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Reduced Awareness of Hypoglycemia in Adults With IDDM

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Reduced Awareness of
Hypoglycemia in Adults
A prospective study of hypoglycemic frequency
and associated symptoms
OBJECTIVE To prospectively evaluate the frequency and severity of hypoglyce-
mic episodes in IDDM subjects who declare themselves to have reduced awareness of
hypoglycemia, to validate their self-designations in their natural environment, and to
determine objectively the presence or absence of autonomic and neuroglycopenic
symptoms associated with their low blood glucose (BG) levels.
RESEARCH DESIGN AND METHODS A total of 78 insulin-dependent
diabetes mellitus (IDDM) subjects (mean age 38.3 – 9.2 years; duration of diabetes
19.3 – 10.4 years) completed two sets of assessments separated by 6 months. The
assessments included reports of frequency and severity of low BG, symptoms associ-
ated with low BG, and a BG symptom/estimation trial using a hand-held computer
(HHC). Diaries of hypoglycemic episodes were kept for the intervening 6 months.
levels were determined at each assessment.
RESULTS Of the subjects, 39 declared themselves as having reduced awareness
of hypoglycemia (reduced-awareness subjects). There were no differences between
these reduced-awareness subjects and aware subjects with regard to age, sex, disease
duration, insulin dose, or HbA^ During the HHC trials, reduced-awareness subjects
were significantly less accurate in detecting BG <3.9 mmol/1 (33.2 – 47 vs. 47.6 –
50% detection, P = 0.001) and had significantly fewer autonomic (0.41 – 0.82 vs.
1.08 – 1.22, P = 0.006, reduced-awareness vs. aware) and neuroglycopenic (0.44 –
0.85 vs. 1.18 – 1.32, P = 0.004, reduced-awareness vs. aware) symptoms per subject.
Prospective diary records revealed that reduced-awareness subjects experienced more
moderate (351 vs. 238, P = 0.026) and severe (50 vs. 17, P = 0.0062) hypoglycemic
events. The second assessment results were similar to the first and verified the reliabil-
ity of the data.
CONCLUSIONS IDDM subjects who believe they have reduced awareness of
hypoglycemia are generally correct. They have a history of more moderate and severe
hypoglycemia, are less accurate at detecting BG <3.9 mmol/1, and prospectively ex-
perience more moderate and severe hypoglycemia than do aware subjects. Neither
disease duration nor level of glucose control explains their reduced awareness of
hypoglycemia. Reduced-awareness individuals may benefit from interventions de-
signed to teach them to recognize all of their potential early warning symptoms.
From the Departments of Pediatrics and of Psychiatric Medicine, the University of Virginia Health Sciences
Center, Charlottesville, Virginia; the Diabetes Research and Training Center (D.S.), Vanderbilt University,
Nashville, Tennessee; and the Joslin Diabetes Clinic (W.P.), Boston, Massachusetts.
Address correspondence and reprint requests to William L. Clarke, MD, Box 386, Department of Pedi-
atrics, University of Virginia Health Sciences Center, Charlottesville, VA 22908.
Received for publication 7 July 1994 and accepted in revised form 22 December 1994.
BG, blood glucose; HFS, Hypoglycemia Fear Survey; HHC, hand-held computer; IDDM, insulin-
dependent diabetes mellitus; SMBG, self-monitoring of blood glucose.
educed awareness of hypoglycemia
is a commonly reported phenome-
non among patients with long-
standing insulin-dependent diabetes mel-
litus (IDDM). Up to 50% of IDDM patients
15-20 years postdiagnosis report having
lost their ability to perceive autonomic
symptoms associated with low blood glu-
cose (BG) levels and thus often fail to act
to prevent severe hypoglycemia (1,2). In-
deed severe hypoglycemia, e.g., loss of
consciousness and/or seizures, has been
reported to occur up to five times more
frequently in patients with reduced
awareness (3). The mechanism of this re-
duced awareness is not currently known.
However, it has been shown to be associ-
ated with improved glucose control and
defective glucose counterregulation, as
well as with longer disease duration (4,5).
In addition, recent low BG (<3.9 mmol/1
within the previous 72 h) may be associ-
ated with an acute transient reduction in
hypoglycemic symptom awareness (6-9).
