ARTICLE
Auteur(s) : Ettore
Capoluongo1, Dario Pitocco2, Concetta
Santonocito1, Paola Concolino1,3, Stefano
Angelo Santini1,3, Andrea Manto2, Paola
Lulli1, Giovanni Ghirlanda2, Cecilia
Zuppi1, Franco Ameglio1
1Laboratory of Molecular Biology, Institute of
Biochemistry & Clinical Biochemistry, Catholic University,
Rome, Italy. Tel.: (+00 39) 06-30154250
2Internal Medicine Institute - Catholic University,
Largo A. Gemelli 8, 00168 Rome, Italy
3Laboratorio Analisi biomediche - Casa Sollievo della
Sofferenza – I.R.C.C.S., San Giovanni Rotondo (Foggia, Italy)
accepté le 19 Juin 2006
Insulin-like growth factors (IGFs) represent one of the most
important molecular complexes (the IGF system) involved in the
regulation of cell proliferation, body and organ size, fetus
development, apoptosis induction, immune and autoimmune disease
responses [1, 2]. Two molecules (IGF-I and IGF-II with their two
receptors) and 6 binding proteins (IGFBP-1-6) comprise this system.
The binding proteins regulate the bioavailability of the IGF-I
molecules. In fact, the active form of IGF-I is the free form (free
IGF-I) [1, 3, 4]. IGF-I synthesis is mainly induced by growth
hormone (GH) in the liver, and its inhibition is mediated by GH
release [2]. However, several cells may produce IGF-I induced
through GH activity or other modulators, such as cytokines and
growth factors [5, 6].IGF-I has been largely studied in type 1
diabetes (T1DM) [7], since IGF-I exerts functions similar to those
of insulin, which is an IGF-I inducer. Some studies reported that
T1DM patients present lower serum IGF-I (both free and total)
levels [8, 9]. Interestingly, free IGF-I concentrations are reduced
in sera of various diseases with different pathogenic mechanisms,
including heart acute infarctions and stroke [10, 11], possibly by
modulation of suppressors of cytokine signalling (SOCS) genes [12],
as suggested by the inverse correlation between blood SOCS-1-3
products and levels of IGF-I [4, 12, 13].T1DM is a disease of young
individuals that, from its beginning or over time, is often
accompanied by autoimmune thyroiditis or gluten-sensitive
enteropathy (GSE, coeliac disease), two diseases that may also be
present concomitantly in the same patient [14]. Besides these two
diseases, other diabetic complications may be found in patients
with T1DM, such as retinopathy, nephropathy and neuropathy.Previous
studies have analyzed the possible involvement of IGF-I in the
induction of diabetic retinopathy, although with different
interpretations [15-17]. A recent report shows that (in a few
patients), the reduction in insulin levels or octreotide treatment
improves retinopathy in T1DM patients and this is accompanied by a
fall in serum IGF-I levels [15]. It is intriguing that T1DM
patients have low IGF-I serum levels, although the development of
retinopathy has been associated with higher IGF-I levels [16]. In
addition, reductions in IGF-I levels have been noted in serum
samples from subjects with chronic renal disease and diabetes
mellitus [18], while neurodegenerative diseases have been reported
as showing increased serum IGF-I levels [19].Few observations of
reduced serum IGF-I levels have been published regarding children
with GSE. In these subjects, a significant correlation between
serum IGF-I levels and disease evolution, evaluated by the
variations in bone alkaline phosphatase levels, was observed,
together with weight reduction, antibody positivity and
inflammation of small intestinal mucosa [20, 21]. A possible
explanation for a mechanism driving the changes in IGF-I levels is
malnutrition [22], known to modulate serum IGF-I values [2]. As far
as autoimmune thyroiditis is concerned, the mechanism of IGF-I
regulation may depend on the effect of T3 and T4 on IGF-I
production. In fact, serum free T3 and free T4 levels have been
reported to be correlated with free IGF-I levels, independently
from GH [19], and T4 administration is followed by an increase in
serum IGF-I [23].This report aims to study the behaviour of free
IGF-I and IGFBP-3 in sera of T1DM patients with or without
associated autoimmune (thyroiditis or coeliac) diseases and/or the
main complications of T1DM already mentioned.
