Drfl
ORIGINAL ARTICLES
Unawareness of Hypoglycaernia in Insulin-treated Diabetic Patients: Prevalence and Relationship to Autonomic Neuropathy D.A. Hepburn, A.W. Patrick, D.W. Eadington, D.J Ewing“, B.M. Frier Diabetic Department and “Univenity Department of Medicine, Royal Infirmary, Edinburgh, Scotldnd
Three-hundred and two insulin-treated diabetic patients were questioned about hypoglycaemia using a structured questionnaire interview. Two-hundred and twenty-six patients (75 YO) had normal symptomatic awareness, 48 (16 Yo) had partial awareness, 21 (7 %) had absent awareness of hypoglycaemia, and 7 (2 %) denied ever experiencing hypoglycaemia. Patients with complete loss of awareness of hypoglycaemia had diabetes of longer duration; none had a HbA, concentration within the non-diabetic range. Loss of awareness of hypoglycaemia was associated with an increased incidence of severe hypoglycaemia, 19 (91 %) of the patients with absent awareness, and 33 (69 %) with partial awareness of hypoglycaemia experiencing severe hypoglycaemia over 1 year compared with only 41 (18 %) of patients with normal awareness of hypoglycaemia ( p < 0.001). Cardiovascular autonomic function tests were performed in 226 (75 % of the whole group). Of the patients who had diabetes for more than 15 years, 54 % ( n = 39) with normal awareness of hypoglycaemia, compared with 59 % ( n = 10) with absent awareness of hypoglycaemia, had evidence of cardiovascular autonomic impairment (NS). Seven (41 %) of the 17 patients with absent awareness of hypoglycaemia and diabetes of > 15 years duration had no evidence of autonomic dysfunction. Loss of hypoglycaemia awareness i s a common problem in patients with insulin-treated diabetes of long duration, i s associated with an increased incidence of severe hypoglycaemia, but i s not invariably associated with abnormal cardiovascular autonomic function tests. KEY WORDS
Hypoglycaemia Insulin-treated diabetes mellitus Insulin Hypoglycaemia unawareness
Introduction Hypoglycaemia i s a common and potentially dangerous side-effect of treatment with insulin. Two types of symptoms can be distinguished when acute hypoglycaemia is induced: the autonomic symptoms which include sweating, tremor, and palpitations, and result from stimulation of the sympatho-adrenal system; and the neuroglycopenic symptoms, such as confusion, drowsiness, and inability to concentrate, which are caused by the direct effect of glycopenia on cerebral function. The perception of autonomic symptoms alerts the patient to the early development of a low blood glucose and so initiates self-treatment. Neuroglycopenic symptoms may be less reliable for early warning of hypoglycaemia because of concomitant interference with cognitive function. Loss or blunting of the autonomic symptoms of hypoglycaemia (‘hypoglycaemia unawareness‘) occurs in many insulin-treated diabetic patients.’P3 Although often Correspondence to: Dr D . A . Hepburn, Diabetic Department, Royal Infirmary, Edinburgh EH3 9YW, Scotland.
0742-3071/90/080711-07$05.00
0 1990 by John Wiley & Sons,
Ltd.
Autonomic neuropathy
attributed to autonomic n e ~ r o p a t h y , hypoglycaemia ~ unawareness can occur in patients with no discernible evidence of autonomic dysfunction, and the cause is unclear. Improvement of blood glucose control by intensification of insulin regimens may also diminish hypoglycaemia warning symptom^.^ The actual prevalence of hypoglycaemia unawareness and its effect on the frequency and severity of hypoglycaemia are unknown. The aim of the present survey was to determine the prevalence, severity, and morbidity of hypoglycaemia unawareness in a group of randomly selected, insulintreated diabetic patients, and to establish its relationship to abnormal autonomic function.
Patients and Methods Patients Diabetic patients who had been treated with insulin for more than 1 year were considered for inclusion in this study. At each daily diabetic clinic at Edinburgh Royal Infirmary during a 6-month period (October 1987-March Accepted 9 May 1990 DIABETIC MEDICINE, 1990; 7: 71 1-71 7
71 1
DcTl
ORIGINAL ARTICLES 1988) four insulin-treated diabetic patients were selected using random number tables. All 302 patients selected in this way agreed to participate. The characteristics of the total group of patients are detailed in Table 1 . Thirtyfour patients (11 %) had Type 2 diabetes and had been converted to treatment with insulin because of failure of oral hypoglycaemic therapy. To ensure that this randomly selected survey population was representative of the whole clinic population, the clinical characteristics of the 302 patients were compared with 572 consecutive (and different) insulin-treated patients attending the diabetic clinic over a separate 2-month period (Table 1).
Structured Questionnaire The patients were interviewed using a structured questionnaire about socio-demographic details, personal history of diabetes and its management, current daily insulin dose, and number of daily injections. Each patient was asked about hypoglycaemic episodes during the preceding year, how frequently these had occurred, which symptoms were usually experienced and whether they were aware of the onset of symptoms of hypoglycaemia. The patients were not informed about a specific interest in hypoglycaemia unawareness. The information which was collected about the severity and frequency of hypoglycaemic episodes during the preceding year was verified, where possible, from hospital records and patients’ home monitoring diaries. Following the interview venous blood was taken for measurement of total glycosylated haemoglobin (HbA,) which was estimated by gel-electrophoresis.“
Definition of H ypogl ycaemia In a retrospective survey of this nature, strict adherence to the use of Whipple’s triad to define hypoglycaemia was not considered practical. A hypoglycaemic event was defined as an episode which was accompanied by
typical common symptoms of hypoglycaemia (sweating, tremor, palpitations, blurring of vision, confusion, inability to concentrate, and drowsiness), and which was corrected by oral carbohydrate, parenteral glucose or glucagon therapy, irrespective of whether biochemical hypoglycaemia (blood glucose < 2.2 mmol I-’) had been demonstrated. Episodes of loss of consciousness or confusion which had been corrected either with oral or parenteral glucose, or with glucagon, were also classified as hypoglycaemia. ‘Severe hypoglycaemia’ was defined as an episode of hypoglycaemia requiring the external assistance of another person for treatment, either at home or in hospital. All other episodes were designated as being ‘mi Id’.
Classification of Awareness of H ypoglycaemia Patients were categorized according to their state of awareness of the onset of hypoglycaemia during the preceding year. Those patients who were always aware of the onset of their hypoglycaemic episodes were classified as having ’normal awareness‘; those who were aware of some episodes of hypoglycaemia but not others were classified as having ‘partial awareness‘. Patients who were unable to recognize any episodes of hypoglycaemia were classified as having ‘absent awareness‘. To validate the questionnaire the accuracy of allocation of patients on historical grounds to each of the groups was assessed by studying prospectively a small number of patients from each group with acute insulin-induced hypoglycaemia, the results of which will be reported in detail elsewhere. Nine patients who had reported absent symptomatic awareness of hypoglycaemia, eight patients with normal awareness and six patients with autonomic neuropathy (three with normal awareness and three with absent awareness) were studied, within 3 months of the survey, and symptom scores were measured during acute hypoglycaemia induced with an intravenous infusion of
Table 1. Clinical characteristics of the randomly selected study patienb, the clinic patients, and the subgroup of the study patients w h o had autonomic function tests Consecutive patients
n Age (years) Sex ratio (maleifemale) Body mass index (kg m-*) Duration of diabetes (years) Insulin therapy (years) Insulin dose (U kg-’ day-’) HbA, (%)
Randomly selected patients
Study patients having au tonotn ic function tests
5 72 302 226 41 t 17 (16-82) 44 i- 16 (14-7’3) 45 t 16 (14-79) 28212’3 0 1451157 109111 7 25 t 3 (17-38) 25 -t 3 (18-38) 25 3 (18-38) 16 1 1 (1-47) 16 t 1 1 (1-62) 17 1 1 (1-62) 15 t 1 1 (1-47) 15 t 1 1 (1-62) 16 1 1 (1-62) 0.8 t 0.3 (0.2-2.5) 0.8 t 0.3 (0.2-2.5) 0.8 -t 0.2 (0.2-2.4) 10.8 t 1.6 (6.0-16.2) 10.8 1.8 (6.0-16.4) 10.8 i- 1.8 (6.0-16.4)
*
* * *
Mean ? SD (range). All patients were insulin-treated. Normal range for HbA, 4.5-8.0 %.