Reduced awareness is usually de-
clared by patients themselves in response
to questioning. However, confirmation of
their designations (aware, partially aware,
or unaware) has been validated in only
one laboratory study (10). Nine subjects
identifying themselves as aware, partially
aware, or unaware were infused with in-
sulin in the laboratory to produce hypo-
glycemia, while autonomic and neurogly-
copenic symptoms were monitored. Only
one of nine subjects self-designated as un-
aware was able to identify either auto-
nomic or neuroglycopenic symptoms as
BG was lowered. In the other subjects,
severe neuroglycopenia developed at
higher BG levels than did autonomic
symptoms (1.33 –0.15 vs. 0.94 –0.11
mmol/1, P < 0.02) and prevented the rec-
ognition of hypoglycemia. In subsequent
prospective analyses, 66% of IDDM sub-
jects declaring themselves unaware of hy-
poglycemic symptoms experienced se-
vere hypoglycemia within the next 12
months compared with 25% of aware pa-
tients (11).
The present study was designed to

Reduced awareness of hypoglycemia in IDDM
evaluate prospectively the frequency, se-
verity, and consequences of reduced
awareness of hypoglycemia as declared by
IDDM subjects, to validate their designa-
tions in their natural environment, and to
identify characteristics that might be use-
ful in distinguishing people with reduced
awareness. Such information could be
particularly helpful in designing interven-
tions that might prevent or interrupt se-
vere hypoglycemic episodes and improve
patients’ awareness.
METHODS Subjects in this study
were recruited from the University of Vir-
ginia, Vanderbilt University, and the Jos-
lin Diabetes Clinic for a larger study of
blood glucose awareness training
(12,13). Adults who had IDDM for at
least 2 years, who were between 21 and
55 years old, and who were routinely per-
forming self-monitoring of blood glucose
(SMBG) were solicited by newspaper an-
nouncements to participate in a study in-
volving "improved metabolic control and
awareness of hypoglycemia." Particular
efforts were made to recruit and include
subjects with extreme degrees of hypogly-
cemic awareness. Subjects attended an
orientation meeting at which the study
was explained, and informed consent was
The study consisted of two assess-
ments separated by 6 months. Each as-
sessment included a battery of question-
naires and a BG symptom rating/
estimation trial. During the intervening 6
months, subjects completed diaries of hy-
poglycemic events, which they mailed in
monthly. HbA
was determined before
the initial assessment and after the second
assessment. No other intervention oc-
curred during this time.
Assessments included demographic, dis-
ease management, and hypoglycemic
awareness questionnaires. Subjects an-
swered questions concerning personal
experiences with hypoglycemia including
a history of mild, moderate, and severe
episodes, and symptoms that are believed
to be associated with low BG. The follow-
ing definitions of hypoglycemia, similar
to those used in the Diabetes Control and
Complications Trial feasibility study,
were used: mild symptoms such as
shakiness, headache, or sweating, re-
lieved with simple carbohydrate; moder-
ate lethargy, confusion, or requiring
assistance for treatment; severe uncon-
scious, seizure, or requiring glucagon or
intravenous glucose (14). Each subject
completed the Hypoglycemia Fear Survey
(HFS) to measure their worry associated
with low BG (15). Glycosylated hemoglo-
bin (HbA
) was measured for each subject
to determine glucose control over the pre-
vious 6-8 weeks. All HbA
levels were
assayed at the University of Virginia Clin-
ical Laboratory, where the nondiabetic
range was 4.4-6.9%.
BG symptom rating/estimation trial
Subjects were taught to use a hand-held
computer (HHC) (Psion P-250) pro-
grammed to collect BG estimates, symp-
toms ratings, and SMBG determinations.
The HHC prompts subjects to estimate
their current BG, enter the value into the
computer, and rate (on a scale of 0-6) the
degree to which they are currently expe-
riencing each of five neuroglycopenic
symptoms (dizziness, uncoordination,
tiredness, visual disturbance, and diffi-
culty concentrating) and four autonomic
symptoms (sweatiness, pounding heart,
trembling, and nervous/tense). Subjects
next performed SMBG and entered that
result as well. The HHC records the date
and time of each entry. Actual SMBG val-
ues entered sooner than 45 s after the
prompt "Measure your BG" are desig-
nated false, since an insufficient length of
time would have occurred for the deter-
mination of BG using most meters; such
data are disregarded. We have previously
demonstrated that the HHC BG symptom
rating/estimation procedure permits ac-
curate identification of symptoms that are
sensitive and specific to high and low BG
levels for each individual (12,13,16,17).
