major side effect of insulin

treatment (1). More precise analyses of the pathophysiology did not emerge

until around 20 years later in R D Lawrence’s account of symptoms of

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iatrogenic hypoglycaemia as “being akin to a dose of adrenaline” (2). A more

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detailed understanding of why individuals with insulin treated diabetes are so

vulnerable to hypoglycaemia had to await accurate measurements of both

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blood glucose and the relevant endocrine responses in the 1980s. These

insights have been followed by the development of experimental human and

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animal models. Studies have continued to the present day, although to date
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there have been few specific treatments which can prevent hypoglycaemia.
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The key to managing and preventing hypoglycaemia requires a good

understanding of both the pathophysiology and insulin therapeutics. In this

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review we will consider the epidemiology, pathophysiology and consequences

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of hypoglycaemia, but concentrate on its practical management.

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Definition and Epidemiology

The precise definition of hypoglycaemia continues to be debated. An

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American Diabetes Association (ADA) working party has attempted a

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comprehensive definition (3). They have defined “severe hypoglycaemia” as

an episode requiring the assistance of another person to administer

treatment, “documented symptomatic hypoglycaemia” as the presence of

common symptoms of hypoglycaemia with a measured plasma glucose <3.9

mmol/L, “probable symptomatic hypoglycaemia” as self-reported symptoms

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not verified by a glucose measurement and “relative hypoglycaemia” as the

presence of symptoms with a plasma glucose >3.9 mmol/L.

It is clear that a single definition cannot encompass all types of

hypoglycaemia. Indeed, even within these categories there continues to be

no consensus. For example, the definition of severe hypoglycaemia does not

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apply to children who rely on their parents or other adults for recovery even

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from relatively mild episodes. Thus, paediatricians define severe

hypoglycaemia as coma or needing parenteral treatment.

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Furthermore, in clinical trials, organisations, both commercial and academic,

frequently use different definitions. It is therefore often difficult to compare

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directly, epidemiological studies and clinical trial data. This also means that
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meta-analyses often exclude detailed discussion of even severe
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hypoglycaemia due to the observed ‘heterogeneity’ between studies.

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It is important to note that data from clinical trials report rates of

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hypoglycaemia, including severe, which are many times lower than rates

collected from observational data. In the Diabetes Control and Complications

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Trial (DCCT), which is considered to have resulted in an epidemic of severe

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hypoglycaemia in the intensive arm, reported rates expressed in episodes per

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patient year were considerably lower than rates from observational studies.

More recent clinical trials have reported even lower rates of severe

hypoglycaemia (4) . In contrast, data reported in observational studies have

shown virtually no reduction in rates of severe hypoglycaemia over the last 20

years, despite the introduction of analogue insulins and continuous

subcutaneous insulin infusion (CSII) (Table 1) (5)(6)(7)(8)(9). These data

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suggest that clinicians are either failing to exploit technological developments

or that other factors often determine hypoglycaemic risk. Prospective

population based studies which have examined hypoglycaemic rates indicate

that rates of severe hypoglycaemia in insulin treated patients with type 2

diabetes mellitus (T2DM) are generally around a third of those with type 1

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diabetes mellitus (T1DM) (10). Interestingly, comparable rates of

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hypoglycaemia have been reported in T1DM and T2DM once patients were

matched for duration of insulin treatment (11). Data from another prospective

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study also showed that severe hypoglycaemia rates rise in both T1DM and

T2DM with increasing duration of treatment (8). These findings may be

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explained by a progressive decline in endogenous insulin production leading
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to both diminished physiological protection from glucagon release and more
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variable free insulin levels. Finally, as T2DM is much more common than

T1DM with an increasing incidence predicted in the coming years (12),

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management of hypoglycaemia in T2DM in terms of numbers of cases is at

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least as important as in T1DM.

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Physiological consequences of hypoglycaemia

The reliance of the brain on glucose as an obligate fuel explains both the
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vulnerability of patients to hypoglycaemia and the array of defences that have

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evolved as stress responses. These physiological responses are termed

counter-regulatory (opposing the regulatory effect of insulin) (Figure 1). Two

key responses are triggered by hypoglycaemia: 1) Increased endogenous

glucose production via glycogenolysis and gluconeogenesis; 2) A behavioural

response, prompting the individual to consume food. In non-diabetic

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individuals, the initial response to glucose values falling below 4.6 mmol/L is a

reduction in endogenous insulin secretion (13). Since individuals with T1DM

and insulin treated T2DM depend on injected insulin boluses in the absence

of endogenous insulin secretion, their ability to defend themselves against

hypoglycaemia requires additional mechanisms. Initially, as glucose

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concentrations fall below 3.8 mmol/L, endogenous glucagon secretion from

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pancreatic alpha cells induces both glycogenolysis and gluconeogenesis (14).

