Exenatide for Klinefelter syndrome
125
J. St. Marianna Univ.
Vol. 5, pp. 125–129, 2014
Case Report
Exenatide Combined with Metformin and Glimepiride Allows
Successful Weaning from Insulin in an Obese Diabetic Patient with
Klinefelter Syndrome
Yoshio Nagai, Yuta Nakamura, Atsushi Hiroishi, Yasuko Abe, Shiko Asai,
Hiroyuki Kato, Akio Ohta, and Yasushi Tanaka
(Received for Publication: July 14, 2014)
Abstract
Klinefelter syndrome is the most common numerical sex chromosome disorder. Affected males have an
additional X chromosome, resulting in a tall and slender build, hypogonadism, gynecomastia, small testes,
sparse body hair, diminished libido, and infertility. It has been reported that patients with Klinefelter syndrome
tend to develop diabetes mellitus. Here, we report a 59-year-old man who had Klinefelter syndrome and type
2 diabetes with a body mass index (BMI) of 36.0 kg/m2. Glycemic control was poor despite high-dose insulin
therapy (150 units daily). Administration of the GLP-1 analog exenatide together with metformin and
glimepiride improved his glycemic control, and allowed weaning from insulin. Interestingly, his weight decreased by 17.5 kg during hospitalization for 39 days, but the patient did not complain of hunger.
In conclusion, GLP-1 analog may be a therapeutic option for obese diabetic patients with Klinefelter
syndrome.
Key words
Klinefelter syndrome, Type 2 diabetes mellitus, obesity, insulin resistance, exenatide
fects to the incretin hormone glucagon-like peptide 1
(GLP-1). Its actions include glucose-dependent enhancement of insulin secretion, suppression of glucagon secretion, and slowing of gastric emptying. Exenatide also reduces food intake and causes weight
loss, thus having an insulin-sensitizing effect7).
Here we report on an obese diabetic patient with
Klinefelter syndrome, in whom administration of
exenatide combined with metformin and glimepiride
achieved successful weaning from high-dose insulin
therapy at 150 units / day.
Introduction
Abnormalities of the sex chromosomes can be
classified as numerical abnormalities or structural
defects. Klinefelter syndrome1) is the most common
numerical sex chromosome disorder with a frequency
of approximately 1/500 to 1/1000 male births2–4). Affected males have at least one additional X chromosome (47, XXY is the classic form), resulting in a tall
and slender build, hypogonadism, gynecomastia,
small testes, sparse body hair, diminished libido, and
infertility. Hormone replacement therapy with testosterone enanthate is performed to improve libido,
bone density, and quality of life5). It has been reported that patients with Klinefelter syndrome tend to
develop diabetes mellitus6).
Exenatide (exendin-4) is a 39 amino acid incretin analog that exhibits similar glucoregulatory ef-
Case Report
In September 2012, a 59-year-old man was admitted to our hospital for the management of acute
pyelonephritis and poor glycemic control. He had a
history of type 2 diabetes that had been diagnosed
more than 32 years earlier, and was on insulin thera-
Division of Metabolism and Endocrinology, St. Marianna University School of Medicine
89
Nagai Y Nakamura Y et al
126
py. Despite a high daily insulin dose of 150 units,
blood glucose was poorly controlled, and the patient
had a neurogenic bladder with recurrent urinary tract
infections. He showed mental impairment, but his
behavior was gentle. He was 175 cm tall and weighed
114 kg (his body mass index (BMI) was 36.0 kg/m2).