Subjects in the present study completed
50 HHC trials over 3 weeks at both assess-
Monthly diaries
During the 6 months between assess-
ments, subjects kept hypoglycemia dia-
ries in which they recorded information
concerning mild, moderate, and severe
hypoglycemic episodes. In addition to ac-
tual BG level and time of occurrence, sub-
jects recorded information regarding
driving errors (speeding, out of lane,
etc.), violations, and accidents. Diaries
were mailed in on a monthly basis.
Statistical analysis
Subjects were divided into those who
were aware of hypoglycemia (aware
group) and those who had reduced
awareness (reduced-awareness group)
based on their responses to questions 1-8
in Table 1. Four or more answers desig-
nated R categorized a subject as having
reduced awareness, while two or fewer R
answers categorized a subject as aware.
Group assignments using these criteria
were compared with potential aware/
reduced-awareness group assignments
based on subjects’ answers to the single
question, "To what extent can you tell
by your symptoms that your sugar is
low? (never, sometimes, often, always)."
Agreement of categorization between
the two methods was demonstrated
by a cross-table (/ = 40.29, P <
The means of information from
assessment questionnaires, HHC trials,
and HbA
levels were obtained, and data
from the two groups were analyzed after a
Bonferroni correction using nonpaired
Student’s t tests. In addition, data from
the assessments, HHC trials, and HbA
levels obtained after the prospective diary
recordings were compared with the initial
findings to assess reliability. Monthly di-
ary data were added over the 6-month
period and analyzed using the Mann-
Whitney U test.

Clarke and Associates
Table 1 Survey items used to categorize aware or having reduced awareness of
hypoglycemia in subjects
1) Check the category that best describes you: (check one only)
I always have symptoms when my blood sugar is low (A)
1 sometimes have symptoms when my blood sugar is low (R)
1 no longer have symptoms when my blood sugar is low (R)
2) Have you lost some of the symptoms that used to occur when your blood sugar was low?
yes (R) no (A)
3) In the past six months how often have you had moderate hypoglycemia episodes?
(Episodes where you might feel confused, disoriented, or lethargic and were unable to treat
Never (A) Once or twice (R) Every other month (R)
. Once a month (R) More than once a month (R)
4) In the past year how often have you had severe hypoglycemic episodes? (Episodes where
you were unconscious or had a seizure and needed glucagon or intravenous glucose)
Never (A) 1 time (R) 2 times (R) 3 times (R)
5 times (R) 6 times (R) 7 times (R) 8 times (R)
9 times (R) 10 times (R) 11 times (R)
12 or more times (U)
5) How often in the last month have you had readings <70 mg/dl with symptoms?
Never 1 to 3 times 1 time/week 2 to 3 times/week 4 to 5 times/week
Almost daily
6) How often in the last month have you had readings <70 mg/dl without any symptoms?
Never 1 to 3 times 1 time/week 2 to 3 times/week
4 to 5 times/week , Almost daily
(R = answer to 5 < answer to 6, A = answer to 6 > answer to 5)
7) How low does your blood sugar need to go before you feel symptoms?
60-69 mg/dl (A) 50-59 mg/dl (A) 40-49 mg/dl (R)
<40 mg/dl (R)
8) To what extent can you tell by your symptoms that your blood sugar is low?
Never (R) Rarely (R) Sometimes (R) Often (A)
Always (A)
Four or more R responses = reduced awareness; 2 or fewer R responses = aware.
Subject characteristics
A total of 78 IDDM adults (28 men), aged
38.3 – 9.2 (mean – SD) years, with dis-
ease duration of 19.3 – 10.4 years, were
recruited. Of these, 39 were categorized
as aware and 39 were categorized as hav-
ing reduced awareness by the criteria
listed above. There were no differences in
mean age, disease duration, daily insulin
dose, or initial HbA
between the two
groups (Table 2). The number of subjects
with known nephropathy or retinopathy
was similar in both groups. More re-
duced-awareness subjects had known
neuropathy than aware subjects (12 vs.
4), but the difference was not statistically
Retrospective questionnaire data
On the retrospective questionnaire there
were no differences between aware and
reduced-awareness subjects in the re-
ported frequencies of mild hypoglycemia
during the month before the study. How-
ever, reduced-awareness subjects re-
ported significantly more moderate hypo-
glycemia (1.9 – 1.6 vs. 0.9 – 1.3
episodes/month, P = 0.002) during the
previous 6 months, and >10 times the
number of severe hypoglycemic episodes
during the previous year (2.6 – 3.4 vs.
