ARTICLE
Auteur(s) : Tugba Rezan
EkmekciTugba Rezan
Ekmekci1, Sema Ucak2, Okcan
Basat2, Adem Koslu1, Yuksel
Altuntas2
1Department of Dermatology, Sisli Etfal Research and
Training Hospital, Istanbul, Turkey
2Division of Endocrinology Metabolism Diabetes,
Department of Internal Medicine, Sisli Etfal Research and Training
Hospital, Istanbul, Turkey
accepté le 8 Septembre 2006
Insulin resistance occurs when normal circulating concentrations of
insulin are insufficient to regulate normal physiological
responses. Insulin resistance affects 10% to 25% of the general
population [1]. It is generally accepted that the emergence of type
2 diabetes mellitus is preceded by stage of impaired glucose
tolerance (IGT) [2-5]. Type 2 diabetes mellitus ensues when the
beta cell is not able to secrete sufficient amounts of insulin to
offset the severity of insulin resistance. According to the
criteria established by the American Diabetes Association [6],
impaired glucose tolerance is defined by a 2-h plasma glucose
concentration between 7.8 and 11.1 mmol/l during an oral glucose
tolerance test (OGTT). Many studies have shown impaired glucose
tolerance in individuals who are resistant to the action of insulin
and that the progression from impaired glucose tolerance to type 2
diabetes mellitus is associated with a decline in beta cell
function, with a little additional worsening of peripheral insulin
resistance [5, 7-9].Simple methods, calculated from fasting
glucose, insulin and OGTT, are usually used to measure insulin
sensitivity because they are easy to perform, quick and
inexpensive. However none of these methods alone is ideal for
assessing the action of insulin.Androgenetic alopecia (AGA) is
caused by androgens in genetically susceptible women and men. The
inheritance pattern is polygenic. In susceptible hair follicles,
dihydrotestosterone binds to the androgen receptor, and the
hormone-receptor complex activates the genes responsible for the
gradual transformation of large terminal follicles to miniaturized
follicles [10]. Some authors prefer the term “female pattern hair
loss” because the role of androgens in women with hair loss is far
from clear-cut [11].It has been showed that early onset of
androgenetic alopecia in men represents a risk group for the
development of impaired glucose tolerance or diabetes mellitus type
2 [12, 13]. There are few studies showing the relation between
insulin resistance and women with AGA [14, 15].The aim of this
study was to identify the association of female AGA with insulin
resistance and to evaluate various simple insulin sensitivity
indices and beta cell function in women with AGA.
Materials and methods
Subjects
A cross-sectional study was performed in 66 non-obese (body mass
index [BMI] < 27 kg/m2) adults (24-44 years old), 41
with AGA (29 with Ludwig I, 12 with Ludwig II) and 25 healthy
individuals. The diagnosis of AGA was made by clinical findings,
including early age of onset, the pattern of increased hair
thinning over the frontal/parietal scalp with greater hair density
over the occipital scalp, retention of the frontal hairline, and
the presence of miniaturized hairs. Women with symptoms and signs
of androgen excess such as loss of the frontal hairline, menstrual
irregularities, history of infertility, hirsutism, severe
unresponsive cystic acne, virilization, or galactorrhea were
excluded.
None of those patients had diabetes mellitus or any functional
deficiency of thyroid, kidney and liver, nor received any drugs
that could affect hormonal and carbohydrate metabolism. Patients of
both groups were matched by sex, age, and BMI. Written informed
consent was obtained from all patients and the protocol was
approved by the hospital-based ethics committee.
BMI was calculated as weight (in kilograms) divided by the
square of height (in meters).
Methods
A diet of 300-gram carbohydrate for three days was given before
OGTT. An OGTT using 75 g glucose was performed in all groups after
an overnight fast at 08:00 h on day 2. The patients remained
supine during the test. An indwelling catheter was inserted in an
antecubital vein and samples were collected 30 minutes after and
just before the glucose ingestion (75 g glucose dissolved in
250 mL lemon-flavoured water was ingested in about 3 minutes)
and subsequently every hour for 2 hours. Blood glucose levels were
studied in whole blood by enzymatic colorimetric methods using
commercial devices (Roche Diagnostics, GmbH, Mannheim, Germany)
with an intra-assay coefficient variance of 6% and a inter-assay
coefficient variance of 8%. Plasma insulin levels were studied by
RIA with double antibodies (assayed in duplicate by solid phase RIA
(double antibody)) (DPC, Los Angeles, CA, USA) with an intra-assay
coefficient variance of 5.8% and a inter-assay coefficient variance
of 7.8%.