His temperature was 38.5°C, blood pressure was
113/83 mmHg (on losartan at 50 mg/day), and pulse
rate was 68/min. Neither rales nor heart murmurs
were audible. Ankle jerk reflexes and vibration sensations in his feet were decreased due to diabetic
neuropathy. Examination of the ocular fundus
showed stage A3p diabetic retinopathy according to
the modified Fukuda’s classification. His sense of
smell was normal. Gynecomastia was evident. His
penis was the size of a thumb, and each testis was the
size of the tip of the little finger. Pubic hair was very
sparse. There was no relevant family history. Laboratory data obtained on admission are shown in Table
1. Biochemistry tests revealed normal liver and renal
function, as well as a normal lipid profile. Fasting
plasma glucose was 335 mg/dl and hemoglobin A1c
(HbA1c) was 9.1%. Fasting serum C-peptide reactivity (CPR) and urine CPR were 0.9 ng/ml and 36.7 µg/
day, respectively, which were moderately low. Serological tests showed slight elevation of C-reactive
protein (CRP), while antiglutamic acid decarboxylase (GAD) antibody and IA-2 antibody were negative. Other test results were almost all within the
normal range. Urinalysis showed moderate proteinuria, and the sediment contained 10–19 red cells and
20–29 white cells per high-power field. Chromosomal analysis revealed that his karyotype was 47,
XXY (Fig. 1). Deletion of chromosome 15q11-q13
was not detected by fluorescence in situ hybridization
(FISH) analysis. Hormonal studies showed that both
LH and FSH were elevated, while the levels of total
and free testosterone were very low (Table 2). These
findings were consistent with hypergonadotropic hy-
Table 1. Laboratory Findings on Admission
Urinalysis
Glucose
Protein
Ketone bodies
WBC
Occult blood
Urine CPR
Complete blood count
RBC
Hb
Ht
WBC
Platelets
Biochemistry tests
Total protein
Albumin
AST
ALT
ALP
LDH
γGTP
CPK
BUN
Creatinine
Uric acid
T-chol
Triglycerides
HDL-C
Na
K
Cl
Ca
P
CRP
FPG
HbA1c
Other tests
Ccr 24h
Karyotype
(2+)
(+)
0.4
(-)
(2+)
20-29
(2+)
10-19
36.7
6
369㽙10
12.7
37.7
6600
3
9.3×10
7.3
3.7
16
16
203
157
34
90
11.7
0.8
5.9
148
83
41
131
4.2
91
9.0
2.4
3.76
335
9.1
74.3
47, XXY
g/day
/HPF
/HPF
μg/day
/μl
g/dl
%
/μl
/μl
g/dl
g/dl
IU/l
IU/l
IU/l
IU/l
IU/l
IU/l
mg/dl
mg/dl
mg/dl
mg/dl
mg/dl
mg/dl
mEq/l
mEq/l
mEq/l
mg/dl
mg/dl
mg/dl
mg/dl
%
Table 2. Results of Endocrine Studies
LH
FSH
ACTH
PRL
GH
TSH
Free T3
Free T4
Serum cortisol
Serum total testosterone
Serum free testosterone
Serum DHEA-S
ml/min
90
19.4
21.2
37.2
28.9
0.03
1.3
2.6
1.2
11.9
0.42
<0.4
126
mIU/ml
mIU/ml
pg/ml
ng/ml
ng/ml
μU/ml
pg/ml
ng/dl
μg/dl
ng/ml
pg/ml
μg/dl
Exenatide for Klinefelter syndrome
127
Fig. 1. Karyotype of the patient shows the 47, XXY pattern.
decreased after starting this regimen, and the insulin
dose also gradually declined from 150 units. Eventually, insulin was stopped on the 37th day. Klinefelter
syndrome was diagnosed from the chromosomal and
hormonal findings, although his physical characteristics (e.g. gross obesity) did not fit the classical phenotype of the syndrome. Because he had hypogonadism, 125 mg of testosterone enanthate was injected
intramuscularly every 2 weeks (on the 14th and 28th
days of the month). At discharge, total %FAT was
unchanged (39.8%), even though his weight had decreased by 17.5 kg.
pogonadism, suggesting the presence of primary hypogonadism. The chest radiograph and electrocardiogram were normal. The percentage of body fat
(%FAT) and the bone mineral density (BMD) were
evaluated by dual energy X-ray absorptiometry
(DEXA). On admission, the total %FAT was 40%
and the BMD was normal at 1.086 g/cm2 (92% of the
young adult mean).
Clinical course (Fig. 2)
After admission, antibiotic therapy was started
with intravenous infusion of tazobactam sodium/
piperacillin sodium (TAZ/PIPC) at 9.0 g daily for the
first 10 days, followed by oral trimethoprim-sulfamethoxazole (4.0 g/day) for 2 weeks. The patient’s
fever and CRP level improved after 7 days. Before
admission, he injected 30 units of insulin glulisine
before each meal and 30 units of insulin glargine
before breakfast and dinner (a total of 150 units/day).