As blood glucose falls further, the adrenal medulla secretes adrenaline which

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promotes hepatic glucose release through similar mechanisms. Raised

cortisol and growth hormone concentrations stimulate gluconeogenesis but

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since subsequent increases in blood glucose are not observed for some
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hours, these responses are not relevant in the acute setting (15).
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Symptoms of hypoglycaemia

Our knowledge of the symptomatic response to hypoglycaemia is largely

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based on clinical observations, but Frier and colleagues have used factor
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analysis to refine our understanding (16). By exploring statistical associations

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of symptoms reported by two cohorts of adults with insulin treated diabetes,

they were able to demonstrate that hypoglycaemia symptoms could be

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divided into three categories, namely autonomic activation, neuroglycopenia

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and malaise (nausea and headache) (Table 2). Symptoms vary between

individuals, and also by age and type of diabetes. For example, children

exhibit emotional and behavioural changes in response to hypoglycaemia as

well as autonomic and classical neuroglycopenic symptoms (17). Older

patients with T2DM report neurological symptoms which are different when

compared to a younger cohort of diabetes patients on insulin (18). This

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classification can help patients (and their families) to identify symptoms

indicating hypoglycaemia at an early stage and take corrective action before a

falling glucose value impairs their cognitive ability.

Counter-regulatory defences in diabetes

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Counter-regulatory responses oppose the effects of exogenous insulin on

blood glucose concentrations whilst the associated sympatho-adrenal

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activation also contributes to autonomic symptoms such as sweating, tremor

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and palpitations. Experimental data indicate that counter-regulatory responses

to hypoglycaemia whilst intact at diagnosis of diabetes, are gradually lost with

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increasing disease duration (19). In T1DM, impaired glucagon responses to
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hypoglycaemia are apparent by 2 years, and are established in most

individuals within 5 years after diagnosis (19). The diminished glucagon

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response is thought to occur due to a failure of paracrine ‘cross-talk’ between

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pancreatic α-cells and β-cells, as the latter are destroyed progressively by

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the autoimmune process (20).

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Sympatho-adrenal responses to hypoglycaemia are also progressively

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impaired, although the mechanisms are different (19). Impaired adrenaline

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responses appear to be due to a shifting of the glycaemic threshold for

activation to lower glucose values, whilst the secretory capacity of the adrenal

glands remain intact to other stimuli (21). Thus, a combined diminution in

glucagon and adrenaline responses to hypoglycaemia progressively

increases vulnerability to hypoglycaemia in T1DM (22). A diminished

adrenaline response reflects an attenuated autonomic response to

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hypoglycaemia, as the autonomic nervous system is key to the activation of

the neuro-endocrine response to hypoglycaemia. It also appears that the

mechanism underlying the diminished sympatho-adrenal response to

hypoglycaemia may be distinct from that driving impaired glucagon responses

(see below).

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Counter-regulatory responses to hypoglycaemia have been less extensively

studied in individuals with T2DM, but the limited evidence available suggests

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that early in the course of the disease physiological protection to

hypoglycaemia is intact with glucagon responses which are normal or

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modestly reduced (23). As disease duration increases and endogenous
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insulin production falls, both glucagon and sympathoadrenal responses to
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hypoglycaemia become impaired (24). Thus the same drivers which increase

vulnerability in T1DM may operate in longstanding T2DM. However, the

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experimental data are somewhat inconsistent and some studies suggest that,
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particularly in poorly controlled patients, the threshold for the activation of

counter-regulatory responses to hypoglycaemia may occur at normal glucose

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values (25).
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Impaired awareness of hypoglycaemia

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The impaired sympatho-adrenal response to hypoglycaemia is a

consequence, at least in part, of repeated episodes of iatrogenic

hypoglycaemia which attenuate the autonomic response to subsequent

hypoglycaemia (26). This process resets the glycaemic threshold for the

activation of symptoms to a lower glucose level. The phenomenon was first

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described in non-diabetic individuals (26) and subsequently in both T1DM (27)

and T2DM (28), and reduces an individual’s ability to perceive the onset of

hypoglycaemic symptoms (28). Whether the progressive impairment in

sympatho-adrenal responses which occurs with increasing duration of

diabetes is entirely due to repeated hypoglycaemic episodes remains unclear.

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Clinical experience indicates that many individuals with longstanding insulin

treated diabetes have a diminished ability to perceive acute hypoglycaemia.

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To date, no satisfactory comprehensive definition of impaired hypoglycaemia

awareness has been suggested, although the term “hypoglycaemia

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unawareness” has largely been replaced by “impaired hypoglycaemia
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awareness” since complete unawareness is rare. Gold (29) and Clarke (30)
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have proposed scales which can be used to identify impaired awareness of

hypoglycaemia in T1DM. Recent studies have used a Gold score of 4 or

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above to denote impaired hypoglycaemia awareness (31)(32). The

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prevalence of impaired hypoglycaemia awareness is difficult to compare

across studies and populations given the use of different definitions and
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treatment durations. Impaired hypoglycaemia awareness represents a

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progression along a continuum from normal responses to hypoglycaemia,

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including an altered symptom profile (with early loss of autonomic symptoms),

reduced number or intensity of symptoms and, rarely, an absence of

symptoms altogether. Impaired hypoglycaemia awareness is more common in

those with T1DM but can occur in insulin-treated T2DM (11).

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The reported prevalence of impaired hypoglycaemia awareness in T1DM is

around 20-25%, rising to around 50% after 25 years or more of treatment

(33)(34)(35). In those with T2DM, prevalence has been estimated at between

8-10% (36)(37). It is unclear if impaired hypoglycaemia awareness also

develops in those with T2DM taking oral hypoglycaemic agents. Those with

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impaired hypoglycaemia awareness are at particular risk of severe episodes

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of hypoglycaemia, with severe hypoglycaemia rates up to seven times as

common compare with those who retain hypoglycaemia awareness in

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prospective observational studies (29).