Serum C-peptide levels were measured by the chemiluminescence
method using commercial kits (DPC Immulite, Holliston, MA, USA)
with an intra-assay coefficient variance of 6.3% and a inter-assay
coefficient variance of 8.8%.
To estimate beta cell function and insulin sensitivity we used
HOMA beta cell index derived from either fasting or OGTT
(0,60,120 min), measurements of glucose and insulin (table 1)(
Table 1 ).
HOMA beta cell index was calculated from OGTT, based upon
glucose and insulin levels.
The insulin sensitivity indices such as Raynaud index, Belfiore
index, fasting insulin resistance index (FIRI), reciprocal fasting
insulin resistance index (FIRI–1), Quicky index, hepatic
insulin sensitivity (ISI HOMA), HOMA insulin resistance (HOMA-IR),
HOMA insulin sensitivity (HOMA-IS) and glucose/insulin ratio (GIR)
were estimated using a single fasting sample of glucose and insulin
levels (table 1).
The glucose/insulin ratio was obtained by dividing fasting
glucose (mg/dl) into fasting insulin (μU/mL) [23].
The cut-off point of fasting insulin level for insulin
resistance accepted as 13 μU/mL according to Ludvig et al.
[24].
The cut-off value for HOMA-IR accepted as 3.2 or greater,
according to Marques-Vidal et al [25].
Table 1 Formulas and references of indices of beta cell
function and insulin sensitivity derived from fasting and OGTT
measurements of glucose and insulin
|
Index
|
Formula
|
Ref.
|
|
Beta cell function indices
|
|
|
|
- HOMA beta cell index (mIU/mmol)
|
20 . insulin 0’/ (glucose 0’ – 3.5)
|
[16]
|
|
Insulin sensitivity indices
|
|
|
|
- Fasting insulin–1 (μU/ml)
|
1/insulin 0’
|
[17]
|
|
- glucose to insulin ratio (U. Mg)
|
Glucose 0’/insulin 0’
|
[18]
|
|
- Raynaud index (μUI–1.l)
|
40 / insulin 0’
|
[19]
|
|
- Belfiore index(pmol–1. l. Mmol–1.l)
|
2 / [(insulin 0’ . glucose 0’) + 1]
|
[20]
|
|
- Fasting insulin resistance index (FIRI) mmol. mUI. l . l
|
FIRI = (glu 0’. ins 0’) / 25
|
[21]
|
|
- Reciprocal fasting insulin resistance index (FIRI–1)
mmol–1. mUI–1. l . l
|
FIRI–1 = 1 / FIRI
|
[21]
|
|
- Quicky index (μU–1. mg–1)
|
1/log insulin 0’+ log glucose 0’
|
[22]
|
|
- Hepatic insulin sensitivity (ISI HOMA) (μU–1.
mg–1)
|
(22.5 .18)/fasting insulin . fasting glucose
|
[19]
|
|
- HOMA insulin resistance (HOMA-IR) (μU. mg)
|
(fasting insulin. fasting glucose) / 22.5
|
[20]
|
|
- HOMA insulin sensitivity (HOMA-IS) (%)
|
1/HOMA-IR
|
[20]
|
Statistical analysis
Data analysis was performed using the SPSS 11.0 (SPSS Inc, USA).
Parametric and non-parametric two samples Mann-Whitney U test were
used to determine the differences between the two groups. The
Spearman correlation test was used for correlation analysis. ANOVA
was used for multiple comparisons. Values were reported as the
mean ± SD; statistical significance was attributed to two-tailed
p < 0.05.
Results
OGTT
When OGTT results were evaluated, the AGA group had impaired
glucose tolerance rates of 12.5%. In the control group, impaired
glucose tolerance was 0%.
Fasting glucose, c-peptide, insulin were higher in the AGA group
than in controls.