In order to decrease his insulin requirement, after
initiating diet therapy at 1,800 kcal (26.7 kcal/ideal
body weight), we started to administer 5 µg of exenatide twice daily, which was increased to 10 µg twice
daily after 2 weeks. He also commenced treatment
with metformin (750 mg/day) 10 days after admission, and glimepiride (0.5 mg/day) was added on the
33rd hospital day. His blood glucose level gradually
Discussion
One characteristic of our patient was gross obesity, although patients with Klinefelter syndrome are
typically tall and slender. One of the most common
genetic causes of obesity is Prader-Willi syndrome
(PWS), which is characterized by hypogonadism,
mental retardation, and hyperphagia. The deletion
responsible for PWS has been localized to 15q11q13, but FISH did not detect this deletion of chromosome 15 in our patient. Instead, he had Klinefelter
syndrome with the 47, XXY karyotype, as shown in
Fig. 1. Some patients with Klinefelter syndrome exhibit all of the typical signs of this disorder, whereas
others lack many of its features, because of the wide
91
Nagai Y Nakamura Y et al
Insulin(U)
Exenatide (μg)
Metformin(mg)
128
2500
2000
1500
1000
500
0
20
10
0
150
100
50
0
500
BG 8:00
BG 12:00
Blood glucose (mg/dl)
Testosterone enanthate (125 mg)
↓
400
↓
BG 18:00
BG 21:00
300
200
100
weight: 96.6 kg
body fat: 39.8%
weight: 114.0 kg
body fat:
40.0%
0
0
5
10
15
20
25
30
35
40
Days after admission
Fig. 2. Clinical course of the patient after admission.
variability in phenotypic expression8). Ota reported
that 24% of Japanese Klinefelter syndrome patients
with diabetes had a BMI of more than 25.09). The
weight gain in our patient may have been caused by
overeating due to being overfed by his 90-year-old
mother and by low energy expenditure because of his
bedridden lifestyle.
There was a marked improvement in his weight
coupled with reduced food consumption over a 39day period of hospitalization. During the hospital
stay, he never complained of hunger, probably due to
the effects of exenatide. Interestingly, he never had a
positive urine test for ketone bodies, which are produced from excess acetyl-CoA derived from the
β-oxidation of fatty acids. These findings suggest that
exenatide is well tolerated and is effective for increasing satiety and improving glycemic control in
obese diabetic patients with Klinefelter syndrome.
Treating hypogonadism with testosterone may
also have influenced glycemic control. We have previously reported that the serum testosterone level is
negatively associated with metabolic syndrome,
which features visceral obesity, insulin resistance,
hypertension, glucose intolerance, and dyslipidemia10). Testosterone treatment of middle-aged men
with abdominal obesity decreases intra-abdominal fat
and increases insulin sensitivity11). In addition, Bojesen et al. reported a reduction of both truncal fat and
fasting plasma glucose by testosterone treatment
compared to these parameters without treatment in a
study of 70 Klinefelter syndrome patients12). However, testosterone did not alter the body composition
of our patient (at least, not after one month), suggesting that hormone replacement was not the main reason for his reduced insulin requirement. Longer follow-up will be needed to determine whether
testosterone replacement therapy has a beneficial effect on body composition and glycemic control in
this patient.
It was recently reported that obesity and diabetes
could be successfully treated by using exenatide in
patients with PWS13)14). A single dose of exenatide
increases satiety separately from appetite hormones,
and exerts glucose-lowering and insulinotropic effects on PWS15). A similar mechanism might explain
the association between exenatide treatment and in92
Exenatide for Klinefelter syndrome
creased satiety in our case, but this remains speculative because we did not measure ghrelin or other
appetite hormones. Delayed gastric emptying could
also possibly have made a contribution. Nevertheless,
it is noteworthy that our patient required no insulin
for glycemic control following the administration of
exenatide.
In conclusion, GLP-1 analog may be a therapeutic option for obese diabetic patients with Klinefelter
syndrome due to appetite suppression and weight
reduction that decrease insulin resistance and improve overall glycemic control.
7)
8)
9)
Disclosure
10)
None of the authors have any potential conflicts
of interest associated with this research.
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