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Factors contributing to impaired awareness of hypoglycaemia
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Several factors contribute to impaired hypoglycaemia awareness.
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Antecedent or recurrent hypoglycaemia and tight glycaemic control

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In addition to the seminal studies conducted in the early 1990s described

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above, further studies have demonstrated that an episode of antecedent

hypoglycaemia can diminish normal counter-regulatory responses to further

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episodes of hypoglycaemia for up to a week later (38). Twice weekly episodes

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of mild hypoglycaemia have a similar effect (39), and antecedent

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hypoglycaemia also impairs counterregulatory responses to subsequent

exercise (40). This mechanism appears to explain why tight glycaemic control

with intensive insulin therapy can lead to a resetting of the glucose threshold

values at which the normal counter-regulatory mechanisms are activated (29).

Whilst tight glucose control and episodes of antecedent hypoglycaemia may

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induce transient impaired hypoglycaemia awareness, it remains unclear how

these factors lead to chronic impaired awareness.

Recurrent, episodic hypoglycaemic events of sufficient depth and duration,

however, progressively blunt and impair normal counter-regulatory responses

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to hypoglycaemia predisposing patients to a vicious cycle of ever more

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frequent hypoglycaemic episodes with a falling glucose threshold to trigger

counter-regulation (41). Cryer has termed this sequence of events,

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hypoglycaemia-associated autonomic failure (HAAF)(42). It is important to

note that the term denotes a condition which is entirely separate from

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classical autonomic dysfunction, a common neuropathic complication of
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diabetes.
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Peripheral autonomic neuropathy

Traditionally, peripheral autonomic neuropathy was thought to play a role in

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impaired hypoglycaemia awareness (43) by impeding the secretory capacity

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of adrenaline in response to hypoglycaemia, thus attenuating classical

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autonomic symptoms of hypoglycaemia (44). Circulating adrenaline, however,

plays a marginal role in the generation of autonomic symptoms which are

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primarily generated by activation of the sympathetic nervous system (45).

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Moreover, Hilsted et al. have shown that in the presence of autonomic

neuropathy, there is an increase in peripheral β-adrenoreceptor sensitivity

which may offset any deficit due to reduced secretion of adrenaline (45).

Furthermore, a normal sympatho-adrenal response to hypoglycaemia has

been demonstrated in subjects with T1DM despite the presence of

concomitant cardiovascular autonomic neuropathy (46). Although the

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experimental and observational data are inconsistent, peripheral autonomic

neuropathy associates with impaired awareness of hypoglycaemia, probably

as a consequence of long-standing diabetes, and appears to play only a

minor role as a cause of impaired hypoglycaemia awareness.

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Mechanistic insights into impaired hypoglycaemia awareness

Precisely how tight glycaemic control and antecedent hypoglycaemia

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contribute to the development of impaired awareness of low glucose levels

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remains unclear. Since the demonstration that repeated episodes of

hypoglycaemia led to an alteration in the threshold for activation of the neuro-

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endocrine response, experimental work in both humans and animal models
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has centred on the central nervous system (CNS). The reader is directed to a

recent comprehensive review (47) since a detailed discussion of these studies

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and their interpretation is beyond the scope of this article. Figure 2

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summarises some of the putative mechanisms leading to impaired

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hypoglycaemia awareness which have been identified as potentially relevant.

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Morbidity and mortality associated with hypoglycaemia

Biological consequences of hypoglycaemia

Cardiovascular effects

Whilst the role of tight glycaemic control in reducing microvascular

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complications is well established (48) , the contribution of tight glucose control

in reducing macrovascular complication remains less certain. Three large

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randomised controlled trials have recently tested this hypothesis by

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measuring the accumulation of hard cardiovascular (CV) end-points in

patients randomised to either intensive glucose or standard glucose

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control(49)(50)(51). In none of the trials was there a reduction in overall CV
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risk in those randomised to intensive glucose control, although a patient-level

meta-analysis that included data from the first five years of the UK
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Prospective Diabetes study showed that the risk of major cardiovascular

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events was reduced by 9% (52). In the Action to Control Cardiovascular Risk

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in Diabetes (ACCORD) trial, however, a significant excess CV mortality was

noted in the intensive glucose arm (257 deaths) compared with the standard
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treatment arm (203 deaths) resulting in early trial closure. Possible

explanations for this result include chance, specific medications and weight
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gain. It is noteworthy that severe hypoglycaemia rates were more common in

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in ACCORD in those treated intensively, and far higher than in the ADVANCE

trial which reported no such increase. Nevertheless, the hypothesis that

hypoglycaemia may contribute to increased mortality (and thus negate the

potential macrovascular benefit of improved glucose control) continues to be

the subject of intense debate.

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It is extremely challenging to confirm or refute a causal link between

hypoglycaemia and observed CV mortality. One reason is that these trials

were not designed originally to examine the relationship between

hypoglycaemia and CV outcomes. The ACCORD investigators have argued

that there is scant evidence linking severe hypoglycaemia to increased CV

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mortality in the intensive glycaemic control arm of their trial, since they

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observed no direct relationship between severe hypoglycaemic episodes and

subsequent deaths (53). Nevertheless, the potential role of hypoglycaemia in

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exacerbating CV risk in patients randomised to intensive glucose control in

ACCORD was underestimated (54). Hypoglycaemia may have been

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underreported in in the intensive treatment arm since repeated episodes of
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hypoglycaemia leads to reduced awareness. Furthermore, a causal
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hypoglycaemic event may have lead to pathophysiological changes, leading

to increased mortality downstream of the event. Indeed, it is striking that in all

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three of these major CV outcome trials, a severe hypoglycaemic event

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predicted mortality, not at the time but weeks or months after the event.