Patients and methods
Patients
This study involved 201 consecutive, unrelated Caucasian subjects,
enrolled between January and September 2004, and belonging to
a medium social-economic status. The recruitment was carried out by
the Diabetes Care Unit of the Catholic University (where they
received regular health care), when presenting with a diagnosis of
T1DM according to American Diabetes Association (ADA) guidelines.
Enrolment inclusion criteria included: 1) Clinical and laboratory
diagnosis of T1DM (WHO and ADA guidelines); 2) all T1DM patients
diagnosed were aged under 35 and required permanent therapy in
order to optimize metabolic control. They were submitted, on a
regular basis, to three injections of insulin at meal times, and
one of neutral protamine insulin at bedtime. Exclusion criteria
were: 1) non-Caucasian patients; 2) C-peptide serum values over
cut-off.
The main characteristics of the subjects enrolled in this study
are reported in table 1( Table 1 ).
For each patient, HbA1c mean values of the previous year were
obtained by means of HPLC analysis performed on Diamat BioRad
(BioRad, Milan Italy). The HbA1c reference range for healthy
subjects with normal fasting blood glucose was 3.6-5.0% for
individuals < 50 years and 4.0-5.3% for patients > 50 years.
In addition, fasting C-peptide values were assayed by means of a
commercially available RIA kit (Double Antibody C-peptide kit
Behring, EURO/DPC, Gwynedd, UK, detection limit = 0.1 nmol/L). All
T1DM patients had fasting serum C-peptide values lower than 0.3
nmol/L, considered as the cut-off between negative and positive
subjects.
Three complications were considered: 1) Neuropathy: all patients
had a diagnosis of peripheral neuropathy with a Neuropathy
Disability Score greater than 5 and a pathological conduction
velocity. Autonomic neuropathy was diagnosed according to a
standardized procedure by Ewing and Clarke, including four
cardiovascular autonomic tests [24]; 2) Retinopathy was evaluated
following the EURODIAB IDDM complication study [25]. The diagnosis
evaluation was undertaken by a trained ophthalmologist of the
ophthalmology unit of our hospital; 3) Nephropathy was defined by
albumin excretion rate (AER) (normal AER < 30 mg/24 h;
micro-albuminuria 30-300 mg/24 h;
macro-albuminuria > 300 mg/24 h). In order to be
classified as normal, micro- or macro-albuminuria, AERs had to be
elevated on at least two occasions in the absence of a urinary
tract infection [26].
Body mass index was calculated as weight (kg)/height (expressed
as m2). Serum creatinine determination was performed
using the Jaffè method, suitable for the Olympus AU2700
instrumentation.
The diagnosis of thyroiditis was made following the criteria
defined by Glastras et al. [13]. All of these patients received T4
replacement (L-thyroxine, 1.8-2.0 mg/kg) and were euthyroid
(TSH ranged from 0.1 to 1 mU/L) at the enrolment.
The diagnosis of coeliac disease was arrived at by evaluation of
anti-transglutaminase and anti-endomisium antibodies, and confirmed
by histological analyses. For each subject, age, age-at-diagnosis
and disease duration were all tabulated. The information regarding
all enrolled patients was obtained by means of a questionnaire
filled in by all subjects.
According to WHO guidelines, at family history of T1DM was also
considered when a patient had at least one first-degree relative
affected with T1DM. The study was in agreement with the Helsinki’s
statement, and was approved by the Ethics Committee of our
hospital. All subjects provided informed consent.