71 2
D.A. HEPBURN, ET A l
Dm soluble insulin (2.5 m U kg-’ min-’). All of the eight patients with ’normal awareness‘ reported the development of hypoglycaemic symptoms, while eight of the nine patients with ‘absent awareness‘ failed to develop any symptoms of hypoglycaemia, with only one individual being able to identify some symptoms which indicated its onset.’ The presence or absence of hypoglycaemic symptoms in the patients with autonomic neuropathy also confirmed accurate allocation to the correct groups (data not shown). These subsequent hypoglycaemic studies of subgroups of patients confirmed that the questionnaire did accurately differentiate the state of hypoglycaemia awareness in individual patients at the time of the original survey.
Autonomic function Tests Two-hundred and twenty-nine of the diabetic patients agreed to have five standard cardiovascular autonomic function tests performed, which have been described p r e v i o ~ s l y . The ~ , ~ tests were: the heart rate responses to the Valsalva manoeuvre, standing up and deep breathing, and the blood pressure responses to standing up and sustained handgrip. The Valsalva manoeuvre was omitted in patients with proliferative retinopathy. Each test was scored: 0 for normal, 1 for borderline, and 2 for abnormal according to previously defined normal ranges,8 giving a total score of 0-10 for the five tests. Two hundred and twenty-six patients (75 % of the total survey sample) performed four or more tests (four tests: 54; five tests: 172). The other three patients performed fewer tests and their results are not included in the analysis. Where only four tests were performed, the total score of 0-8 was averaged up to 0-10. Patients with an autonomic score of 0-2 were designated as ‘normal‘, patients with a score of 3-5 were considered to have ‘definite’ and patients scoring 6-1 0 to have ’severe’ autonomic dysfunction.
Statis tica I Ana I ys is Statistical analysis was performed on the Minitab Data Analysis Software System using analysis of variance, paired and unpaired Student’s t-test, chi-square, and Wilcoxon rank sum tests as appropriate. The results are expressed as mean k SD (range).
Results Awareness of Hypoglycaemia Seven (2 %) of the patients denied ever having ~. experienced hypoglycaemia. The characteristics of the 295 patients who had experienced hypoglycaemia are shown in Table 2. Two hundred and twenty-six (75 %) of the 302 patients reported normal awareness of hypoglycaemia, 48 (16 %) had partial awareness and 21 (7 %) had absent awareness. Similar proportions of the 34 patients with HYPOCLYCAEMIA UNAWARENESS AND AUTONOMIC NEUKOPATHY
ORIGINAL ARTICLES Type 2 diabetes, who had been converted to treatment with insulin, reported partial or absent awareness of hypoglycaemia. One hundred and eighty-nine patients had been transferred from animal to human insulin in the preceding 24 months and 12 (6 %) attributed their alteration in awareness of hypoglycaemia to this transfer.’O The 21 patients with absent awareness of hypoglycdemia were older ( p < 0.051, had diabetes of greater duration (p < 0.001), and had been receiving insulin therapy for longer (p < 0.001) than the group with normal awareness. Only nine of the patients with partial awareness had diabetes of less than 10 years duration and none of the patients with absent awareness of hypoglycaemia had diabetes of less than 5 years duration. The mean daily insulin doses and HbA, concentrations were similar in the three groups. Most patients were using conventional regimens of twice daily soluble and intermediate-acting insulins. None of the patients with absent awareness, two patients (4 %) with partial awareness, and 11 patients (5 %) with normal awareness of hypoglycaemia had HbA, concentrations below 8.0 % (normal non-diabetic range: 4.5-8.0 %).
frequency and Severity of Hypoglycaemia No significant differences were apparent between the three groups of patients in the frequency of hypoglycaemic episodes during the preceding year (Table 3). Almost half the patients experienced at least one episode of hypoglycaemia per month (Table 3). One-third had required external assistance for one or more severe hypoglycaemic episodes in the past year of whom a significantly higher proportion had absent or partial awareness of hypoglycaemia (Table 4). Glucagon therapy was administered outside hospital on one or more occasions to 14 (29 %) patients with partial awareness and to eight (38 %) patients with absent awareness of hypoglycaemia. Only 14 (6 %) of the patients with normal awareness required this treatment ( p < 0.001). Half the hypoglycaemic episodes which required hospital treatment occurred in the 21 patients (7 % of total group) who had absent awareness of hypoglycaemia.
Autonomic Neuropathy and Awareness o f H ypogl ycaem ia Of the 226 patients tested, 85 (38 %) had abnormal autonomic function tests. Thirty-seven percent of those patients with normal awareness of hypoglycaemia had abnormal autonomic tests, while one-third (33 Yo) with absent awareness demonstrated no autonomic abnormalities on testing (Table 5). To allow a valid statistical examination of the association between loss of hypoglycaemia awareness and autonomic neuropathy, the total group was subdivided by duration of diabetes into those with a dwation of diabetes of less than 15 years and those of longer duration (greater than 1 5 years). There were similar percentages of diabetic patients with longer 71 3
DT17
ORIGINAL ARTICLES
Table 2. Clinical data of the patients who had experienced hypoglycaemia characterized by their reported state of hypoglycaemia awareness
n Age (years)" Duration of diabetes (years)h Insulin therapy (years)b Insulin dose (U kg-' day-') HbA, (%)
Normal awareness
Partial awareness
Absent awareness
226 17 (14-77) 15 t 1 1 (1-62) 14 +- 1 1 (1-62) 0.8 t 0.3 (0.2-2.4) 10.8 t 1.9 (6.1-16.4)
48 44 i 16 (1 8-74) 17 t 8 (3-40) 1 6 2 9 (2-40) 0.8 t 0.3 (0.2-1.6) 10.2 t 1.4 (6.0-1 3.8)
21 52 2 15 (21-79) 26 t 1 1 (3-43) 26 t 1 2 (1-43) 0.7 ? 0.3 (0.3-1.5) 10.9 ? 2.0 (8.2-16.0)
43
?
Mean t SD (range). a p < 0.05; p < 0.001, comparison is between the three groups using one-way ANOVA Normal range for HbA, 4.5-8.0 %.
Table 3. Numbers of diabetic patients who experienced hypoglycaemic episodes in the previous year, according to awareness of hypoglycaernia
n Hypoglycaernia rate (events yr-') N o hypoglycaemia last 12 months Frequency of hypoglycaemia < 1 per month 1 per month
Total group
Normal awareness
Partial awareness
Absent awareness
302 9.9(8.4-1 1.5) 44 (13)
226 9.6(8.1-11.5) 3 3 (15)
48 13.2(8.7-19.9) 5 (9)
21 8.4(4.6-15.4) 1 (5)
127 (43) 131 (44)
96 (42) 99 (43)
19 (41) 24 (52)
1 2 (57) 8 (38)
Median (range), or number (%).
Table 4. Number of diabetic patients who experienced one or more severe hypoglycaemic episodes in the previous year, according to awareness of hypoglycaemia Total group
n Hypoglycaemia requiring hospital treatment All severe hypoglycaemia
302
Normal Partial Absent awareness awareness awareness
226
20 (7) 94 (31)
8 (4) 41 (18)
48
21
3 (6) 33 (69)"
9 (43)" 19 (91)"
Number (%I. p < 0.001, comparison with the normal awareness group. All severe hypoglycaemia includes ho5pital treatment, intravenous glucose, intramu5cular glucagon and external assistance by a third party.
a
duration and evidence of abnormal autonomic function in the 'normal', 'partial' and 'absent' awareness groups (NS) (Table 5). Only four patients with absent awareness of hypoglycaemia had diabetes of less than 15 years duration, all of whom had definite autonomic abnormalities. More than half (54 %) of the subgroup of patients with normal awareness and longer duration of diabetes had demonstrable evidence of autonomic damage, while 41 % of the patients with absent awareness had no evidence of autonomic dysfunction.