(49)(50)(51)(54)(55).
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Furthermore, some excess deaths in the intensive treatment arm may have
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been erroneously coded as being due to coronary events with no possibility of

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glucose measurement post-mortem (54).

Whilst it is challenging to establish causation rather than association, due to

potential confounding, hypoglycaemia is probably associated with excess CV

mortality, at least in part, by being more prevalent in those with concomitant

liver disease and kidney disease, comorbidities which may independently

increase the risk of CV mortality. Hence, hypoglycaemia might merely be a

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physiological marker for susceptibility, as opposed to being a direct cause of

mortality. Nevertheless, a recent large systematic review and meta-analysis

using specific statistical adjustment, concluded that it was unlikely that

comorbidities alone explained the relationship between hypoglycaemia and

CV disease (57). The authors studied the relationship in studies involving

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nearly a million participants and demonstrated that severe hypoglycaemia

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was strongly associated with CV disease (relative risk 2.05, 95% confidence

interval 1.74 to 2.42; P<0.001). In this systematic review and meta-analysis,

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Goto et al. highlighted the many plausible mechanisms whereby

hypoglycaemia might increase CV risk. These included the haemodynamic

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consequences of the counter-regulatory response (particularly sympatho-
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adrenal activation), which might precipitate CV events such as angina or
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myocardial infarction. Indeed, electrocardiographic features of cardiac

ischemia have been noted in a patient with hypoglycaemic coma (58). Others
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have reported iatrogenic hypoglycaemia inducing angina pectoris in a patient

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with diabetes and concomitant coronary artery disease (59). Hypoglycaemia

can be pro-arrhythmogenic via a number of mechanisms. Tattersall and Gill in

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1991, described the phenomenon of unexplained nocturnal sudden death in

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young patients with T1DM (60), termed the “dead-in-bed syndrome” in an

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accompanying editorial (61). One hypothesis is that nocturnal hypoglycaemia

generates arrhythmias leading to the dead-in-bed syndrome (62)(63)(64).

Hypoglycaemia also might increase the propensity to tachyarrhythmias

consequent on an increase in the QT interval (QTc) (65) and QT dispersion

(66). An increase in catecholamine levels generated during the sympatho-

adrenal response to hypoglycaemia has been shown to contribute to QTc

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prolongation (65)(67). The adrenergic response to hypoglycaemia may also

precipitate ventricular tachycardia by increasing myocardial calcium

concentrations (68), and hypoglycaemia has been associated with

bradyarrhythmias (69)(70). A recent study has proposed that an increase in

vagal tone resulting from the counter-regulatory response to hypoglycaemia

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may underlie the onset of bradyarrhythmias during hypoglycaemia (71).

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These events appeared to be precipitated by nocturnal hypoglycaemic

episodes with bradycardia, atrial and ventricular ectopics occurring more

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frequently at night (71). Sleep modulates the counter-regulatory response to

hypoglycaemia with the glucose threshold for initiation of counter-regulation

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falling in early sleep, and late sleep reducing the induction of counter-
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regulatory hormones (72).
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Acute and recurrent hypoglycaemia exert a plethora of effects on thrombosis

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and inflammation, thus potentially increasing cardiovascular risk.

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Hypoglycaemia can cause both platelet activation and aggregation (73)(74),

probably mediated by the adrenergic response to hypoglycaemia (74).

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Hypoglycaemia promotes a pro-inflammatory state by increasing levels of

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factor VIII, von Willebrand factor, and through the inhibition of thrombolysis
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(75)(76)(77). The latter changes appear to be mediated by increased

circulating adrenaline (78) as are increased levels of IL-6 and TNF-α

(77)(79)(80) and rises in cell adhesion molecules, ICAM-1, VCAM-1 and E-

selectin (77). Repeated episodes of hypoglycaemia may also damage the

vascular endothelium by reducing endogenous and exogenous nitric oxide

mediated endothelial function (81). Studies in rodents have shown that

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repetitive hypoglycaemia can increase monocyte adherence to the aorta, and

that monocyte-endothelial interactions are catecholamine driven (82).

CNS effects

Cognitive function

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Hypoglycaemia, and in particular impaired hypoglycaemia awareness, have

been linked to cognitive dysfunction (83). In addition, a decline in intellectual

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capacity has been noted with progressive loss of hypoglycaemia awareness

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(84). However, the data are inconsistent with other studies suggesting

cognitive function maybe preserved in those with impaired hypoglycaemia

awareness (85).
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Psycho-social consequences of hypoglycaemia
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Hypoglycaemia carries a significant economic burden in terms of health care

costs and lost productivity at work (86)(87), although these indirect costs are
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rarely acknowledged when therapy costs are calculated. In addition, there are
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important psychological consequences with hypoglycaemia associated with a

poor quality of life in both T1DM and T2DM (88)(89). Episodes of

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hypoglycaemia lead to fear of further episodes and consequent negative