Table 1 Characteristics of 201 T1DM patients
|
Variables
|
Overall patients
|
Males
|
Females
|
p
|
|
n = 201
|
n = 109
|
n = 92
|
|
Age
|
38.7 ± 10.8
|
38.7 ± 10.6
|
38.8 ± 11.0
|
0.96
|
|
Age at diagnosis
|
21.2 ± 10.1
|
21.6 ± 9.0
|
20.8 ± 11.2
|
0.59
|
|
Disease duration
|
17.5 ± 11.0
|
17.1 ± 10.2
|
17.9 ± 12.1
|
0.96
|
|
Daily insulin requirement (UI/kg per day)
|
0.60 ± 0.21
|
0.63 ± 0.22
|
0.57 ± 0.21
|
0.06
|
|
HbA1c (%)
|
7.37 ± 0.83
|
7.34 ± 0.85
|
7.41 ± 0.82
|
0.55
|
|
Body Mass Index (kg/m2)
|
24.7 ± 3.5
|
25.6 ± 2.9
|
23.5 ± 3.9
|
0.0002
|
|
Serum creatinine (mg/dL)
|
0.95 ± 0.40
|
1.00 ± 0.44
|
0.91 ± 0.34
|
0.13
|
Methods
Sample collection: in order to avoid changes to the free IGF-I
levels because of delayed time intervals between centrifugation and
freezing, blood samples were immediately centrifuged at 4°C and
sera were quickly stored at -80 °C until processed.
Free IGF-I assay: serum free IGF-I was measured in triplicate
using the IRMA method (Diagnostic Systems Laboratories, Inc. USA,
commercialized in Italy by Pantec S.r.l., Turin – Italy) [26]. CV
Intra-assay 6-8% on 10 repetitions, CV inter-assay 7-9% on 10
repetitions (two levels).
This assay determines the amount of free IGF-1, plus a component
of IGF-1 defined as “readily dissociable”. This component depends
on the concomitant presence of various IGF binding proteins.
IGFBP-3 assay: serum IGFBP-3 was measured in triplicate using
the IRMA method (Diagnostic Systems Laboratories, Inc. USA,
commercialized in Italy by Pantec Turin - Italy) [27]. CV
Intra-assay 4-6% on 10 repetitions, CV inter-assay 6-8% on 10
repetitions (two levels).
Statistical analysis
X2 (2x2 tables) or contingency tables (2x more than 2
tables) were used to analyze qualitative results. Students’ t test
(two groups) or ANOVA (more than two groups) were used to compare
quantitative data. The significance cut-off value was p = 0.05.
Yates’ correction or the two-sided Fisher exact test were performed
when necessary. Linear regression coefficient (R) was also used to
analyze correlations between variables.
Multivariate analysis: the effects on the relationship between
T1DM patient groups and free IGF-I or IGFBP-3 values were analyzed
in the multivariate logistic model using the “SPSS enter method”
and applying stepwise logistic regression (“SPSS backward and
forward LR method”, program for SPSS 12.0, Chicago, Illinois
(USA)). The following potential confounding factors were evaluated:
age, gender, HbA1c levels, body mass index, serum creatinine and
daily insulin requirement.
Results
Patients’ characteristics
No significant differences for age, age-at-diagnosis and disease
duration were found between the male and female T1DM patients
(table 1). As expected, age and disease duration were higher
in subjects presenting retinopathy, nephropathy and neuropathy.
Age-at diagnosis-was lower in patients with complications and in
coeliac patients; no difference was noted between the group with
thyroiditis as compared to other groups (table 2( Table 2 )).
Daily insulin requirement, blood Hb1Ac concentrations, and body
mass index and serum creatinine levels were also considered to
describe the patient group. Only body mass index presented
significant differences between genders.
Table 2 Means and SD for age, age-at-diagnosis and
disease duration in different groups of T1DM patients presenting or
not diabetic complications or autoimmune diseases
|
T1DM patients
|
N
|
Age (years)
|
Age at diagnosis (years)
|
Disease duration (years)
|
|
Complications
|
|
Mean ± SD
|
p
|
Mean ± SD
|
p
|
Mean ± SD
|
p
|
|
None
|
110
|
35.8 ± 10.0.