71 4
Discussion Acute insulin-induced hypoglycaemia in humans activates the sympatho-adrenal system via autonomic centres in the hypothalamus and produces the typical autonomic symptoms of hypoglycaemia. The early perception of autonomic manifestations such as sweating, tremor, and blurred vision allows self-treatment with glucose which prevents progression to severe neuroglycopenia. Blunting or loss of the autonomic warning symptoms of hypoglyD.A. HEPBURN, ET A l .
DTT7
ORIGINAL ARTICLES Table 5. Numbers of patients with normal and abnormal autonomic function tests, according to their awareness of hypoglycaemia and duration ot diabetes n
Normal awareness Partial awareness Absent awareness Less than 15 years duration Normal awareness Partial awareness Absent awareness More than 15 years duration Normal awareness Partial awareness Absent awareness Number (96). For calculation of score
see
Normal (score 0-2)
Abnormal Definite (score 3-5)
Severe Total (score 6-1 0) (score 3-1 0)
169 34 21
107 (63) 25 (74) 7 (33)
34 4 6
28 5 8
62 (37) 9 (26) 14 (67)
97 16 4
74 (76) 14 (87) 0 (0)
12 2 2
11 0 2
23 (24) 2 (13) 4 (100)
72 18 17
33 (46) 1 1 (61) 7 (41)
22 2 4
17 5 6
39 (54) 7 (39) 10 (59)
text.
caemia occurs in some diabetic patients,’--’ and failure of the protective role of autonomic stimulation has been implicated previously as a cause of hypoglycaemia Unawareness.’ Hypoglycaemia unawareness in diabetic patients has therefore been attributed to co-existing autonomic neuropathy. Some diabetic patients with symptomatic autonomic neuropathy do describe a diminution of hypoglycaemia awareness, and in one small study six of nine diabetic patients with overt autonomic neuropathy had reduced subjective awareness of hypoglycaemia. Autonomic neuropathy diminishes the secretion of adrena I i ne d uri ng insu Ii n-induced hy pogIycaem ia, 4, and this has been alleged to reduce autonomic warning symptoms, and hence cause loss of awareness. Autonomic symptoms in response to hypoglycaemia were absent in tetraplegic subjects who have a pre-ganglionic sympathectomy,16,’ but were not significantly reduced in non-diabetic patients who had undergone either a bilateral adrenalectomy or a splanchnicectomy and in whom the autonomic nervous system was otherwise intact.20,2’ It is possible that in some diabetic patients with autonomic neuropathy the reduction in intensity of autonomic symptoms is associated primarily with impairment of autonomic neural activity rather than with a decreased rise in plasma adrenaline. In some diabetic patients who have described hypoglycaemia unawareness the secretion of adrenaline following hypoglycaemia has been shown to be of normal magnitude,2L and loss of awareness of hypoglycaemia may occur in diabetic patients who have no objective evidence of autonomic n e ~ r o p a t h y . Perception ~~ of hypoglycaemia can be reduced by non-selective P-adrenergic blocking 2 5 and a reduction in sensitivity of peripheral P-adrenergic receptors has been proposed as the mechanism causing loss of symptoms of h y p ~ g l y c a e m i a . ~ Thus, ~ , ~ ’ loss of hypoglycaemia awareness may be caused by mechanisms
’ ’
HYPOCLYCAEMIA UNAWARENESS A N D AUTONOMIC NEUROPATHL
other than peripheral autonomic dysfunction, and failure or delay in the activation of central autonomic centres during acute hypoglycaemia has been suggested as a further putative cause of attenuated autonomic activity.L0,2y In the present study, most patients with loss of awareness of hypoglycaemia had diabetes of long duration, which is consistent with previous observations.” In the subgroup of patients reporting loss of awareness, the incidence of autonomic neuropathy, ascertained by non-invasive cardiovascular reflex tests, was higher than in the total group. Those diabetic patients who had autonomic neuropathy also had diabetes of longer duration than those with no evidence of autonomic dysfunction. Patients who had a longer duration of diabetes had similar frequencies of autonomic neuropathy when subdivided into those with normal awareness and those with loss of awareness of hypoglycaemia, demonstrating that autonomic dysfunction and hypoglycaemia unawareness are not invariably related. However, all of the patients with diabetes for less than 15 years, who had total loss of hypoglycaemia awareness, had coexisting autonomic dysfunction and in these patients with diabetes of short duration autonomic neuropathy may be an important aetiological factor. In a retrospective crosssectional survey it is not possible to exclude autonomic dysfunction as the cause of hypoglycaemia unawareness in those patients in which both are present, but a significant number of the patients who had indisputable evidence of autonomic abnormalities retained normal awareness of hypoglycaemia. This is consistent with an observation made by Hilsted et a/. that many of his diabetic patients with autonomic neuropathy developed subjective hypoglycaemic symptoms during insulininduced h y p ~ g l y c a e m i a . ~The ~ precise relationship between diabetic autonomic neuropathy and loss of hypoglycaemia awareness remains undefined. 71 5
Drn
O R I G I N A L ARTICLES The induction of ‘tight’ blood glucose control using intensified insulin therapy reduces the subjective perception of hypoglycaemic symptoms and lowers the blood glucose threshold for the release of adrenaline in response to h y p ~ g l y c a e m i a . ~It, ~also ’ increases the frequency of hypoglycaemia two to three fold.jL In the present study none of the patients with absent awareness of hypoglycaemia had HbA, concentrations within the nondiabetic range, so excluding optimal blood glucose control as a possible factor responsible for diminished hypoglycaemia awareness. Two patients who had partial hypoglycaemia awareness had HbA, concentrations below 8.0 % and in these individuals it i s possible that optimal blood glucose control contributed to their blunted awareness of symptoms. However, a similar proportion of patients with normal awareness also had a HbA, concentration within the non-diabetic range, and as a single measurement represents a relatively short time interval, this provides very limited information about the quality of previous long-term blood glucose control. A previous study of severe hypoglycaemia causing coma in diabetic patients identified that one-quarter of these patients requiring emergency treatment had experienced few or no warning symptoms of hypoglycaemia.33Hypoglycaemia unawareness i s clearly associated with an increase in the severity of hypoglycaemia with its attendant morbidity. The prevalence of severe hypoglycaemia in the present survey was of similar magnitude to that reported in two French studies in which a similar definition of severe hypoglycaemia was used and in which 30 % of insulin-treated diabetic patients experienced one or more episodes of severe hypoglycaemia per year.34,35 Other studies which ~-~~~ reported a lower incidence of h y p o g l y ~ a e m i a ~had defined severity by the development of coma alone and omitted episodes where the patient was unable to initiate self-treatment. However, retrospective historical enquiry may underestimate the magnitude of the problem, because some patients experience difficulty in recalling the total number of episodes of severe hypoglycaemia, possibly as a result of ‘retrograde amnesia‘ associated with severe neuroglycopenia. The absence of warning symptoms of hypoglycaemia might be expected to increase the frequency of severe hypoglycaemia by promoting vulnerability to severe neuroglycopenia. The present study supports this premise and allows quantification of the risk of hypoglycaemia in affected patients. A considerable proportion of the patients with partial awareness of hypoglycaemia and the majority with absent awareness in the present study had experienced one or more episodes of severe hypoglycaemia in the preceding year.
Acknowledgements We thank R.J. Prescott, Department of Medical Statistics, University of Edinburgh, for statistical advice and N.R.