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behaviour such as more lax glycaemic control (90)(91). Patients that suffer
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recurrent hypoglycaemia and have hypoglycaemia unawareness are more

likely to be anxious and depressed. Negative psychological consequences of

hypoglycaemia may present a cognitive barrier to the treatment of further

episodes and thus hinder effective treatment of impaired hypoglycaemia

awareness. (31)

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Recent qualitative work has highlighted both the psychological barriers and

consequences of reduced hypoglycaemia awareness. Rogers et al. found that

attitudes to impaired awareness in a group of their patients fell into two broad

categories. The first described severe hypoglycaemia as aversive and were

keen to regain awareness. The second expressed what the authors described

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as ‘unhelpful attitudes’ which included normalizing the presence of

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hypoglycaemia unawareness, underestimating its consequences; wanting to

avoiding the 'sick role'; and overestimating the consequences of high glucose

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values (92). Reduced hypoglycaemia awareness also has a major impact on

people's confidence their careers and personal relationships (93). These

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adverse consequences are not confined to patients but also apply to their
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families. In a recent powerful account, Lawton et al. describe the fear that
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family members experience due to aggressive and argumentative behaviour.

Repeated episodes of coma led to feelings of anxiety about leaving their

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partners unsupervised. Resentment could build up over time, and family

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members highlighted extensive unmet needs for information and emotional

support (94).
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Internationally, various regulations exist to regulate driving in those that suffer

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from episodes of hypoglycaemia and indeed hypoglycaemia unawareness.

The loss of a driving licence, especially if use of a motor vehicle is key to

employment, can further precipitate and perpetuate feelings of depression

and anxiety. The European Driving regulations have recently been updated

and made more stringent, presumably on the basis that a strong predictor of a

severe hypoglycaemic event is a previous episode. Individuals now stand to

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lose their license if they experience more than one severe episode in a

calendar year even if an episode occurs at a time unrelated to driving, such as

at night. Ironically, these new rules may have actually made it more difficult

for professionals to support people with these problems. A recent paper

suggests that reported rates of severe hypoglycemia in individuals with T1DM

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have suddenly reduced markedly following implementation of EU driver's

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licensing legislation (95). The authors make a strong case that this is due to

concealed severe hypoglycemia and highlight the paradox that this might

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actually reduce driving safety if patients fail to report problems with

hypoglycaemia.

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Risk reduction in hypoglycaemia
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Treatment of acute hypoglycaemia

Acute hypoglycaemia warrants expeditious action. Whilst the definition of

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hypoglycaemia is debated, a capillary blood glucose threshold of 3.5 mmol/L

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has been suggested as acceptable clinically for initiation of treatment of

hypoglycaemia (96). The Joint British Societies have provided comprehensive

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guidance on emergency management of hypoglycaemia (97). Figure 3

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summarises the key points for the inpatient management of acute

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hypoglycaemia in adults, with treatment needed for patients that have a

capillary blood glucose <4.0 mmol/L.

Strategies for recurrent hypoglycaemia and hypoglycaemia

unawareness

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Various strategies have been proposed for managing patients that are prone

to recurrent hypoglycaemia, and patients that have established impaired

hypoglycaemia awareness.

Programmes aimed at reversing impaired hypoglycaemia awareness

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The original observation that a few hours of antecedent hypoglycaemia

fundamentally impairs physiological responses to hypoglycaemia indicated

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that these defects were functional, rather than structural, and as such might

be reversible (26). A number of subsequent clinical studies showed that even

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prolonged hypoglycaemia unawareness can be reversed in part, with

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restoration of hypoglycaemic symptoms and resetting of glycaemic thresholds
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for adrenaline release, hypoglycaemic symptoms and cognitive function (98)

(99). Interestingly this was not always associated with a restoration of

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counter-regulatory hormone release (100) . Nevertheless, these studies have

highlighted an important clinical approach to the problem of impaired

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awareness. Programmes to reverse impaired hypoglycaemia awareness,

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whereby patients work to avoid all episodes of hypoglycaemia for a few weeks
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without running their blood glucose high, can be effective. The important

features appear to include intensive blood glucose monitoring, including

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measurements at night, frequent contact with the doctor or nurse and a

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willingness of the patient to adopt a more relaxed view about the occasional

high blood glucose value. Importantly, these studies showed that it was

possible to eliminate hypoglycaemia without significant deterioration in

glycaemic control although HbA1C inevitably drifted upwards.

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The importance of structured training to ensure that patients have the skills to

use insulin appropriately in T1DM was recognised in a few European

countries as far back as the 1980s (101). However, it is only recently been

more widely adopted despite early publications reporting improved glycaemic

control and marked reductions in severe hypoglycaemia rates. More recent

PT
reports both from this group and others who have translated the approach to

RI
other countries, continue to report falls in severe hypoglycaemia rates of

around 50% following the attendance at training courses teaching self-

SC
management skills. One observational study involving over 9,000 individuals

also demonstrated that the exponential relationship between severe

U
hypoglycaemia and HbA1C first demonstrated in the DCCT could also be
AN
abolished in those who underwent structured training (102). Similar falls in
M

severe hypoglycaemia rates have also been reported following participation in

a UK adaptation of a similar skills based training course (Dose Adjustment for

D

Normal Eating (DAFNE) course (103), suggesting that structured training

TE

courses teaching people to use insulin safely leads to clinically relevant

reductions in the risk of severe hypoglycaemia (104). Following structured

EP

training, however, a significant minority of patients continue to experience or

C

develop reduced hypoglycaemia awareness, with an associated high risk of

AC

hypoglycaemia. Those affected often have psychological barriers and

programmes which target these issues have reported some success. The

most longstanding is the “Blood glucose awareness training” (BGAT), which

has been developed by Cox and colleagues at the University of Virginia (105).

