The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 2 523-525
Copyright © 2000 by The Endocrine Society
Reversal of Hypoglycemia Unawareness in a Long-Term Type 1 Diabetic Patient by Improvement of ß-Adrenergic Sensitivity after Prevention of Hypoglycemia
Andreas Fritsche,
Michael Stumvoll,
Hans U. Häring and
John E. Gerich
Department IV of Internal Medicine, Endocrinology, and
Pathobiochemistry, University of Tubingen, 72076 Tubingen, Germany; and
the Departments of Medicine, Physiology, and Pharmacology, University
of Rochester School of Medicine, Rochester, New York 14642
Address all correspondence and requests for reprints to: Dr. Andreas Fritsche, Medizinische Universitätsklinik IV, Otfried Müller Strasse 10, 72076 Tubingen, Germany. E-mail:
andreas.fritsche{at}med.unituebingen.de
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Abstract
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The purpose of this study was to assess the effect of strict avoidance
of hypoglycemia on ß-adrenergic sensitivity in a type 1 diabetic
patient with hypoglycemia unawareness and a diabetes duration of 55 yr.
ß-Adrenergic sensitivity was determined by an isoproterenol test and
was expressed as the lowest dose of isoproterenol that increases the
heart rate by 25 beats/min (IC25). Plasma epinephrine and
symptom responses to hypoglycemia were determined during a 3-h
hypoglycemic (3 mmol/L) clamp. Initially, the patient had a near-normal
counterregulatory plasma epinephrine response to hypoglycemia but
reduced ß-adrenergic sensitivity (IC25, 2 µg) compared
to 10 hypoglycemia aware, type 1 diabetic patients (0.65 ± 0.14
µg) and 10 normal control subjects (1.13 ± 0.21 µg). After 1
yr of strict avoidance of blood glucose levels below 4 mmol/L, the
IC25 decreased to 0.25 µg, reflecting improved
ß-adrenergic sensitivity. In conclusion, the reduced ß-adrenergic
sensitivity in this patient was probably the reason for hypoglycemia
unawareness and was reversed by strict avoidance of hypoglycemia.
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Introduction
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HYPOGLYCEMIA unawareness is a common problem in
patients with type 1 diabetes (1) and is characterized by loss of
autonomic warning symptoms before the development of neuroglycopenia
(2). Risk factors include diabetes duration, degree of glycemic
control, and the occurrence of repeated episodes of hypoglycemia
(1, 2, 3, 4, 5). There is evidence that both reduced counterregulatory hormone
responses to hypoglycemia (1, 3) and impaired ß-adrenergic
sensitivity (6, 7) contribute to the pathophysiology of hypoglycemia
unawareness. Recently, a model for the development of this condition
has been proposed that hypothesizes that increased ß-adrenergic
sensitivity initially compensates for reduced epinephrine responses and
that reversible reduction in ß-adrenergic sensitivity is the critical
factor leading to the development of hypoglycemia unawareness (8).
Herein, we present a patient with long-standing type 1 diabetes
and hypoglycemia unawareness characterized by near-normal epinephrine
responses and impaired ß-adrenergic sensitivity in whom the effect of
strict avoidance of hypoglycemia for 1 yr on ß-adrenergic sensitivity
was assessed.
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Case Report
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A 57-yr-old man (body mass index, 22.5
kg/m2) with a type 1 diabetes duration of 55 yr
presented with hypoglycemia unawareness and a hemoglobin
A1c (HbA1c) of 7.0%
(normal range, 4.3–6.1%). He reported a minimum of 500 episodes of
severe hypoglycemia (unconsciousness or requiring assistance)
during his lifetime and 2 episodes/yr during the last 3 yr. He reported
the absence of warning symptoms in recent years, for which reason he
usually measured blood glucose (BG) every 3–4 h during the day. He had
no signs of nephropathy (repeated urinary albumin excretion during
24 h, <20 mg/g creatinine), neuropathy (normal pallaesthesia), or
macrovascular disease. Furthermore, he had no signs of autonomic
neuropathy, as shown by normal cardiovascular reflex tests. Funduscopy
showed nonproliferative retinopathy. The patient was being managed on
an insulin regimen consisting of 10 U human NPH insulin in the morning
and 8 U NPH insulin injected at bedtime. He injected short acting
insulin at mealtimes, 3 times a day.