71 6
Colledge for assistance with collection of data. DAH was in receipt of a Novo Research Fellowship and DJE i s a Wellcome Trust Senior Lecturer.
References 1.
Joslin EP, Gray H, Root HF. Insulin in hospital and home.
l Metab Re5 1922; 2: 651-699. 2. 3. 4.
5.
6.
7.
8.
9.
10.
11. 12.
13.
14.
15.
16.
17.
18.
19.
Banting FG, Campbell WR, Fletcher AA. Further clinical experience with insulin. Br Med 1 1923; i: 8-12. Maddock SJ, Trimble HC. Prolonged insulin hypoglycemia without symptoms. IAMA 1928; 91 : 61 6-621. Cryer PE. The metabolic impact of autonomic neuropathy in insulin-dependent diabetes mellitus. Arch Intern Med 1986; 146: 2127-2129. Lager I, Attvall S, Blohme G, Smith U . Altered recognition of hypoglycaemic symptoms in type 1 diabetes during intensified control with continuous subcutaneous insulin infusion. Diabetic Med 1986; 3: 322-325. Reid A, Tibi L, Smith AF. Assessment of a simple method for measuring HbA,. Clin Chim Acta 1980; 108: 487-491. Hepburn DA, Patrick AW, Frier BM. Severe neuroglycopenia precedes autonomic activation during acute hypoglycemia in insulin-dependent diabetic patients with hypoglycemia unawareness (Abstract). Diabetes 1989; 38: (suppl 2): 76A. Ewing DJ, Recent advances in the non-invasive investigation of diabetic autonomic neuropathy. In: Bannister R, ed. Autonomic Failure. A Textbook of Clinical Disorders of the Autonomic Nervous System. 2nd edn. Oxford: Oxford Medical Publications, 1988: 667-689. Ewing DJ, Martyn CN, Young RJ, Clarke BF. The value of cardiovascular autonomic function tests: 10 years experience in diabetes. Diabetes Care 1985; 8: 491-498. Hepburn DA, Eadington DW, Patrick AW, Colledge NR, Frier BM. Symptomatic awareness of hypoglycaemia: does it change on transfer from animal to human insulin? Diabetic Med 1989; 6: 586-590. Baldimos MC, Root HF. Hypoglycemic insulin reactions without warning symptoms. /AMA 1959; 171 : 261-266. Sussman KE, Crout JR, Marble A. Failure of warning in insulin-induced hypoglycemic reactions. Diabetes 1963; 12: 38-45. Hoeldtke RD, Guenther B, Shuman CR, Owen OE. Reduced epinephrine secretion and hypoglycemia unawareness in diabetic autonomic neuropathy. Ann lntern Med 1982; 96: 459-462. Polinsky RJ, Kopin IJ, Ebert MH, Weise V. The adrenal medullary response to hypoglycemia in patients with orthostatic hypotension. / Clin Endocrinol Metab 1980; 51: 1401-1406. Hilsted J, Madsbad S, Krarup T, et a/. Hormonal, metabolic and cardiovascular responses to hypoglycemia in diabetic autonomic neuropathy. Diabetes 1981 ; 30: 626-63 3. Frier BM, Corrall RJM, Ratcliffe JG, Ashby JP, McClemont EJW. Autonomic neural control mechanisms of substrate and hormonal responses to acute hypoglycaemia in man. C/in Endocrinol 1981 ; 14: 425-433. Corrall RIM, Frier BM, McClemont EJW,Taylor SJ, Christie NE. Recovery mechanisms from acute hypoglycaemia in complete tetraplegia. Paraplegia 1979; 17: 31 4-31 8. Palmer JP, Henry DP, Benson JW, Johnson DG, Ensinck JW. Glucagon responses to hypoglycemia in sympathectomised man. ] Clin lnvest 1976; 57: 522-525. Mathias CJ, Frankel JL, Turner RC, Christensen NJ. Physiological responses to insulin hypoglycaemia in spinal D.A. HEPBURN, ET A l .
Dr17 20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
man. Paraplegia 1979; 17: 319-326. Ginsberg J, Paton A. Effects of insulin after adrenalectomy. lancet 1956; i: 491-494. French EB, Kilpatrick R. The role of adrenaline in the hypoglycaemic reaction in man. Clin Sci 1955; 14: 639-651. Polonsky K, Bergenstal R, Pons G, Schneider M, Jaspan 1, Rubenstein A. Relation of counterregulatory responses to hypoglycemia in type 1 diabetics. N E n g / / M e d 1982; 307: 1106-1 1 12. Heller SR, Herbert M, MacDonald I, Tattersall RB. Influence of sympathetic nervous system on hypoglycaemic warning symptoms. Lancet 1987; ii: 359-363. Smith U, Blohmi. G, Lager I, Lonnroth P. Can insulintreated diabetics be given beta-adrenergic-blocking drugs? Br M e d / 1980; 281 : 1 143-1 144. Popp DA, Tse TF, Shah SD, Clutter WE, Cryer PE. Oral propranolol and metoprolol both impair glucose recovery from insulin-induced hypoglycemia in insulin-dependent diabetes mellitus. Diabetes Care 1984; 7: 243-247. Berlin I, Grimaldi A, Payan C, et a / . Hypoglycemic symptoms and decreased P-adrenergic sensitivity in insulin-dependent diabetic patients. Diabetes Care 1987; 10: 742-747. Berlin I, Grimaldi A, Londault F, et a/. Lack of hypoglycemic symptoms and decreased P-adrenergic sensitivity in insulin-dependent diabetic patients. Clin Endocrinol Metab 1988; 66: 273-278. Frier BM. Hypoglycaemia and diabetes. Diabetic M e d 1986; 3: 513-525. Frier BM, Fisher BM, Gray CE, Beastall G H . Counterregulatory hormonal responses to hypoglycaemia in type 1 (insulin-dependent) diabetes: evidence for diminished hypothalamic-pituitary hormonal secretion. Diabetologia
HYPOCLYCAEMIA UNAWARENESS A N D A U T O N O M I C NEUROPATHY
ORIGINAL ARTICLES 30.
31.
32.
33.
34.
35.
36.
37.
38.
1988; 31: 421-429. Hilsted J. Pathophysiology in diabetic autonomic neuropathy: cardiovascular, hormonal, and metabolic studies. Diabetes Care 1982; 31 : 730-737. Amiel SA, Sherwin RS, Simonson DC, Tamborlane WV. Effect of intensive insulin therapy on glycemic threshold for counterregulatory hormone release. Diabetes 1988; 37: 901-907. The DCCT Research Group. Diabetes control and complications trial (DCCT): results of feasibility study. Diabetes Care 1987; 10: 1-19. Collier A, Steedman DJ, Patrick AW, et a/. Comparison of intravenous glucagon and dextrose in treatment of severe hypoglycemia in an accident and emergency department. Diabetes Care 1987; 10: 712-71 5. Goldgewicht C, Slama G, Papoz L, Tchobrousky G . Hypoglycaemic reactions in 172 type 1 (insulindependent) diabetic patients. Diabetologia 1983; 24: 95-99. Basdevant A, Costaglida D, Lanoe JL, et a / . The risk of diabetic control: a comparison of hospital versus general practice supervision. Diabetologia 1982; 22: 309-31 4. Goldstein DE, England JD, Hess R, Rawlings SS, Walker B. A prospective study of symptomatic hypoglycemia in young diabetic patients. Diabetes Care 1981 ; 4 : 601-605. Potter J, Clarke P, Gale EAM, Dave SH, Tattersall RB. Insulin-induced hypoglycaemia in an accident and emergency department: the tip of an iceberg. Br M e d ) 1982; 285: 1180-1182. Muhlhauser I, Berger M, Sonnenberg G, e t a / . Incidence and management of severe hypoglycemia in 434 adults with insulin-dependent diabetes mellitus. Diabetes Care 1985; 8: 268-273.