BGAT, which teaches individuals to recognise and respond to symptoms of a

low blood glucose is taught to groups of individuals in an outpatient setting,

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although an online version is also available. Randomised controlled trials

have demonstrated reductions in time spent at low glucose levels and

improved increases in adrenaline. Observational studies have shown falls in

impaired hypoglycaemia awareness and rates of severe hypoglycaemia

(106)(105)(107).

PT
Within the DAFNE programme a course has also been developed with a

RI
psychological underpinning for individuals who experience impaired

awareness following DAFNE training. This course, developed primarily by

SC
clinical psychologists, is delivered by diabetes educators, initially in groups but

then 1:1. In a pilot study involving 23 T1DM adults, de Zoysa et al. have

U
demonstrated that a pilot psychoeducational programme improved both
AN
awareness of hypoglycaemia and reduced severe hypoglycaemia at 12
M

months (31). Importantly both approaches reduced hypoglycaemic problems

without a deterioration in glycaemic control. However, more studies are

D

needed to establish whether these results can be achieved in standard

TE

secondary care diabetes centres as opposed to centres with a specialist

interest in hypoglycaemia.
EP

Insulin regimens, technology and pancreatic transplantation

C

Differences between human and animal insulin in generating varying degrees

AC

of hypoglycaemia have been an area of controversy in the past. Current

scientific evidence does not support the notion of an increased frequency of

severe hypoglycaemia, or impaired hypoglycaemia awareness, with human

insulin preparations (108).

Choice of insulin therapy may also dictate therapeutic benefits in treatment of

recurrent severe hypoglycaemia and impaired hypoglycaemia awareness.

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Basal insulin analogues are potentially effective in reducing nocturnal

hypoglycaemia when compared to Neutral Protamine Hagedron (NPH) insulin

in T1DM (109). Furthermore, in those with T1DM complicated by recurrent

severe hypoglycaemia, recent trial data suggests that the use of insulin

analogues (detemir and aspart) can result in a clinically significant reduction in

PT
severe hypoglycaemia rates compared with human insulin (110). CSII has

RI
previously been shown to improve hypoglycaemia symptom awareness in

those with impaired hypoglycaemia awareness (111). A recent meta-analysis

SC
suggests, however, that CSII confers no additional benefit versus multiple

daily injections (MDI) in reducing the frequency of severe hypoglycaemia

U
(112). An earlier meta-analysis by Pickup et al., comparing CSII with MDI,
AN
only examined studies in those prone to multiple episodes of severe
M

hypoglycaemia per year (>10 episodes per 100 patient years on MDI) (113).

Pickup et al., reported that the rate of severe hypoglycaemia in T1DM was
D

significantly reduced during CSII compared with MDI, and that those with the
TE

longest duration of disease and most severe hypoglycaemia benefitted most.

Furthermore, the HypoCOMPaSS trial has recently reported that

EP

hypoglycaemia awareness can be improved in those with long-standing

C

T1DM, and severe hypoglycaemia reduced equally using conventional MDI

AC

and SMBG compared with CSII and continuous glucose monitoring (CGM),

although patient satisfaction was higher with CSII (32). The factors common

to all treatment groups were a brief education followed by intensive weekly

support from a healthcare professional.

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Intense research is currently focussing on the artificial pancreas which

employs wireless technology communication between a CGM device and an

insulin pump. Real time data on interstitial glucose levels are communicated

to the insulin pump, which then delivers an appropriate dose of insulin.

Results using the closed-loop system have recently been reported from two

PT
multi-centre, crossover, randomised controlled trials showing improved HbA1C

RI
levels and less time spent at hypoglycaemic levels, although Thabit et al. did

report three severe hypoglycaemic episodes during the closed-loop phase

SC
(114). Closed-loop technology is on the verge of moving from the research

arena to a clinical tool, and it is likely that this technology will become clinically

U
available in the next 5 to 10 years. In some individuals with severe recurrent
AN
hypoglycaemia and impaired hypoglycaemia awareness, referral for either
M

islet cell or whole pancreatic transplantation may restore hypoglycaemia

awareness (115).
D

Potential therapeutic targets

TE

A number of potential pharmacological agents under development for the

EP

treatment of impaired hypoglycaemia awareness and reducing recurrent

hypoglycaemia are summarised in Table 3. Whilst these potential therapies

C

have shown promising results in animal studies and small scale Phase 2
AC

human studies, no large scale clinical trials appear to have been undertaken

(116)(117)(118)(119) (120).