Fasting insulin
When the cut-off value of 13 μU/mL for insulin resistance was
used, 20% of AGAs were more insulin resistant than the control
group (p < 0.003). It was statistically higher when compared to
healthy subjects (p = 0.001).
Evaluation of beta cell function indices
HOMA beta cell index: There was no statistically significant
difference between the two groups (p = 0.273) (table 2)( Table 2 ).
Table 2 Comparison of insulin sensitivity indices in
AGA group and healthy subjects
|
Variable
|
AGA group
|
Control group
|
Comparison of AGA and control group
|
|
No of participants
|
41
|
25
|
|
|
Age (Y)
|
34.30 ± 10.55
|
36.17 ± 6.76
|
Ns
|
|
BMI (kg/m2)
|
23.65 ± 2.92
|
24.42 ± 2.33
|
Ns
|
|
HOMA β-cell index (%)
|
5.8 ± 5.34
|
4.76 ± 2.02
|
0.273
|
|
Fasting insulin–1
|
0.14 ± 0.07
|
0.22 ± 0.08
|
0.001
|
|
Glucose insulin ratio (U/mg)
|
13.67 ± 8.03
|
18.65 ± 7.2
|
0.012
|
|
Raynaud index (μUI–1/L)
|
5.92 ± 3.1
|
8.83 ± 3.42
|
0.001
|
|
Belfiore index (pmol–1 . mmol–1 . l)
|
0.05 ± 0.31
|
0.01 ± 0.006
|
0.385
|
|
FIRI
|
35.06 ± 29.23
|
17.53 ± 6.84
|
0.001
|
|
FIRI–1 (mmol–1/mUI–1/L)
|
0.04 ± 0.02
|
0.06 ± 0.02
|
< 0.001
|
|
QUICKY index (μU–/mg–1)
|
0.35 ± 0.03
|
0.38 ± 0.02
|
< 0.001
|
|
ISI HOMA (μU–1/mg–1)
|
0.65 ± 0.35
|
1.06 ± 0.41
|
< 0.001
|
|
HOMA-IR (μU/mg)
|
2.16 ± 1.8
|
1.08 ± 0.42
|
0.001
|
|
HOMA-IS (mg/μU)
|
0.65 ± 0.35
|
1.06 ± 0,41
|
< 0.001
|
Evaluation of insulin sensitivity
Fasting insulin-1: AGA patients had lower levels than
the controls (p = 0.001) (table 2).
Glucose/insulin ratio: AGAs had lower levels than controls
(p = 0.012) (table 2).
Raynaud index
Raynaud index was higher in control subjects than AGAs (p = 0.001)
(table 2).
Belfiore index
There was no statistically significant difference in the two groups
(p = 0.385) (table 2).
Fasting insulin resistance index
The index was significantly higher in AGAs than in controls
(p = 0.001) (table 2).
Reciprocal fasting insulin resistance index
The index was significantly lower in AGAs than in controls
(p < 0.001) (table 2).
QUICKY index
AGAs had lower levels than controls (p < 0.001) (table 2).
Hepatic insulin sensitivity
AGAs had lower levels than controls (p < 0.001) (table 2).
HOMA insulin resistance
HOMA-IR was significantly higher in AGAs than in controls
(p = 0.001) (table 2). Patients were considered to be insulin
resistant on the basis of a HOMA-IR > 3.2 [26]. The patients
with HOMA-IR greater than 3.2 were 22.5% of AGAs and 0% of controls
and these results were statistically significant (p = 0.002).
HOMA-IR correlated positively with HOMA beta cell index (r = 078,
p < 0.001), and FIRI (r = 1, p < 0.001). It was correlated
negatively with fasting insulin–1 (r = – 0.7,
p < 0.001), GIR (r = – 0.63, p < 0.001), Raynaud (r=
–0.7, p < 0.001), Belfiore (r = – 0.73, p < 0.001),
FIRI–1 (r = – 0.73, p < 0.001), QUICKY
(r = – 0.85, p < 0.001) and ISI-HOMA (r = – 0.73,
p < 0.001).
HOMA insulin sensitivity
AGAs had lower levels than controls (p < 0.001).