71 7
ORIGINAL ARTICLES
Unawareness of Hypoglycaernia in Insulin-treated Diabetic Patients: Prevalence and Relationship to Autonomic Neuropathy D.A. Hepburn, A.W. Patrick, D.W. Eadington, D.J Ewing“, B.M. Frier Diabetic Department and “Univenity Department of Medicine, Royal Infirmary, Edinburgh, Scotldnd
Three-hundred and two insulin-treated diabetic patients were questioned about hypoglycaemia using a structured questionnaire interview. Two-hundred and twenty-six patients (75 YO) had normal symptomatic awareness, 48 (16 Yo) had partial awareness, 21 (7 %) had absent awareness of hypoglycaemia, and 7 (2 %) denied ever experiencing hypoglycaemia. Patients with complete loss of awareness of hypoglycaemia had diabetes of longer duration; none had a HbA, concentration within the non-diabetic range. Loss of awareness of hypoglycaemia was associated with an increased incidence of severe hypoglycaemia, 19 (91 %) of the patients with absent awareness, and 33 (69 %) with partial awareness of hypoglycaemia experiencing severe hypoglycaemia over 1 year compared with only 41 (18 %) of patients with normal awareness of hypoglycaemia ( p < 0.001). Cardiovascular autonomic function tests were performed in 226 (75 % of the whole group). Of the patients who had diabetes for more than 15 years, 54 % ( n = 39) with normal awareness of hypoglycaemia, compared with 59 % ( n = 10) with absent awareness of hypoglycaemia, had evidence of cardiovascular autonomic impairment (NS). Seven (41 %) of the 17 patients with absent awareness of hypoglycaemia and diabetes of > 15 years duration had no evidence of autonomic dysfunction. Loss of hypoglycaemia awareness i s a common problem in patients with insulin-treated diabetes of long duration, i s associated with an increased incidence of severe hypoglycaemia, but i s not invariably associated with abnormal cardiovascular autonomic function tests. KEY WORDS
Hypoglycaemia Insulin-treated diabetes mellitus Insulin Hypoglycaemia unawareness
Introduction Hypoglycaemia i s a common and potentially dangerous side-effect of treatment with insulin. Two types of symptoms can be distinguished when acute hypoglycaemia is induced: the autonomic symptoms which include sweating, tremor, and palpitations, and result from stimulation of the sympatho-adrenal system; and the neuroglycopenic symptoms, such as confusion, drowsiness, and inability to concentrate, which are caused by the direct effect of glycopenia on cerebral function. The perception of autonomic symptoms alerts the patient to the early development of a low blood glucose and so initiates self-treatment. Neuroglycopenic symptoms may be less reliable for early warning of hypoglycaemia because of concomitant interference with cognitive function. Loss or blunting of the autonomic symptoms of hypoglycaemia (‘hypoglycaemia unawareness‘) occurs in many insulin-treated diabetic patients.’P3 Although often Correspondence to: Dr D . A . Hepburn, Diabetic Department, Royal Infirmary, Edinburgh EH3 9YW, Scotland.
0742-3071/90/080711-07$05.00
0 1990 by John Wiley & Sons,
Ltd.
Autonomic neuropathy
attributed to autonomic n e ~ r o p a t h y , hypoglycaemia ~ unawareness can occur in patients with no discernible evidence of autonomic dysfunction, and the cause is unclear. Improvement of blood glucose control by intensification of insulin regimens may also diminish hypoglycaemia warning symptom^.^ The actual prevalence of hypoglycaemia unawareness and its effect on the frequency and severity of hypoglycaemia are unknown. The aim of the present survey was to determine the prevalence, severity, and morbidity of hypoglycaemia unawareness in a group of randomly selected, insulintreated diabetic patients, and to establish its relationship to abnormal autonomic function.
Patients and Methods Patients Diabetic patients who had been treated with insulin for more than 1 year were considered for inclusion in this study. At each daily diabetic clinic at Edinburgh Royal Infirmary during a 6-month period (October 1987-March Accepted 9 May 1990 DIABETIC MEDICINE, 1990; 7: 71 1-71 7
71 1
DcTl
ORIGINAL ARTICLES 1988) four insulin-treated diabetic patients were selected using random number tables. All 302 patients selected in this way agreed to participate. The characteristics of the total group of patients are detailed in Table 1 . Thirtyfour patients (11 %) had Type 2 diabetes and had been converted to treatment with insulin because of failure of oral hypoglycaemic therapy. To ensure that this randomly selected survey population was representative of the whole clinic population, the clinical characteristics of the 302 patients were compared with 572 consecutive (and different) insulin-treated patients attending the diabetic clinic over a separate 2-month period (Table 1).
Structured Questionnaire The patients were interviewed using a structured questionnaire about socio-demographic details, personal history of diabetes and its management, current daily insulin dose, and number of daily injections. Each patient was asked about hypoglycaemic episodes during the preceding year, how frequently these had occurred, which symptoms were usually experienced and whether they were aware of the onset of symptoms of hypoglycaemia. The patients were not informed about a specific interest in hypoglycaemia unawareness. The information which was collected about the severity and frequency of hypoglycaemic episodes during the preceding year was verified, where possible, from hospital records and patients’ home monitoring diaries. Following the interview venous blood was taken for measurement of total glycosylated haemoglobin (HbA,) which was estimated by gel-electrophoresis.“
Definition of H ypogl ycaemia In a retrospective survey of this nature, strict adherence to the use of Whipple’s triad to define hypoglycaemia was not considered practical. A hypoglycaemic event was defined as an episode which was accompanied by
typical common symptoms of hypoglycaemia (sweating, tremor, palpitations, blurring of vision, confusion, inability to concentrate, and drowsiness), and which was corrected by oral carbohydrate, parenteral glucose or glucagon therapy, irrespective of whether biochemical hypoglycaemia (blood glucose < 2.2 mmol I-’) had been demonstrated. Episodes of loss of consciousness or confusion which had been corrected either with oral or parenteral glucose, or with glucagon, were also classified as hypoglycaemia. ‘Severe hypoglycaemia’ was defined as an episode of hypoglycaemia requiring the external assistance of another person for treatment, either at home or in hospital. All other episodes were designated as being ‘mi Id’.
Classification of Awareness of H ypoglycaemia Patients were categorized according to their state of awareness of the onset of hypoglycaemia during the preceding year. Those patients who were always aware of the onset of their hypoglycaemic episodes were classified as having ’normal awareness‘; those who were aware of some episodes of hypoglycaemia but not others were classified as having ‘partial awareness‘. Patients who were unable to recognize any episodes of hypoglycaemia were classified as having ‘absent awareness‘. To validate the questionnaire the accuracy of allocation of patients on historical grounds to each of the groups was assessed by studying prospectively a small number of patients from each group with acute insulin-induced hypoglycaemia, the results of which will be reported in detail elsewhere. Nine patients who had reported absent symptomatic awareness of hypoglycaemia, eight patients with normal awareness and six patients with autonomic neuropathy (three with normal awareness and three with absent awareness) were studied, within 3 months of the survey, and symptom scores were measured during acute hypoglycaemia induced with an intravenous infusion of
Table 1. Clinical characteristics of the randomly selected study patienb, the clinic patients, and the subgroup of the study patients w h o had autonomic function tests Consecutive patients
n Age (years) Sex ratio (maleifemale) Body mass index (kg m-*) Duration of diabetes (years) Insulin therapy (years) Insulin dose (U kg-’ day-’) HbA, (%)
Randomly selected patients
Study patients having au tonotn ic function tests
5 72 302 226 41 t 17 (16-82) 44 i- 16 (14-7’3) 45 t 16 (14-79) 28212’3 0 1451157 109111 7 25 t 3 (17-38) 25 -t 3 (18-38) 25 3 (18-38) 16 1 1 (1-47) 16 t 1 1 (1-62) 17 1 1 (1-62) 15 t 1 1 (1-47) 15 t 1 1 (1-62) 16 1 1 (1-62) 0.8 t 0.3 (0.2-2.5) 0.8 t 0.3 (0.2-2.5) 0.8 -t 0.2 (0.2-2.4) 10.8 t 1.6 (6.0-16.2) 10.8 1.8 (6.0-16.4) 10.8 i- 1.8 (6.0-16.4)
*
* * *
Mean ? SD (range). All patients were insulin-treated. Normal range for HbA, 4.5-8.0 %.