0.2 – 0.7 episodes/year, P < 0.0001).
Subjects rated the usefulness of the nine
low BG symptoms to their recognition of
hypoglycemia. Symptoms were consid-
ered to be significant for an individual if
that subject rated a particular symptom as
occurring often or always in association
with low BG. The mean number of symp-
toms so endorsed was significantly
greater in aware than in reduced-aware-
ness subjects (4.32 –1.5 vs. 2.10 – 1.7
symptoms/subject, P < 0.001). Despite
these differences in frequencies of moder-
ate and severe hypoglycemia and in
symptom beliefs, fear of hypoglycemia, as
measured by the HFS worry scale, did not
differ in the two groups (22.3 –11.3 vs.
25.1 – 9.3, NS, aware vs. reduced-aware-
Prospective HHC data
To identify symptoms sensitive and spe-
cific to low BG (<3.9 mmol/1), the prob-
ability of a symptom being rated ^1
when BG was low versus when it was not
low (>3.9 mmol/1) was compared (17).
The number of significant symptoms per
subject was not linearly dependent on the
number of low BG episodes (r = 0.02,
NS). The HHC trial demonstrated signif-
icant differences in the actual number of
significant symptoms per subject in the
two groups (2.26 – 2.23 vs. 0.85 – 1.44
symptoms/subject, P = 0.002, aware vs.
reduced-awareness). This was true for
both autonomic and neuroglycopenic
symptoms (Table 2). Similar numbers of
subjects in each group had at least one
significant symptom associated with their
BG <3.9 mmol/1. In addition, detection
of low BG (percentage of actual BG <3.9
mmol/1 estimated as <3.9 mmol/1) was
significantly lower in reduced-awareness
subjects. Mean number of actual BG read-
ings in the ranges <3.9 mmol/1, 2.8-3.9
mmol/1 and <2.8 mmol/1, during the
HHC trial were similar for both groups.
Thus, reduced-awareness subjects be-
lieved (retrospective questionnaire)
themselves to have fewer significant
symptoms associated with their low BG

Reduced awareness of hypoglycemia in IDDM
Table 2 Characteristics of aware and reduced-awareness groups
Age (years)
Duration (years)
Insulin dose (U/day)
HbA! (%)
Retrospective data
Moderate episodes in past 6 months (n)
Severe episodes in past 12 months (n)
Low BG symptoms reported/subject (n)
Prospective HHC data
Autonomic symptoms/subject (n)
Neuroglycopenic symptoms/subject (n)
Detection of BG <3.9 mmol/l (%)
BG <3.9 mmol I"
36.6 – 8.8
16.5 – 9.9
40 – 15.9
10.7 – 2.2
0.9 – 1.3
0.2 – 0.7
4.3 – 1.5
1.08 – 1.22
1.18 – 1.32
47.6 – 50
6.5 – 5.7
Reduced awareness
40.0 – 9.3
22.0 – 10.3
37.2 – 16.2
9.8 – 1.9
1.9 – 1.6
2.6 – 3.4
2.1 – 1.7
0.41 – 0.82
0.44 – 0.85
33.2 – 47
7.0 – 4.5
P value
Data are means – SD. * Data for these variables were not normally distributed. Thus, nonparametric Mann-
Whitney 17 tests were used to compare these data.
and to be less accurate at detecting BG
<3.9 mmol/l than aware subjects. This
was confirmed by the HHC.
Reduced-awareness subjects may
be specifically less sensitive to low BG
events or generically less sensitive to in-
ternal events. Consequently, reduced-
awareness and aware subjects were com-
pared on symptoms and detection of high
BG (>10 mmol/l) using HHC data. Both
reduced-awareness and aware subjects
had a similar number of high BG symp-
toms (need to urinate, dry mouth and
nose, and sweet/funny taste in mouth). In
addition, while reduced-awareness sub-
jects were less accurate at detecting BG
3.9-2.8 mmol/l and <2.8 mmol/l, they
were equally accurate at detecting high
BG (Fig. 1). This indicates that reduced
awareness is specific to low BG and not a
generic insensitivity to internal bodily
Prospective documentation of
hypoglycemic events
Reduced-awareness subjects had signifi-
cantly fewer mild, but more moderate
and more severe, hypoglycemic episodes
during the 6-month period (Table 3). Re-
duced-awareness subjects had similar
numbers of moderate and severe hypo-
glycemic events during the night as did
aware subjects, but significantly more
such events than aware subjects during
the day (P = 0.015). Total driving errors
(speeding, time out of lane, etc.) were
greater in aware subjects (2,210 vs.