|
-
|
22.5 ± 9.7
|
-
|
13.2 ± 8.3
|
-
|
|
Retinopathy
|
59
|
45.0 ± 11.2
|
< 0.0001
|
18.4 ± 9.0
|
0.007
|
26.6 ± 10.3
|
< 0.0001
|
|
Neuropathy
|
34
|
48.9 ± 9.8
|
< 0.0001
|
18.2 ± 9.0
|
0.022
|
30.7 ± 8.1
|
< 0.0001
|
|
Nephropathy
|
20
|
48.6 ± 9.9
|
< 0.0001
|
18.6 ± 9.9
|
0.008
|
30.0 ± 8.8
|
< 0.0001
|
|
Thyroiditis
|
33
|
39.6 ± 9.6
|
0.06
|
24.1 ± 12.7
|
0.46
|
15.5 ± 11.1
|
0.21
|
|
Coeliac disease
|
14
|
36.7 ± 8.4
|
0.73
|
15.8 ± 8.9
|
0.015
|
20.9 ± 9.6
|
0.0017
|
Effect of gender and diabetic complications on free IGF-I and
IGFBP-3 levels
Significant differences of free IGF-I, IGFBP-3 levels
(table 3( Table 3 )) were observed
between males and females belonging to groups: 1) T1DM
without complications or associated autoimmune diseases
(T1DM-WCOAAD) and 2) T1DM + retinopathy. Males always presented
lower levels than females. The thyroiditis group was characterized
by significantly lower levels of IGFBP-3 in males, while free IGF-I
levels did not show statistical variations. The values observed for
IGFBP-3, both in males and females, were also significantly lower
than those calculated in the T1DM- WCOAAD groups (p = 0.024 and
p = 0.005, respectively).
Table 3 Means and SD of free IGF-I (ng/mL) and IGFBP3
(ng/mL) in different subgroups of T1DM patients presenting or not
diabetic complications or autoimmune diseases
|
Pts
|
No.
|
No.
|
Free IGF-I (ng/mL)
|
IGFBP-3 (ng/mL)
|
|
T1DM +
|
M
|
F
|
Males
|
Females
|
p =
|
Males
|
Females
|
p =
|
|
None
|
69
|
41
|
0.63 ± 0.57
|
1.05 ± 0.76
|
0.002
|
5221 ± 1239
|
5967 ± 1315
|
0.004
|
|
Retinopathy
|
25
|
34
|
0.34 ± 0.17
|
0.62 ± 0.45
|
0.004
|
4699 ± 1172
|
5525 ± 1085
|
0.007
|
|
Neuropathy
|
15
|
19
|
0.38 ± 0.16
|
0.52 ± 0.39
|
0.20
|
4775 ± 1216
|
5404 ± 1198
|
0.15
|
|
Nephropathy
|
10
|
10
|
0.37 ± 0.19
|
0.52 ± 0.43
|
0.66
|
4922 ± 1319
|
5575 ± 1258
|
0.28
|
|
Thyroiditis
|
9
|
24
|
0.51 ± 0.39
|
0.91 ± 0.86
|
0.19
|
4240 ± 826
|
5066 ± 995
|
0.03
|
|
GSE
|
6
|
8
|
0.35 ± 0.25
|
0.58 ± 0.28
|
0.14
|
4453 ± 921
|
5055 ± 1257
|
0.66
|
Stratification of patients for diabetic complications and
associated autoimmune diseases
In order to distinguish the effects of individual diseases on serum
free IGF-I and IGFBP-3 concentrations, the patients presenting
autoimmune diseases and/or diabetic complications were stratified
into subgroups (table 4( Table 4
)), excluding concomitant diseases.
Only two patients were concomitantly affected with thyroiditis
and gluten-sensitive enteropathy (GSE - coeliac disease). In
addition, all subjects presenting neuropathy or nephropathy were
also affected with retinopathy.