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A Care pathway for individuals

Figure 4 shows a care pathway which reflects our own clinical approach in a

clinic we run for individuals with hypoglycaemia problems, many of whom

PT
have reduced hypoglycaemia awareness. Probably the most important

question is to ask an individual, is at what blood glucose level they experience

RI
hypoglycaemic symptoms. A blood glucose level consistently below 3 mmol/L

SC
indicates reduced hypoglycaemia awareness and increased risk of

hypoglycaemia. This information needs to be supplemented by a detailed

U
history of the course and frequency of episodes of hypoglycaemia, particularly
AN
those that are severe, together with a joint examination of meter downloads of

glucose measurements. A joint discussion between patient, diabetes

M

specialist nurse and physician allows the clinicians to establish the

D

psychological and emotional reaction to low blood glucose values. Ideally the
TE

consultation should also include an important family member or partner who

may corroborate or add to the patient’s account, particularly as they are

EP

frequently the first person to note the onset of hypoglycaemia. They may also

contradict the clinical account and it is often helpful to witness the interchange
C

between partners and family members. CGM monitoring often provides

AC

additional useful information, although probably the most important next step

is a series of consultations between a diabetes nurse educator/dietician with

wide experience of insulin therapy and hypoglycaemia problems. This should

be followed by specific skills training, supplemented by the use of

technologies such as analogue insulins, CSII/CGM and on occasions insulin

25
 ACCEPTED MANUSCRIPT
suspend pumps. Our experience is that new technologies are not successful

unless those affected are willing to use them and acquire the skills to self

manage their diabetes, and that the health care professionals have the

experience to use the technology appropriately.

Those who continue to experience problems may benefit from interventions

PT
such as BGAT or DAFNE-HART. There are a few individuals (thankfully rare)

RI
who fail to improve after those approaches and in these cases, when

available, islet transplantation can be transformational. A recent meta-

SC
analysis recently endorsed a similar clinical approach pointing out that the

steps in this pathway were largely supported by reasonably high quality

evidence (121).
U
AN
Conclusion
M

The key pathophysiological defects, which explain the vulnerability of

D

individuals with insulin treated diabetes to hypoglycaemia, were described in

TE

human studies in the 1980s and 90s. Yet despite nearly 20 years of

extensive subsequent research involving both clinical and animal studies, no

EP

specific therapeutic interventions have emerged to prevent or treat

hypoglycaemia.
C
AC

Improving technology can now deliver insulin more precisely and flexibly and

alert individuals to falling glucose levels before they develop severe cognitive

impairment. However, for many the cost of such technology is prohibitive.

Although these and other developments, including the artificial pancreas and

islet transplantation, have moved or are moving from the research to the

26
 ACCEPTED MANUSCRIPT
clinical arena, their use will remain beyond the means of most individuals or

health care systems for many years.

In the meantime the principles of preventing and managing problematic

hypoglycaemia will depend upon training patients to use insulin safely and to

PT
take the appropriate action when their blood glucose levels are low. These

RI
approaches require a good understanding of the pathophysiology, the

limitations of current insulin delivery systems and the psychological barriers

SC
that prevent some patients from treating themselves appropriately.

Implementing these principles is not expensive and should be available

U
wherever insulin therapy is used to achieve tight glycaemic control.
AN
Practice points
M
D

• Hypoglycaemia problems are common in the management of insulin

TE

treated diabetes and clinicians responsible for managing individuals

with diabetes need to have a good grasp of the pathophysiology and

EP

systematic clinical approaches to assist those affected.

• Recurrent hypoglycaemia and impaired hypoglycaemia awareness

C

need to be anticipated recognised and addressed.

AC

• Structured education programmes, insulin analogues and CSII all have

a role in management of impaired hypoglycaemia awareness and

should be provided if patients are to be encouraged to achieve HbA1c

targets <7.5% (<58.5 mmol/mol).

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 ACCEPTED MANUSCRIPT
• Scrupulous avoidance of hypoglycaemia and empowering the patient

to achieve individualised glycaemic targets is key.

PT
Research agenda

RI
• Future human research is needed to elucidate mechanisms leading to

SC
counter-regulatory failure following recurrent hypoglycaemia.

U
Further experimental work exploring neuronal pathways involved in
AN
hypoglycaemia homeostasis is warranted to understand if specific

treatments can be developed for the management of impaired

M

hypoglycaemia awareness.

• Mechanisms whereby hypoglycaemia can precipitate fatal cardiac

D

arrhythmias need to be identified as those at risk could be protected.

TE

• Inflammatory pathways activated following hypoglycaemia that

EP

potentially increase CV risk need to be identified as they maybe

amenable to therapeutic targeting.

C
AC

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Table 1: Frequency of severe hypoglycaemia in diabetes, a summary of

observational studies.

Study Number Age Follow Frequency of Proportion

of (years) up hypoglycaemia affected

patients median (months) (episodes/per (%)

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(range) person/year)

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or mean

± SD

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MacLeod, 600 41 (14- 12 1.6 29

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1993 (5) 79) AN
(Scotland)

ter Braak 2000 195 41±14 12 1.5 41

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(6)

(Denmark)
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Pedersen- 1076 40 (18- 12 1.3 37

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Bjergaard 81)
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2004 (7)

(Denmark)
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UK 100 <5y 9-12 1.1 22

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Hypoglycaemia (46<5 41±13

Study Group years; >15y: 3.2 46

2007 (8) 54>15 53±10

(United years)

Kingdom)

Kristensen 3861 48±15 12 1.2 31

2012 (9)

(Denmark)
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Table 2: Symptoms of hypoglycaemia.