1,065, P = 0.026) as were driving viola-
tions (29 vs. 11, P = 0.020, aware vs.
reduced-awareness). The number of acci-
% Detection
dents was not significantly different be-
tween the two groups.
Repeat assessment and HHC trial
After 6 months of diary recordings, all
subjects repeated the HFS and the HHC
trial. HbA
levels remained unchanged in
both aware and reduced-awareness sub-
jects. Fear of hypoglycemia scores, as re-
flected by HFS worry scale, also were un-
changed. HHC results validated the
reliability of the initial findings in terms of
percentage detection of BG <3.9 mmol/l
(45.9 – 49% vs. 35.3 – 48%, P = 0.014,
aware vs. reduced-awareness) and num-
ber of significant hypoglycemic symp-
toms per subject (2.26 – 2.26 vs. 1.0 –
1.41, P = 0.003, aware vs. reduced-
awareness) when BG <3.9 mmol/l. The
number of subjects with at least one
symptom significantly associated with BG
<3.9 mmol/l was similar in both groups
(25 vs. 18, NS, aware vs. reduced-aware-
CONCLUSIONS This is the first
nonlaboratory study to examine the accu-
racy of IDDM subjects’ self-categorization
of their ability to recognize hypoglyce-
mia. In their natural environment, IDDM
<2.8 2.8-3.3 3.3-3.9 Normal Range
Measured BG level mmol/L
Figure 1 Percent detection of hypo- or hyperglycemia. P8883, aware group;
10.-13.3 13.3-16.7 >16.7
I, reduced-awareness

Clarke and Associates
Table 3 Six-month prospective hypoglycemia diaries
Mild episodes
Moderate episodes
Severe episodes
Driving errors
Driving violations
Driving accidents
Aware group
Reduced-awareness group
P value
Data are n.
subjects who believe that they have a re-
duced ability to detect low BG are correct.
HHC data, for both assessments, demon-
strated that while reduced-awareness
subjects had a similar number of BG <3.9
mmol/1 measurements as aware subjects,
they had fewer low BG symptoms and
poorer detection of low BG. In addition,
prospectively, reduced-awareness sub-
jects experienced more moderate and se-
vere hypoglycemic episodes. The rela-
tively large number of subjects studied,
their geographic diversity, and the stabil-
ity of the findings over 6 months attest to
the reliability of these data.
Previous studies have suggested
that hypoglycemic unawareness is associ-
ated with long disease duration, im-
proved glucose control, and defective
glucose counterregulation (1,4,5). In the
present study, reduced-awareness sub-
jects had similar disease duration and
HbAj levels as aware subjects. We did not
test the ability of our subjects to counter-
regulate to hypoglycemia. However, since
autonomic symptoms occurred less fre-
quently in reduced-awareness than in
aware subjects, it is possible that sympa-
thochromafiin cell insufficiency may have
contributed to their reduced awareness
During insulin-induced hypogly-
cemia in the laboratory, unaware 1DDM
subjects have been shown to have neuro-
glycopenic symptoms at higher BG levels
than autonomic symptoms (2). In addi-
tion, laboratory studies of normal adults
with hypoglycemic unawareness induced
transiently by repeated insulin infusions
have demonstrated that neuroglycopenic
symptoms are not affected by pharmaco-
logical autonomic blockade (18). Thus, it
would appear that neuroglycopenic
symptoms of low BG are important warn-
ing signs of impending severe hypoglyce-
mia that are often present, but rarely used
as prompts to raise BG levels.
It has been suggested that IDDM
subjects with hypoglycemic unawareness
are incapable of recognizing neuroglyco-
penic symptoms and have lost autonomic
symptoms of hypoglycemia (18). The
present study evaluated both autonomic
and neuroglycopenic symptoms during
the HHC trials. Despite a reduced num-
ber of hypoglycemic symptoms and a re-
duced ability to detect low BG, subjects
with reduced awareness had some auto-
nomic and neuroglycopenic symptoms.