To diagnose and characterize his hypoglycemia unawareness, we
initially assessed ß-adrenergic sensitivity with an isoproterenol
test and counterregulatory hormone and symptom responses during a 3-h
hypoglycemic clamp. Subsequently, the patient was given a regimen to
avoid BG levels below 4 mmol/L. He performed self monitoring of BG at
least five times a day and adjusted his insulin dose according to the
actual BG level and the carbohydrate content of the meal. When the BG
reading was below 8 mmol/L before bedtime, he was told to eat a snack
with a variable carbohydrate content aiming for a BG level of 10 mmol/L
before going to bed to avoid nocturnal hypoglycemia. He attended the
diabetic out-patient clinic bimonthly. After 1 yr, we reduced the
insulin dose by 25% from 0.55 to 0.4 U/kg BW for another 6 weeks and
repeated the isoproterenol test. During the period of avoidance of
hypoglycemia, the patient’s HbA1c, measured
every 3 months, ranged between 7.3–8.4%. The patient reported no
episodes of severe hypoglycemia and recognized mild hypoglycemia at
higher BG levels. During the last 6 weeks with strict avoidance of
hypoglycemia, the HbA1c level rose from 7.6% to
8.1%, and the patient measured no BG levels below 4 mmol/L.
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Materials and Methods
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ß-Adrenergic sensitivity was assessed using an isoproterenol
test (8). A 5-mL bolus containing 0 (5 mL 0.9% NaCl), 0.25, 0.5, 0.75,
1, 1.5, 2, and 2.5 µg isoproterenol was injected into a forearm vein
at 20-min intervals. An electrocardiogram was recorded on-line before
and after each injection. ß-Adrenergic sensitivity was expressed as
the dose of isoproterenol that increased the heart rate by 25 beats/min
(IC25). Two weeks after the isoproterenol
test, we determined counterregulatory hormone response
during a 3-h hypoglycemic clamp (3 mmol/L) using a constant insulin
infusion rate of 1 mU/kg BW·min (8). Arterialized plasma glucose,
plasma epinephrine, and symptoms were measured at baseline and at 30,
90, 150, and 180 min during the clamp (8). Symptoms were assessed by a
semiquantitative symptom questionnaire on which patients scored from 1
(none) to 7 (severe) in response to 9 autonomic, 10 neuroglycopenic,
and 10 dummy questions (9).
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Results
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ß-Adrenergic sensitivity before and after avoidance of
hypoglycemia and plasma epinephrine response to hypoglycemia are shown
in Table 1
. They are compared to results
of hypoglycemic clamps and isoproterenol tests in 10 type 1 diabetic
subjects (mean age, 29 yr; mean diabetes duration, 13 yr; mean
HbA1c, 7.3%) and 10 normal controls, aged 25 yr
(8). The comparison with these groups is somewhat limited by the marked
difference in age and diabetes duration.
The patient’s counterregulatory epinephrine response to hypoglycemia
was somewhat greater at baseline than in hypoglycemia aware, type 1
diabetic patients, but was in the lower range for normal subjects
(Table 1
). At baseline, the patient needed 2 µg isoproterenol to
increase heart rate by 25 beats/min, reflecting a reduced
ß-adrenergic sensitivity. After strict avoidance of hypoglycemia for
1 yr, the IC25 was 0.25 µg, reflecting an
improvement in ß-adrenergic sensitivity.
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Discussion
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Initially, this patient was characterized by hypoglycemia
unawareness despite a near-normal counterregulatory epinephrine
response to hypoglycemia. His hypoglycemia unawareness was thus largely
explained by the reduced ß-adrenergic sensitivity. Strict
avoidance of hypoglycemia for 1 yr improved ß-adrenergic sensitivity.
It is of note that the IC25 of 0.25 µg achieved
after 1 yr was very low, indicating supranormal ß-adrenergic
sensitivity. Taking into consideration that ß-adrenergic sensitivity
decreases with age and diabetes duration (10), this improvement is
remarkable. It is thus unlikely that the marked improvement in
IC25 occurred by chance, because the
isoproterenol test is highly reproducible (11). Furthermore, in both
isoproterenol tests we used a protocol with repeated injections of
increasing isoproterenol doses, showing a higher increment of heart
rate in the second test with the 0.25-µg dose but also with the 0.5-,
0.75-, 1.0-, and 1.5-µg doses. The improved ß-adrenergic
sensitivity after avoidance of low BG levels is in accordance with the
case report of a patient with insulinoma and reduced ß-adrenergic
sensitivity and counterregulatory hormone responses (12). Three weeks
after removal of the tumor, ß-adrenergic sensitivity was
unchanged, but it improved after 34 weeks.
Several aspects of this case are noteworthy. Firstly, the reversal of
hypoglycemia unawareness after long-standing diabetes is remarkable. In
patients with diabetes of short duration, there has been evidence that
avoidance of mild hypoglycemia successfully restores hypoglycemia
awareness (13), but doubt has been raised about whether this is true in
patients with longer diabetes duration. Furthermore, this improvement
of awareness has been reported to occur without restoration of normal
epinephrine responses (14). The observation of increased ß-adrenergic
sensitivity after avoidance of hypoglycemia in our patient could
explain this discrepancy.