Table 4 Distribution of T1DM patients in function of
associated autoimmune diseases or diabetic complications
|
Number of T1DM patients (201)
|
T1DM + Associated autoimmune diseases (45)
|
|
T1DM + complications (59)
|
Associated diseases/complications
|
NO
|
Thyroiditis
|
GSE
|
Thyroiditis + GSE
|
Total
|
|
None
|
110
|
22
|
8
|
2
|
142
|
|
Retinopathy
|
17
|
6
|
2
|
0
|
25
|
|
Retinopathy + neuropathy
|
12
|
1
|
1
|
0
|
14
|
|
Retinopathy + neuropathy + nephropathy
|
17
|
2
|
1
|
0
|
20
|
|
Total
|
156
|
31
|
12
|
2
|
201
|
Serum levels of free IGF-I and IGFBP-3 in subjects with
thyroiditis or GSE
The comparison between the groups described in table 5( Table 5 ) shows that only IGFBP-3 was
significantly different between T1DM patient without associated
autoimmune disease and those with thyroiditis or GSE. In
particular, subjects with thyroiditis presented significantly lower
levels of this molecule (p = 0.02) as well as GSE patients
(p = 0.03) when compared to T1DM patients without diabetic
complications. Even if T1DM+GSE patients showed a mean free IGF-I
level lower than that of T1DM-WCOAAD patients, the comparison was
not significant (p = 0.096), possibly due to the small number of
these patients.
Table 5 Free IGF-I and IGFBP-3 values (median ± DS) in
patients with T1DM or T1DM plus autoimmune diseases (patients with
diabetic complications excluded)
|
Groups
|
Patient number
|
Free IGF-I (ng/mL)
|
IGFBP-3 (ng/mL)
|
|
T1DM
|
110
|
0.781 ± 0.674
|
5488 ± 1306
|
|
T1DM + thyroiditis
|
22
|
0.824 ± 0.854
|
4783 ± 753
|
|
T1DM + GSE
|
8
|
0.375 ± 0.219
|
4448 ± 873
|
|
T1DM + GSE + thyroiditis
|
2
|
0.600 ± 0.424
|
4697 ± 124
|
|
Total
|
142
|
P1 = 0.59
|
P1 = 0.02
|
|
-
|
-
|
-
|
P2 corrected = 0.038
|
Serum levels of free IGF-I and IGFBP-3 in subjects with
diabetic complications (retinopathy, neuropathy and
nephropathy)
Patients with T1DM complications, excluding associated autoimmune
diseases, characteristically presented significantly reduced serum
free IGF-I values, whereas IGFBP-3 remained statistically
unchanged. Interestingly, the free IGF-I concentrations decreased
progressively with the number of complications (table 6( Table 6 )).
Table 6 Free IGF-I and IGFBP3 values (median ± DS) in
patients with only T1DM or T1DM plus diabetic complications
(patients with autoimmune diseases excluded)
|
Groups
|
Patient number
|
Free IGF-I (ng/mL)
|
IGFBP-3 (ng/mL)
|
|
T1DM
|
110
|
0.781 ± 0.674
|
5488 ± 1308
|
|
T1DM + retinopathy
|
17
|
0.500 ± 0.310
|
5425 ± 992
|
|
T1DM + retinopathy + neuropathy
|
12
|
0.400 ± 0.230
|
4956 ± 1191
|
|
T1DM + retinopathy + neuropathy + nephropathy
|
17
|
0.365 ± 0.269
|
5128 ± 1431
|
|
Total
|
156
|
P1 = 0.008
|
P1 = 0.56
|
|
-
|
P2 corrected = 0.01
|
-
|
Comparison of serum values between associated autoimmune
diseases and diabetic complications
A comparison between the 32 patients with one or both associated
autoimmune diseases versus the 46 patients with diabetic
complications (table 7( Table 7 ))
showed that the differences between the values for all three
variables studied were statistically significant.