71 2
D.A. HEPBURN, ET A l
Dm soluble insulin (2.5 m U kg-’ min-’). All of the eight patients with ’normal awareness‘ reported the development of hypoglycaemic symptoms, while eight of the nine patients with ‘absent awareness‘ failed to develop any symptoms of hypoglycaemia, with only one individual being able to identify some symptoms which indicated its onset.’ The presence or absence of hypoglycaemic symptoms in the patients with autonomic neuropathy also confirmed accurate allocation to the correct groups (data not shown). These subsequent hypoglycaemic studies of subgroups of patients confirmed that the questionnaire did accurately differentiate the state of hypoglycaemia awareness in individual patients at the time of the original survey.
Autonomic function Tests Two-hundred and twenty-nine of the diabetic patients agreed to have five standard cardiovascular autonomic function tests performed, which have been described p r e v i o ~ s l y . The ~ , ~ tests were: the heart rate responses to the Valsalva manoeuvre, standing up and deep breathing, and the blood pressure responses to standing up and sustained handgrip. The Valsalva manoeuvre was omitted in patients with proliferative retinopathy. Each test was scored: 0 for normal, 1 for borderline, and 2 for abnormal according to previously defined normal ranges,8 giving a total score of 0-10 for the five tests. Two hundred and twenty-six patients (75 % of the total survey sample) performed four or more tests (four tests: 54; five tests: 172). The other three patients performed fewer tests and their results are not included in the analysis. Where only four tests were performed, the total score of 0-8 was averaged up to 0-10. Patients with an autonomic score of 0-2 were designated as ‘normal‘, patients with a score of 3-5 were considered to have ‘definite’ and patients scoring 6-1 0 to have ’severe’ autonomic dysfunction.
Statis tica I Ana I ys is Statistical analysis was performed on the Minitab Data Analysis Software System using analysis of variance, paired and unpaired Student’s t-test, chi-square, and Wilcoxon rank sum tests as appropriate. The results are expressed as mean k SD (range).
Results Awareness of Hypoglycaemia Seven (2 %) of the patients denied ever having ~. experienced hypoglycaemia. The characteristics of the 295 patients who had experienced hypoglycaemia are shown in Table 2. Two hundred and twenty-six (75 %) of the 302 patients reported normal awareness of hypoglycaemia, 48 (16 %) had partial awareness and 21 (7 %) had absent awareness. Similar proportions of the 34 patients with HYPOCLYCAEMIA UNAWARENESS AND AUTONOMIC NEUKOPATHY
ORIGINAL ARTICLES Type 2 diabetes, who had been converted to treatment with insulin, reported partial or absent awareness of hypoglycaemia. One hundred and eighty-nine patients had been transferred from animal to human insulin in the preceding 24 months and 12 (6 %) attributed their alteration in awareness of hypoglycaemia to this transfer.’O The 21 patients with absent awareness of hypoglycdemia were older ( p < 0.051, had diabetes of greater duration (p < 0.001), and had been receiving insulin therapy for longer (p < 0.001) than the group with normal awareness. Only nine of the patients with partial awareness had diabetes of less than 10 years duration and none of the patients with absent awareness of hypoglycaemia had diabetes of less than 5 years duration. The mean daily insulin doses and HbA, concentrations were similar in the three groups. Most patients were using conventional regimens of twice daily soluble and intermediate-acting insulins. None of the patients with absent awareness, two patients (4 %) with partial awareness, and 11 patients (5 %) with normal awareness of hypoglycaemia had HbA, concentrations below 8.0 % (normal non-diabetic range: 4.5-8.0 %).
frequency and Severity of Hypoglycaemia No significant differences were apparent between the three groups of patients in the frequency of hypoglycaemic episodes during the preceding year (Table 3). Almost half the patients experienced at least one episode of hypoglycaemia per month (Table 3). One-third had required external assistance for one or more severe hypoglycaemic episodes in the past year of whom a significantly higher proportion had absent or partial awareness of hypoglycaemia (Table 4). Glucagon therapy was administered outside hospital on one or more occasions to 14 (29 %) patients with partial awareness and to eight (38 %) patients with absent awareness of hypoglycaemia. Only 14 (6 %) of the patients with normal awareness required this treatment ( p < 0.001). Half the hypoglycaemic episodes which required hospital treatment occurred in the 21 patients (7 % of total group) who had absent awareness of hypoglycaemia.
Autonomic Neuropathy and Awareness o f H ypogl ycaem ia Of the 226 patients tested, 85 (38 %) had abnormal autonomic function tests. Thirty-seven percent of those patients with normal awareness of hypoglycaemia had abnormal autonomic tests, while one-third (33 Yo) with absent awareness demonstrated no autonomic abnormalities on testing (Table 5). To allow a valid statistical examination of the association between loss of hypoglycaemia awareness and autonomic neuropathy, the total group was subdivided by duration of diabetes into those with a dwation of diabetes of less than 15 years and those of longer duration (greater than 1 5 years). There were similar percentages of diabetic patients with longer 71 3
DT17
ORIGINAL ARTICLES
Table 2. Clinical data of the patients who had experienced hypoglycaemia characterized by their reported state of hypoglycaemia awareness
n Age (years)" Duration of diabetes (years)h Insulin therapy (years)b Insulin dose (U kg-' day-') HbA, (%)
Normal awareness
Partial awareness
Absent awareness
226 17 (14-77) 15 t 1 1 (1-62) 14 +- 1 1 (1-62) 0.8 t 0.3 (0.2-2.4) 10.8 t 1.9 (6.1-16.4)
48 44 i 16 (1 8-74) 17 t 8 (3-40) 1 6 2 9 (2-40) 0.8 t 0.3 (0.2-1.6) 10.2 t 1.4 (6.0-1 3.8)
21 52 2 15 (21-79) 26 t 1 1 (3-43) 26 t 1 2 (1-43) 0.7 ? 0.3 (0.3-1.5) 10.9 ? 2.0 (8.2-16.0)
43
?
Mean t SD (range). a p < 0.05; p < 0.001, comparison is between the three groups using one-way ANOVA Normal range for HbA, 4.5-8.0 %.
Table 3. Numbers of diabetic patients who experienced hypoglycaemic episodes in the previous year, according to awareness of hypoglycaernia
n Hypoglycaernia rate (events yr-') N o hypoglycaemia last 12 months Frequency of hypoglycaemia < 1 per month 1 per month
Total group
Normal awareness
Partial awareness
Absent awareness
302 9.9(8.4-1 1.5) 44 (13)
226 9.6(8.1-11.5) 3 3 (15)
48 13.2(8.7-19.9) 5 (9)
21 8.4(4.6-15.4) 1 (5)
127 (43) 131 (44)
96 (42) 99 (43)
19 (41) 24 (52)
1 2 (57) 8 (38)
Median (range), or number (%).
Table 4. Number of diabetic patients who experienced one or more severe hypoglycaemic episodes in the previous year, according to awareness of hypoglycaemia Total group
n Hypoglycaemia requiring hospital treatment All severe hypoglycaemia
302
Normal Partial Absent awareness awareness awareness
226
20 (7) 94 (31)
8 (4) 41 (18)
48
21
3 (6) 33 (69)"
9 (43)" 19 (91)"
Number (%I. p < 0.001, comparison with the normal awareness group. All severe hypoglycaemia includes ho5pital treatment, intravenous glucose, intramu5cular glucagon and external assistance by a third party.
a
duration and evidence of abnormal autonomic function in the 'normal', 'partial' and 'absent' awareness groups (NS) (Table 5). Only four patients with absent awareness of hypoglycaemia had diabetes of less than 15 years duration, all of whom had definite autonomic abnormalities. More than half (54 %) of the subgroup of patients with normal awareness and longer duration of diabetes had demonstrable evidence of autonomic damage, while 41 % of the patients with absent awareness had no evidence of autonomic dysfunction.