This finding, that autonomic and neuro-
glycopenic symptoms may be present in
subjects with reduced awareness of hypo-
glycemia in their natural environment,
emphasizes the need to improve IDDM
subjects’ attention to all of their potential
warning signs of hypoglycemia.
Post hoc analysis of HHC data re-
garding symptoms associated with hyper-
glycemia has failed to demonstrate a cor-
relation between the number of low and
high BG symptoms per subject. In addi-
tion, these data demonstrate that re-
duced-awareness subjects are not generi-
cally unable to perceive symptoms of
bodily events, but rather are uniquely un-
able to recognize low BG symptoms. The
finding of no differences in the HFS worry
scales between aware and reduced-aware-
ness subjects at either assessment may be
surprising. However, we have previously
shown that fear of hypoglycemia as mea-
sured by this instrument is not related to
the absolute number of hypoglycemic ep-
isodes (19). Rather, HFS worry scores are
related to the degree of distress or trauma
associated with hypoglycemic events. The
difference between diary information
with regard to driving errors, etc., in
aware and reduced-awareness subjects
may be the result of increased awareness
by aware subjects of their driving skills
and/or decisions by reduced-awareness
subjects to drive more carefully or less
frequently. Our data do not permit vali-
dation of these speculations.
The recognition of hypoglycemia
is complex and requires at least four bio-
psychological processes: 1) a physiologi-
cal reaction, such as central nervous sys-
tem dysfunction or counterregulation; 2)
physical consequences, such as auto-
nomic or neuroglycopenic symptoms; 3)
symptom detection; and 4) accurate
symptom interpretation (16). A variety of
factors, including (but not limited to) re-
cent low BG, autonomic neuropathy, in-
attention to one’s symptoms, or lack of
knowledge concerning the categorization
of somatic symptoms as related to high or
low BG, can modify these processes. Re-
duced awareness of hypoglycemia does
not have a single cause in all IDDM sub-
jects, nor may a single etiology explain all
episodes of reduced awareness in a single
In the present study, reduced-
awareness subjects had similar numbers
of significant autonomic and neuroglyco-
penic symptoms. Therefore, efforts to im-
prove awareness in these subjects should
focus on enhancing symptom detection
and educating subjects with regard to
symptom interpretation. Other strategies
for improving awareness may be prefera-
ble in other groups of subjects. Hypogly-
cemia unawareness in patients with insu-
linomas is reversible with tumor removal
(20). In addition, Fanelli et al. (21) have
shown in IDDM subjects with shorter dis-
ease duration than our subjects that re-

Reduced awareness of hypoglycemia in IDDM
duced awareness of hypoglycemia maybe
improved by raising overall mean BG lev-
els (21). The latter, although potentially
beneficial in terms of patient safety, may
contribute to poor glucose control and ul-
timately lead to microvascular complica-
tions (22).
Clearly there is a need to identify
causes of reduced awareness of hypogly-
cemia and develop intervention strategies
to restore awareness without sacrificing
metabolic control. Blood glucose aware-
ness training, a behavioral intervention
designed to assist IDDM subjects in rec-
ognizing hyperglycemic and hypoglyce-
mic symptoms, has been shown to im-
prove overall BG estimation accuracy
without altering levels of metabolic con-
trol (12,13). Such an intervention, fo-
cused on improving autonomic and neu-
roglycopenic symptom detection and
predicting and preventing hypoglycemia,
could be an important adjunct to restor-
ing awareness of hypoglycemia while pre-
serving glucose control.
1. CryerP, Binder C, Bolli G, Cherrington A,
Gale E, Gerich J, Sherwin R: Hypoglyce-
mia in IDDM. Diabetes 38:1193-1199,
2. Pramming S, Thorsteeinsson B, Bendtson
I, Binder C: Symptomatic hypoglycemia
in 411 type I diabetic patients. Diabetic
Med 8:217-222, 1991
3. Hepburn D, Patrick A, Eadington D, Ew-
ing D, Frier B: Unawareness of hypogly-
cemia in insulin-treated patients: its prev-
alence and relationship to autonomic
neuropathy. Diabetic Med 7:711-717,
4. Clarke W, Gonder-Frederick L, Richards
F, Cryer P: Multifactorial origin of hypo-
glycemic symptom unawareness in
IDDM. Diabetes 40:680-685, 1991
5. Cryer P: Iatrogenic hypoglycemia as a
cause of hypoglycemia-associated auto-
nomic function. Diabetes 41:255-260,
6. Cox D, Gonder-Frederick L, Polansky W,
Schlundt D, Korachev B, Clarke W: Fre-
quency of hypoglycemia after a low BG
(Abstract). Diabetes 42 (Suppl. 1):124A,
7. Heller S, Cryer P: Reduced neuroendo-
crine and symptomatic responses to sub-
sequent hypoglycemia after 1 episode of
hypoglycemia in nondiabetic humans.