Table 7 Comparison of free IGF-I and IGFBP-3 values
between associated autoimmune diseases and diabetic complications
|
Groups
|
Patient number
|
Free IGF-I (ng/mL)
|
IGFBP-3 (ng/mL)
|
|
1) T1DM+ diabetic complications
|
46
|
0.424 ± 0.277
|
5193 ± 1209
|
|
2) T1DM + autoimmune disease
|
32
|
0.574 ± 0.379
|
4653 ± 747
|
|
3) T1DM + autoimmune disease + diabetic complications
|
13
|
0.608 ± 0.410
|
4823 ± 1429
|
|
p (1 versus 2) =
|
-
|
0.047
|
0.028
|
|
p (1 versus 3) =
|
-
|
0.064
|
0.35
|
Analysis of serum free IGF-I and IGFBP-3 for family history of
T1DM
Significant reductions in free IGF-I (p = 0.04) were observed when
T1DM-WCOAAD were subdivided on the basis of T1DM family history. In
fact, 12 individuals with a family history of T1DM presented lower
values (free IGF-I = 0.400 ± 0.431 ng/mL, IGFBP-3 = 5688 ± 1693
ng/mL) as compared to 98 subjects without a family history of T1DM
(0.828 ± 0.686, 5473 ± 1271, respectively).
Age-at-diagnosis was significantly lower in patients with a
family history of T1DM (15.5 +/- 8.0 versus 23.3 +/- 9.6 years for
those without a family history; p = 0.01).
Correlations
As reported in the literature, serum IGF-I and IGFBP3 presented
correlated values. This result is confirmed in this study
(R = 0.49, p < 0.001, in 201 subjects and R = 0.57, p < 0.001
in 110 subjects without associated autoimmune diseases or diabetic
complications) (( figure 1 )). The same
figure shows the correlations observed in T1DM subjects with
diabetic complications and with associated autoimmune diseases.
Comparisons of these plots show that the correlation is lost in the
associated autoimmune diseases group, while it is maintained in the
remaining ones, although with different slopes. Furthermore, a
significant negative correlation was also found between serum free
IGF-I and age (R = -0.24, p < 0.001) and disease duration
(R = -0.24, p < 0.001).
Data correction for age, sex, glycosylated haemoglobin, body
mass index, serum creatinine and daily insulin requirement
The data correction for all the above mentioned variables, by means
of multivariate logistic regression analysis, confirmed the results
just listed (p values are reported in tables 5 and 6),
indicating that IGFBP-3 and free IGF-1 are independent risk factors
for associated autoimmune diseases and for diabetic complications
respectively.
Discussion
The major amount of serum free IGF-I derives from liver stimulation
by GH, thus serum IGF-I determination represents a reliable marker
of GH function [2, 7]. In addition, free rather than total
circulating IGF-I determines the feedback on GH release in normal
subjects [3] and is capable of stimulating its cognate receptor
production. Serum concentrations of IGF-I decline as from age 25 to
65 years in both genders. Adult males aged under 65 years present
lower serum IGF-I values as opposed to females in the same age
group, whereas females over 65 year show lower serum concentrations
[2, 4, 10, 28] compared to males.
Many cells may synthesize and release IGF-I, which has several
functions both at the local and systemic levels [2]. Besides GH
induction, other independent enhancers of the IGF system have been
described, including oestrogens in the uterus, FSH in the ovary,
PTH in bone tissue and TGF-beta 1. Recently, other molecules have
been shown to be involved in the inhibition of the IGF-I system, in
particular those defined as suppressor of cytokine signalling1-3
(SOCS), as well as some inflammatory cytokines such as TNF-alpha
and IL-1 beta. The latter indirectly acts through the SOCS
molecules induction [4]. IGF-I induction by GH determines a
concomitant increase of IGFBP-3. However, other mechanisms of
regulation of this molecule are separately active, as well as the
p53 or TGFβ-1 induction [29, 30]. Moreover, TNF-alpha seems to
induce IGFBP-3 synthesis on foetal condrocytes [30], while IGFBP-3
from human adult condrocytes is reported to be enhanced by IL-1 and
TNF-alpha [31, 32].
FT4 and FT3 hormones are also known to directly correlate with
IGFBP-3 values, independently of GH [23]. Therefore, patients with
hyperthyroidism are expected to show higher serum values for
IGFBP-3 molecules [20, 23] and, consequently, our patients with
thyroiditis presented lower IGFBP-3 concentrations, even after T4
replacement. Finally, the relationship between IGF-I and IGFBP-3
values may be influenced by individual genetic characteristics,
high IGF-I intracellular consumption and activity of IGF-I
receptor.