Secondly, our patient’s epinephrine response to hypoglycemia seemed to
be near normal and in itself was unlikely to be the reason for his
hypoglycemia unawareness. This is especially remarkable in an older
patient with very long diabetes duration, because the epinephrine
response to hypoglycemia would have been expected to be decreased with
that age and long duration of diabetes (15). This underlines the
importance of reduced ß-adrenergic sensitivity for the development of
hypoglycemia unawareness (8).
Finally, the recovery of ß-adrenergic sensitivity to supranormal
levels is consistent with the recently postulated schema (8) for the
development of hypoglycemia unawareness in which an initially increased
ß-adrenergic sensitivity is viewed as a compensatory mechanism for
reduced epinephrine responses to maintain normal awareness of
hypoglycemia. Subsequently, with repeated episodes of hypoglycemia, it
was postulated that this compensatory mechanism may be lost (7). Our
demonstration that elimination of frequent hypoglycemic episodes
restores ß-adrenergic sensitivity thus supports this schema. Although
this implies a mild increase in HbA1c, the
risk-benefit ratio would justify such a measure in patients with
hypoglycemia unawareness.
Received June 8, 1999.
Revised October 18, 1999.
Accepted October 27, 1999.
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References
|
|---|
-
Mokan M, Mitrakou A, Veneman T, et al. 1994 Hypoglycemia unawareness in IDDM. Diabetes Care. 17:1397–1403.[Abstract]
-
Gerich J, Mokan M, Veneman T, Korytkowski M, Mitrakou
A. 1991 Hypoglycemia unawareness. Endocr Rev. 12:356–371.[Abstract]
-
Clarke W, Gonder-Frederick L, Richards F, Cryer P. 1991 Multifactorial origin of hypoglycemic symptom unawareness in IDDM:
association with defective glucose counterregulation and better
glycemic control. Diabetes. 40:680–685.[Abstract]
-
Cryer P. 1994 Hypoglycemia, the limiting factor of
in the management of IDDM. Diabetes. 43:1378–1389.[Abstract]
-
Amiel S. 1994 R. D. Lawrence Lecture. Limit
of normality: the mechanisms of hypoglycaemia unawareness. Diabetic
Med. 11:918–924.[Medline]
-
Berlin I, Grimaldi A, Payan C, et al. 1987 Hypoglycemic symptoms and decreased ß-adrenergic sensitivity in
insulin-dependent diabetic patients. Diabetes Care. 10:742–747.[Abstract]
-
Korytkowskii M, Mokan M, Veneman T, Mitrakou A, Cryer
P, Gerich JE. 1998 Reduced ß-adrenergic sensitivity in patients
with type 1 diabetes and hypoglycemia unawareness. Diabetes Care. 21:1939–1943.[Abstract]
-
Fritsche A, Stumvoll M, Grüb M, et al. 1998 Effect of hypoglycemia on ß-adrenergic sensitivity in normal and type
1 diabetic subjects. Diabetes Care. 21:1505–1510.[Abstract]
-
Hepburn D, Deary I, Frier B, Patrick A, Qunn J, Fisher
M. 1991 Symptoms of acute insulin-induced hypoglycemia in humans
with and without IDDM. Diabetes Care. 14:949–957.[Abstract]
-
Berlin I, Grimaldi A, Bosquet F, Puech A. 1986 Decreased ß-adrenergic sensitivity in insulin dependent diabetic
subjects. J Clin Endocrinol Metab. 63:262–265.[Abstract]
-
Arnold JMO, McDevitt DG. 1983 Standardised
isoprenaline sensitivity tests: comparison of existant methods. Br
J Clin Phamacol. 15:167–172.[Medline]
-
Vea H, Trovik TS, Sager G, et al. 1997 Return of
ß-adrenergic sensitivity in a patient with insulinomal after removal
of the tumor. Diabetic Med. 14:979–984.[Medline]
-
Fanelli C, Epifano L, Rambotti AM, et al. 1993 Meticulous prevention of hypoglycemia normalizes the glycemic
thresholds and magnitude of most neuroendocrine responses to, symptoms
of, and cognitive function during hypoglycemia in intensively treated
patients with short term IDDM. Diabetes. 42:1683–1689.[Abstract]
-
Dagogo-Jack S, Rattarasan C, Cryer PE. 1994 Reversal of hypoglycemia unawareness, but not defective glucose
counterregulation, in IDDM. Diabetes. 43:1426–1434.[Abstract]
-
Bolli G, De Feo P, Compagnucci P, et al. 1983 Abnormal glucose counterregualtion in insulin-dependent diabetes
mellitus. Interaction of anti-insulin antibodies and impaired glucagon
and epinephrine secretion. Diabetes. 32:134–141.[Abstract]
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Abstract
Introduction