Diabetes 40:223-226, 1991
8. Veneman T, Mitrakou A, Mokan M, Cryer
P, Gerich J: Induction of hypoglycemia
unawareness by asymptomatic nocturnal
hypoglycemia. Diabetes 42:1233-1237,
9. Lingenfelser T, Renn W, Sommerwerck
U, Jung M, Buettner U, Zaiser-Kaschel R,
Eggstein M, Jakober B: Compromised
hormonal counterregulation, symptom
awareness and neuropsychological func-
tion after recurrent short-term episodes of
insulin-induced hypoglycemia in IDDM
patients. Diabetes 424:610-618, 1993
10. Hepburn D, Patrick A, Frier B: Severe hy-
poglycemia precedes autonomic activa-
tion in insulin-dependent diabetic pa-
tients with hypoglycemia unawareness
(Abstract). Diabetes 38 (Suppl. 1):76A,
11. MacLeod K, Gold A, Frier B: Frequency of
severe hypoglycemia in insulin-depen-
dent diabetic patients with altered aware-
ness of hypoglycemia (Abstract). Diabetes
42 (Suppl. 1):73A, 1993
12. Cox D, Gonder-Frederick L, Julian D,
Cryer P, Lee J, Richards F, Clarke W: In-
tensive versus standard blood glucose
awareness training (BGAT) with insulin
dependent diabetes: mechanism and an-
cillary effects. Psychosom Med 53:453-
13. Cox D, Gonder-Frederick L, Julian D,
Clarke W: Long-term follow-up of blood
glucose awareness training. Diabetes Care
17:1-5, 1994
14. The Diabetes Control and Complications
Trial Research Group: Diabetes Control
and Complications Trial (DCCT): results
of feasibility study. Diabetes Care 10:1
15. Cox D, Irvine A, Gonder-Frederick L,
Nowacek G, Butterfield J: Fear of hypo-
glycemia: quantification, validation, and
utilization. Diabetes Care 10:617-621,
16. Cox D, Gonder-Frederick L, Antoun B,
Schroeder D, Clarke W: Perceived symp-
toms in the detection of hypoglycemia.
Diabetes Care 16:519-527, 1993
17. Cox D, Gonder-Frederick L, Kovatchev B,
Polonsky W, Schlundt D, Julian D, Clarke
W: The identification and nature of hypo-
glycemic symptoms among individuals
with insulin dependent diabetes mellitus.
Bid Psychol. In press
18. Towler D, Havlin C, Crafts S, Cryer P:
Mechanism of awareness of hypoglyce-
mia. Diabetes 42:1791-1798, 1993
19. Irvine A, Cox D, Gonder-Frederick L:
Fear of hypoglycemia: relationship to
physical and psychological symptoms in
patients with insulin-dependent diabetes
mellitus. Health Psychol 11:135-138,
20. Mitrakou A, Fanelli C, Veneman T, Perri-
ello G, Calderone S, Plantanisiotis D,
Rambotti A, Raptis S, Brunetti P, Cryer P,
Gerich J, Bolli G: Reversibility of un-
awareness of hypoglycemia in patients
with insulinomas. N EnglJ Med 329:834-
21. Fanelli C, Epifano L, Rambotti A, Pam-
panelli S, DiVincenzo A, Modarelli F,
Lepore M, Annibvale B, Ciofetta M, Bot-
tini P, Porcellati F, Scionti L, Santeusanio
F, Brunetti P, Bolli G: Meticulous preven-
tion of hypoglycemia normalizes the gly-
cemia thresholds and magnitude of most
neuroendocrine responses to, symptoms
of, and cognitive function during hypo-
glycemia in intensively treated patients
with short-term IDDM. Diabetes 42:
1683-1689, 1993
22. The Diabetes Control and Complications
Trial Research Group: The effect of inten-
sive treatment of diabetes on the develop-
ment and progression of long-term com-
plications in insulin-dependent diabetes
mellitus. N EnglJ Med 329:977-986,1993