Discussion
Insulin resistance occurs in association with many cardiovascular
and metabolic abnormalities (e.g., hypertension, dyslipidemia,
atherosclerotic cardiovascular disease, central obesity, impaired
glucose tolerance, microalbuminuria, and elevated plasminogen
activator inhibitor-1). This constellation of disorders has
collectively been referred to as the insulin resistance syndrome
[26, 27]. Because impaired insulin action is an underlying feature
of these commonly encountered clinical disorders, there has been
widespread interest in the development of techniques to assess
insulin sensitivity in humans in vivo [28].
In the present study fasting glucose levels, C-peptide, insulin,
Raynaud index, FIRI and HOMA-IR were significantly higher in AGAs
than in controls. In addition, AGAs had lower levels of GIR,
FIRI–1, QUICKY, ISI-HOMA, HOMA-IS than in controls.
All the indices except the HOMA beta cell index and the Belfiore
index showed the presence of insulin resistance in women with
AGA.
HOMA-IR correlated with all other insulin sensitivity indices.
Based on the cut-off value for HOMA-IR, patients with AGA were
insulin resistant.
Altuntas et al. [29] reported that HOMA-IR should be used as a
global insulin resistance test. The data from this study was
concordant with their results. We suggest that HOMA-IR is a good
predictor of insulin resistance in patients with AGA.
There is some evidence that androgen administration can induce
insulin resistance in both males and females [30]. There are
androgen-mediated receptor effects on the vascular endothelium and
other tissues and cells. Dihydrotestosterone may accelerate
atherosclerosis by stimulating the proliferation of vascular smooth
muscle cells. Individuals with atherosclerosis exhibit both
endothelial dysfunction and impaired insulin action. The peripheral
vascular endothelium at the arteriolar and capillary level plays
the primary role in the pathogenesis of insulin resistance, and the
endothelium is a target for insulin action [13].
Likewise, PCOS patients have increased testosterone or
androstenedione levels. Several studies have clearly shown that
PCOS patients have increased fasting insulin levels and increased
response to an oral glucose challenge test. This is not restricted
to obese patients but can also be found in non-obese patients
[30].
Matilainen et al. found that the insulin-resistance-associated
parameters, such as waist and neck circumferences, abdominal
obesity, fasting insulin or urinary albumin-creatinin ratio were
significantly higher in 97 women with extensive hair loss (Ludwig
II and III) compared to 221 ones with normal hair or only minimal
hair loss (Ludwig I) [14]. In another study, Hirsso et al.
determined that whilst waist circumference and waist-to-hip ratio
were significantly higher in 105 women with extensive hair loss
(Ludwig II and III) compared with 225 with normal hair or only
minimal hair loss (Ludwig I), the QUICKY index was significantly
lower [15]. Three limitations of the two studies are that women
with Ludwig I were accepted as part of the normal group, patients
with BMI > 27 were also included in these studies, and it was
not mentioned if there were women who had symptoms and signs of
androgen excess or not.
In women with AGA, a reduced level of sex-hormone binding
globulin compared to control values and significant elevations of
the androgen metabolites, have been found in studies. Not all women
with hair loss show biochemical evidence of hyperandrogenism [11].
In Vexiau’s study [31], 23% of women with alopecia alone and 16% of
women with both alopecia and hirsutism had normal hormonal
profiles. Futterweit et al. [32] determined that 67 out of 109
women with hair loss (61%) had normal androgen levels. Elevated
androgen levels were seen in 79% of women with hirsutism or
menstrual disturbance as well as hair loss, but in only 16% of
those with hair loss alone. Schmidt et al. [33] found no
significant elevations of circulating androgens in 46 women with
hair loss. Androgens play a role in female pattern hair loss but
androgen-independent mechanisms are also involved in some women
[11].
Although hormone profiles of the patients were not available,
patients who had hyperandrogenism symptoms were not included in
this study. When the available findings and debates are considered,
the cause of the association of insulin resistance with AGA may be
hyperandrogenism.
In conclusion, women with AGA alone are more insulin resistant
than healthy subjects. We suggest that beta cell function and
insulin sensitivity indices are useful methods for measuring
insulin resistance in AGAs and that HOMA-IR is a good predictor of
insulin resistance in patients with AGA. We propose that OGTT
should be used in AGA because of the increased rate of impaired
glucose tolerance.
Acknowledgements
Financial support: None. Conflict of interest: None.
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