Autonomic symptoms Neuroglycopenic symptoms

Tremor Headache

Anxiety Blurred vision

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Palpitations Confusion

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Sweating Dizziness

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Tingling Irritability

Hunger Incoordination

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Trembling Speech disturbance
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Compound Mechanistic No of subjects Pros Cons

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studied in

human trials

(n)

Caffeine Decreased 34 T1D (111) Reduced Increased

cerebral blood 19 T1D (112) nocturnal symptomatic

flow hypoglycaemia hypoglycaemia

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assessed with

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Increased continuous

adrenaline glucose

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monitoring

(CGM)

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Selective Increased 18 T1D (113) Augmentation of Undesirable
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serotonin catechoalamines endogenous psychotropic

reuptake Gluconeogeneis counter- effects

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inhibitors regulation
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(SSRI)

Diazoxide Hypothalamic 12 T1D (114) Augmentation of Small number of

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ATP sensitive endogenous study subjects

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potassium counter-
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channel activator regulation

Gamma- Enhanced 9 healthy Increased No effect on

Aminobutyric neuro-endocrine volunteer (115) autonomic counter-

Acid (GABA) response to symptoms regulation to

hypoglycaemia hypoglycaemia
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Table 3: Potential future pharmacological agents for the treatment of impaired

hypoglycaemia awareness.

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Figure 1: Counter-regulatory response thresholds and accompanying

symptoms in response to hypoglycaemia in non-diabetic individuals.

Figure 2: Antecedent hypoglycaemia results in a diminished autonomic

response to hypoglycaemia with an attenuation of resultant autonomic

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warning symptoms. A maladaptive response also takes place in the brain,

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which promotes increased glucose extraction in a bid to ostensibly preserve

brain function but altered glucose sensing in the ventromedial hypothalamus

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(VMH) mediated by elevated levels of Gamma-Aminobutyric Acid (GABA)

maintains cerebral metabolism consequently resulting in diminished systemic

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counter-regulatory responses to hypoglycaemia. Figure created in the “Mind
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the Graph platform” www.mindthegraph.com.
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Figure 3: Inpatient management of hypoglycaemia. In addition to the listed

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measures, an insulin injection should not to be omitted if due but the insulin
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regimen may need reviewing. Increased blood glucose monitoring and

hypoglycaemia education are key.

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Figure 4: A care pathway for individuals with reduced awareness of

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hypoglycaemia.
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Glucose mmol/L

4.5 Inhibition of endogenous insulin

3.8 Production of glucagon and adrenaline

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3.2 Autonomic symptoms
3.0 Cognitive dysfunction

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2.8 Neuroglycopenic symptoms

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Recurrent hypoglycaemia

• Increased GLUT 1 activity

• Altered VMH sensing of

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glucose
• Increased GABA levels in

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VMH

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Diminished autonomic
Reduced response to
sweating Absence of hypoglycaemia

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palpitations
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Part of glucagon
Reduced Absence of
production under
production of tremor
autonomic
catecholamines
control reduced
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Conscious and orientated Conscious but not orientated Adults with seizures and/or

unconsciousness

1. 15-20 g of quick acting 1. If the patient is able to swallow 1. Urgent medical assessment using the

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carbohydrate (19-20 ml of give either 1-2 tubes of airway, breathing, and circulation
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original Lucozade , 150-200 ml GlucoGel or 1 mg of IM approach. Stop any insulin infusion.

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of pure orange juice). glucagon. 2. If intravenous access (IV) is present

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2. Repeat capillary blood glucose 2. Repeat capillary blood glucose use 75-100 ml of 20% or 150-200 ml of

10 minutes later. If blood glucose 10 minutes later. If blood glucose 10% glucose over 15 minutes. Repeat

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is still below 4.0 mmol/L repeat is still below 4.0 mmol/L repeat capillary blood glucose measurement

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step 1 up to 3 times. step 1 up to 3 times (only give IM after 10 minutes and if blood glucose is

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3. If capillary blood glucose is glucagon once). still < 4.0 mmol/L, repeat treatment.

below 4.0 mmol/L after 30-45 3. If capillary blood glucose is 3. Glucagon 1mg IM in the absence of

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minutes or 3 cycles of treatment below 4.0 mmol/L after 30-45 immediate IV access (less efficacious

consider: a) 150-200 ml of 10%

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glucose over 15 minutes b) 1 mg 150-200 ml of 10% glucose over and in patients suffering chronic liver

of intra-muscular (IM) glucagon. 15 minutes. disease). If prolonged treatment is

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4. Once blood sugar is > 4.0 4. Once blood sugar is > 4.0 needed, IV glucose is better.
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mmol/L give a long acting mmol/L and the patient has 4. Once blood sugar is > 4.0 mmol/L and

carbohydrate. recovered give a long acting the patient has recovered give a long

carbohydrate. acting carbohydrate.

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Recurrent hypoglycaemia, key question: does the patient have symptoms

of hypoglycaemia and if yes, at what blood glucose value?

Step 1: Review of insulin regimen, precipitating factors, e.g. diet, exercise

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and alcohol. Review by an experienced diabetes nurse and dietician.

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Step 2: Structured diabetes education in self- management and insulin

analogues.

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Step 3: Training and use of CSII and CGM in some individuals
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Step 4: Address and overcome psychological barriers in those with impaired

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hypoglycaemia awareness.
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Step 5: Islet cell transplantation and potentially closed-loop technology in the

future for appropriate patients.