Free IGF-I levels are generally decreased in several diseases,
including diabetes [33, 34], intestinal inflammation [35], heart
failure [10], ischemic stroke [10], stress and physical
overtraining [36]. In these conditions, serum IGFBP-3 values are
generally correlated with the free IGF-I levels [2, 28, 37].
Previous literature data reported IGF-I and IGFBP-3 levels in
some autoimmune diseases associated with T1DM (thyroiditis and
coeliac disease) [20, 21, 38-41] as well as in common diabetic
complications of T1DM [14, 16, 17, 42-44], such as retinopathy [17,
43, 45], neuropathy [26] and nephropathy [18]. Most of these
studies analyzed total IGF-I values more frequently than free
IGF-I, although only the latter is considered the really active
molecule [34]. A limit of the method used to evaluate the free
IGF-1 molecules is that this method also reveals a component of
readily dissociable IGF-1. The present study did not evaluate the
total serum IGF-1 levels, and therefore a comparison between the
concentrations of these two forms of IGF-1 cannot be done.
No studies have analyzed free IGF-I and IGFBP-3 values in T1DM
patients, when considering the concomitant pathologies and their
possible associations. In this study, a stratification of T1DM
subjects was performed, including autoimmune diseases and diabetic
complications. Interestingly, the results obtained showed that
serum IGFBP-3 values were significantly lower in coeliac disease
and thyroiditis patients than in T1DM-WCOAAD controls: a
significance that was confirmed after adjusting for age, sex,
glycosylated haemoglobin, body mass index, serum creatinine and
daily insulin requirement. A similar decline was not found for free
IGF-I. As a consequence, the correlation between the two molecules
in patients with associated autoimmune diseases was lost when
compared to the correlation observed in T1DM with diabetic
complications and that of patients without autoimmune diseases or
diabetic complications.
Despite the number of patients with diabetic complications being
not very high, the statistical analysis clearly showed that the
number of complications for each individual induces a progressively
decreasing value of free IGF-I. This finding suggests that free
IGF-I is a highly sensitive marker of cumulative T1DM
complications, independent of age, sex, glycosylated haemoglobin,
body mass index, serum creatinine and daily insulin
requirement.
A familial history of T1DM also seems to be more closely
associated with free IGF-I as opposed to IGFBP-3 values. This
finding, also observed for the first time in this study, might
suggest a worse clinical situation for familial T1DM, possibly
linked to a genetic basis [46, 47]. In fact, more gene activities
may be involved in the IGF-I modulation. The most interesting one
is represented by the SOCS genes, which might represent one of the
general pathophysiological mechanisms regulating IGF-I levels. In
particular, SOCS1-3 seems to be very important for the inhibitory
effects on IGF-I synthesis, since SOCS molecules are induced by
inflammatory cytokines such as those released in autoimmune
processes or diabetic complications [47]. Homozygosity for the
A-allele of the C-920 → A promoter polymorphism of the SOCS-3 gene
has been associated with increased, whole-body insulin sensitivity.
If confirmed, this association might be involved in the
relationships between a family history for T1DM and serum free
IGF-I levels [46, 47].
SOCS production is therefore a mechanism able to control the
GH-IGF axis, through a first molecular domain capable of inhibiting
different cell receptors of these molecules, as well as several
cytokines, and a second domain capable of enhancing IGF-I
degradation [12, 13].
In conclusion, even if the mechanisms driving the relationships
between IGF-I and IGFBP-3 are still to be clarified in different
diseases, this paper shows the different behaviours of these two
molecules in T1DM complications and T1DM-associated autoimmune
disease, underlining, at the same time, the effect of family
history in lowering the free IGF-I values.
A real effect of inflammatory processes, such as those active in
diabetic complications and associated autoimmune disease, may be
speculated, considering that the effective T4 replacement therapy
administered in patients affected with thyroiditis did not restored
the free IGF-1/IGFBP-3 correlation. At present, the recent
information available on the involvement of SOCS genes and cytokine
effects may fit with our findings.
Greater exploration of these fields is therefore necessary for a
better understanding the phenomena described in this report.
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