71 4
Discussion Acute insulin-induced hypoglycaemia in humans activates the sympatho-adrenal system via autonomic centres in the hypothalamus and produces the typical autonomic symptoms of hypoglycaemia. The early perception of autonomic manifestations such as sweating, tremor, and blurred vision allows self-treatment with glucose which prevents progression to severe neuroglycopenia. Blunting or loss of the autonomic warning symptoms of hypoglyD.A. HEPBURN, ET A l .
DTT7
ORIGINAL ARTICLES Table 5. Numbers of patients with normal and abnormal autonomic function tests, according to their awareness of hypoglycaemia and duration ot diabetes n
Normal awareness Partial awareness Absent awareness Less than 15 years duration Normal awareness Partial awareness Absent awareness More than 15 years duration Normal awareness Partial awareness Absent awareness Number (96). For calculation of score
see
Normal (score 0-2)
Abnormal Definite (score 3-5)
Severe Total (score 6-1 0) (score 3-1 0)
169 34 21
107 (63) 25 (74) 7 (33)
34 4 6
28 5 8
62 (37) 9 (26) 14 (67)
97 16 4
74 (76) 14 (87) 0 (0)
12 2 2
11 0 2
23 (24) 2 (13) 4 (100)
72 18 17
33 (46) 1 1 (61) 7 (41)
22 2 4
17 5 6
39 (54) 7 (39) 10 (59)
text.
caemia occurs in some diabetic patients,’--’ and failure of the protective role of autonomic stimulation has been implicated previously as a cause of hypoglycaemia Unawareness.’ Hypoglycaemia unawareness in diabetic patients has therefore been attributed to co-existing autonomic neuropathy. Some diabetic patients with symptomatic autonomic neuropathy do describe a diminution of hypoglycaemia awareness, and in one small study six of nine diabetic patients with overt autonomic neuropathy had reduced subjective awareness of hypoglycaemia. Autonomic neuropathy diminishes the secretion of adrena I i ne d uri ng insu Ii n-induced hy pogIycaem ia, 4, and this has been alleged to reduce autonomic warning symptoms, and hence cause loss of awareness. Autonomic symptoms in response to hypoglycaemia were absent in tetraplegic subjects who have a pre-ganglionic sympathectomy,16,’ but were not significantly reduced in non-diabetic patients who had undergone either a bilateral adrenalectomy or a splanchnicectomy and in whom the autonomic nervous system was otherwise intact.20,2’ It is possible that in some diabetic patients with autonomic neuropathy the reduction in intensity of autonomic symptoms is associated primarily with impairment of autonomic neural activity rather than with a decreased rise in plasma adrenaline. In some diabetic patients who have described hypoglycaemia unawareness the secretion of adrenaline following hypoglycaemia has been shown to be of normal magnitude,2L and loss of awareness of hypoglycaemia may occur in diabetic patients who have no objective evidence of autonomic n e ~ r o p a t h y . Perception ~~ of hypoglycaemia can be reduced by non-selective P-adrenergic blocking 2 5 and a reduction in sensitivity of peripheral P-adrenergic receptors has been proposed as the mechanism causing loss of symptoms of h y p ~ g l y c a e m i a . ~ Thus, ~ , ~ ’ loss of hypoglycaemia awareness may be caused by mechanisms
’ ’
HYPOCLYCAEMIA UNAWARENESS A N D AUTONOMIC NEUROPATHL
other than peripheral autonomic dysfunction, and failure or delay in the activation of central autonomic centres during acute hypoglycaemia has been suggested as a further putative cause of attenuated autonomic activity.L0,2y In the present study, most patients with loss of awareness of hypoglycaemia had diabetes of long duration, which is consistent with previous observations.” In the subgroup of patients reporting loss of awareness, the incidence of autonomic neuropathy, ascertained by non-invasive cardiovascular reflex tests, was higher than in the total group. Those diabetic patients who had autonomic neuropathy also had diabetes of longer duration than those with no evidence of autonomic dysfunction. Patients who had a longer duration of diabetes had similar frequencies of autonomic neuropathy when subdivided into those with normal awareness and those with loss of awareness of hypoglycaemia, demonstrating that autonomic dysfunction and hypoglycaemia unawareness are not invariably related. However, all of the patients with diabetes for less than 15 years, who had total loss of hypoglycaemia awareness, had coexisting autonomic dysfunction and in these patients with diabetes of short duration autonomic neuropathy may be an important aetiological factor. In a retrospective crosssectional survey it is not possible to exclude autonomic dysfunction as the cause of hypoglycaemia unawareness in those patients in which both are present, but a significant number of the patients who had indisputable evidence of autonomic abnormalities retained normal awareness of hypoglycaemia. This is consistent with an observation made by Hilsted et a/. that many of his diabetic patients with autonomic neuropathy developed subjective hypoglycaemic symptoms during insulininduced h y p ~ g l y c a e m i a . ~The ~ precise relationship between diabetic autonomic neuropathy and loss of hypoglycaemia awareness remains undefined. 71 5
Drn
O R I G I N A L ARTICLES The induction of ‘tight’ blood glucose control using intensified insulin therapy reduces the subjective perception of hypoglycaemic symptoms and lowers the blood glucose threshold for the release of adrenaline in response to h y p ~ g l y c a e m i a . ~It, ~also ’ increases the frequency of hypoglycaemia two to three fold.jL In the present study none of the patients with absent awareness of hypoglycaemia had HbA, concentrations within the nondiabetic range, so excluding optimal blood glucose control as a possible factor responsible for diminished hypoglycaemia awareness. Two patients who had partial hypoglycaemia awareness had HbA, concentrations below 8.0 % and in these individuals it i s possible that optimal blood glucose control contributed to their blunted awareness of symptoms. However, a similar proportion of patients with normal awareness also had a HbA, concentration within the non-diabetic range, and as a single measurement represents a relatively short time interval, this provides very limited information about the quality of previous long-term blood glucose control. A previous study of severe hypoglycaemia causing coma in diabetic patients identified that one-quarter of these patients requiring emergency treatment had experienced few or no warning symptoms of hypoglycaemia.33Hypoglycaemia unawareness i s clearly associated with an increase in the severity of hypoglycaemia with its attendant morbidity. The prevalence of severe hypoglycaemia in the present survey was of similar magnitude to that reported in two French studies in which a similar definition of severe hypoglycaemia was used and in which 30 % of insulin-treated diabetic patients experienced one or more episodes of severe hypoglycaemia per year.34,35 Other studies which ~-~~~ reported a lower incidence of h y p o g l y ~ a e m i a ~had defined severity by the development of coma alone and omitted episodes where the patient was unable to initiate self-treatment. However, retrospective historical enquiry may underestimate the magnitude of the problem, because some patients experience difficulty in recalling the total number of episodes of severe hypoglycaemia, possibly as a result of ‘retrograde amnesia‘ associated with severe neuroglycopenia. The absence of warning symptoms of hypoglycaemia might be expected to increase the frequency of severe hypoglycaemia by promoting vulnerability to severe neuroglycopenia. The present study supports this premise and allows quantification of the risk of hypoglycaemia in affected patients. A considerable proportion of the patients with partial awareness of hypoglycaemia and the majority with absent awareness in the present study had experienced one or more episodes of severe hypoglycaemia in the preceding year.
Acknowledgements We thank R.J. Prescott, Department of Medical Statistics, University of Edinburgh, for statistical advice and N.R.
71 6
Colledge for assistance with collection of data. DAH was in receipt of a Novo Research Fellowship and DJE i s a Wellcome Trust Senior Lecturer.
References 1.
Joslin EP, Gray H, Root HF. Insulin in hospital and home.
l Metab Re5 1922; 2: 651-699. 2. 3. 4.
5.
6.
7.
8.
9.
10.
11. 12.
13.
14.
15.
16.
17.
18.
19.
Banting FG, Campbell WR, Fletcher AA. Further clinical experience with insulin. Br Med 1 1923; i: 8-12. Maddock SJ, Trimble HC. Prolonged insulin hypoglycemia without symptoms. IAMA 1928; 91 : 61 6-621. Cryer PE. The metabolic impact of autonomic neuropathy in insulin-dependent diabetes mellitus. Arch Intern Med 1986; 146: 2127-2129. Lager I, Attvall S, Blohme G, Smith U . Altered recognition of hypoglycaemic symptoms in type 1 diabetes during intensified control with continuous subcutaneous insulin infusion. Diabetic Med 1986; 3: 322-325. Reid A, Tibi L, Smith AF. Assessment of a simple method for measuring HbA,. Clin Chim Acta 1980; 108: 487-491. Hepburn DA, Patrick AW, Frier BM. Severe neuroglycopenia precedes autonomic activation during acute hypoglycemia in insulin-dependent diabetic patients with hypoglycemia unawareness (Abstract). Diabetes 1989; 38: (suppl 2): 76A. Ewing DJ, Recent advances in the non-invasive investigation of diabetic autonomic neuropathy. In: Bannister R, ed. Autonomic Failure. A Textbook of Clinical Disorders of the Autonomic Nervous System. 2nd edn. Oxford: Oxford Medical Publications, 1988: 667-689. Ewing DJ, Martyn CN, Young RJ, Clarke BF. The value of cardiovascular autonomic function tests: 10 years experience in diabetes. Diabetes Care 1985; 8: 491-498. Hepburn DA, Eadington DW, Patrick AW, Colledge NR, Frier BM. Symptomatic awareness of hypoglycaemia: does it change on transfer from animal to human insulin? Diabetic Med 1989; 6: 586-590. Baldimos MC, Root HF. Hypoglycemic insulin reactions without warning symptoms. /AMA 1959; 171 : 261-266. Sussman KE, Crout JR, Marble A. Failure of warning in insulin-induced hypoglycemic reactions. Diabetes 1963; 12: 38-45. Hoeldtke RD, Guenther B, Shuman CR, Owen OE. Reduced epinephrine secretion and hypoglycemia unawareness in diabetic autonomic neuropathy. Ann lntern Med 1982; 96: 459-462. Polinsky RJ, Kopin IJ, Ebert MH, Weise V. The adrenal medullary response to hypoglycemia in patients with orthostatic hypotension. / Clin Endocrinol Metab 1980; 51: 1401-1406. Hilsted J, Madsbad S, Krarup T, et a/. Hormonal, metabolic and cardiovascular responses to hypoglycemia in diabetic autonomic neuropathy. Diabetes 1981 ; 30: 626-63 3. Frier BM, Corrall RJM, Ratcliffe JG, Ashby JP, McClemont EJW. Autonomic neural control mechanisms of substrate and hormonal responses to acute hypoglycaemia in man. C/in Endocrinol 1981 ; 14: 425-433. Corrall RIM, Frier BM, McClemont EJW,Taylor SJ, Christie NE. Recovery mechanisms from acute hypoglycaemia in complete tetraplegia. Paraplegia 1979; 17: 31 4-31 8. Palmer JP, Henry DP, Benson JW, Johnson DG, Ensinck JW. Glucagon responses to hypoglycemia in sympathectomised man. ] Clin lnvest 1976; 57: 522-525. Mathias CJ, Frankel JL, Turner RC, Christensen NJ. Physiological responses to insulin hypoglycaemia in spinal D.A. HEPBURN, ET A l .
Dr17 20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
man. Paraplegia 1979; 17: 319-326. Ginsberg J, Paton A. Effects of insulin after adrenalectomy. lancet 1956; i: 491-494. French EB, Kilpatrick R. The role of adrenaline in the hypoglycaemic reaction in man. Clin Sci 1955; 14: 639-651. Polonsky K, Bergenstal R, Pons G, Schneider M, Jaspan 1, Rubenstein A. Relation of counterregulatory responses to hypoglycemia in type 1 diabetics. N E n g / / M e d 1982; 307: 1106-1 1 12. Heller SR, Herbert M, MacDonald I, Tattersall RB. Influence of sympathetic nervous system on hypoglycaemic warning symptoms. Lancet 1987; ii: 359-363. Smith U, Blohmi. G, Lager I, Lonnroth P. Can insulintreated diabetics be given beta-adrenergic-blocking drugs? Br M e d / 1980; 281 : 1 143-1 144. Popp DA, Tse TF, Shah SD, Clutter WE, Cryer PE. Oral propranolol and metoprolol both impair glucose recovery from insulin-induced hypoglycemia in insulin-dependent diabetes mellitus. Diabetes Care 1984; 7: 243-247. Berlin I, Grimaldi A, Payan C, et a / . Hypoglycemic symptoms and decreased P-adrenergic sensitivity in insulin-dependent diabetic patients. Diabetes Care 1987; 10: 742-747. Berlin I, Grimaldi A, Londault F, et a/. Lack of hypoglycemic symptoms and decreased P-adrenergic sensitivity in insulin-dependent diabetic patients. Clin Endocrinol Metab 1988; 66: 273-278. Frier BM. Hypoglycaemia and diabetes. Diabetic M e d 1986; 3: 513-525. Frier BM, Fisher BM, Gray CE, Beastall G H . Counterregulatory hormonal responses to hypoglycaemia in type 1 (insulin-dependent) diabetes: evidence for diminished hypothalamic-pituitary hormonal secretion. Diabetologia
HYPOCLYCAEMIA UNAWARENESS A N D A U T O N O M I C NEUROPATHY
ORIGINAL ARTICLES 30.
31.
32.
33.
34.
35.
36.
37.
38.
1988; 31: 421-429. Hilsted J. Pathophysiology in diabetic autonomic neuropathy: cardiovascular, hormonal, and metabolic studies. Diabetes Care 1982; 31 : 730-737. Amiel SA, Sherwin RS, Simonson DC, Tamborlane WV. Effect of intensive insulin therapy on glycemic threshold for counterregulatory hormone release. Diabetes 1988; 37: 901-907. The DCCT Research Group. Diabetes control and complications trial (DCCT): results of feasibility study. Diabetes Care 1987; 10: 1-19. Collier A, Steedman DJ, Patrick AW, et a/. Comparison of intravenous glucagon and dextrose in treatment of severe hypoglycemia in an accident and emergency department. Diabetes Care 1987; 10: 712-71 5. Goldgewicht C, Slama G, Papoz L, Tchobrousky G . Hypoglycaemic reactions in 172 type 1 (insulindependent) diabetic patients. Diabetologia 1983; 24: 95-99. Basdevant A, Costaglida D, Lanoe JL, et a / . The risk of diabetic control: a comparison of hospital versus general practice supervision. Diabetologia 1982; 22: 309-31 4. Goldstein DE, England JD, Hess R, Rawlings SS, Walker B. A prospective study of symptomatic hypoglycemia in young diabetic patients. Diabetes Care 1981 ; 4 : 601-605. Potter J, Clarke P, Gale EAM, Dave SH, Tattersall RB. Insulin-induced hypoglycaemia in an accident and emergency department: the tip of an iceberg. Br M e d ) 1982; 285: 1180-1182. Muhlhauser I, Berger M, Sonnenberg G, e t a / . Incidence and management of severe hypoglycemia in 434 adults with insulin-dependent diabetes mellitus. Diabetes Care 1985; 8: 268-273.
71 7
