Normal Adiponectin Level and Glycemic Control could Delay Subclinical Atherosclerotic Changes in Lean Type 1 Diabetic Children
Hoda A. Atwa,
Adiponectin is an anti-inflammatory, antiatherogenic and insulin sensitizing hormone. It inhibits neointimal media thickening and vascular smooth muscle cell proliferation. This study aimed to delineate the relation between glycemic control and adiponectin level and its impact on carotid Intima Media Thickness (cIMT) in lean newly diagnosed type 1 diabetic children. Forty six diabetic children their mean age was (11.59±3.64 years). The mean duration of diabetes (2.89±1.15 years), the mean BMI (20.86±3.94) the mean annual HbA1c (7.7±1.5). Forty six healthy control subjects matched in age, sex and BMI are enrolled in this cross-sectional study at Suez canal University Hospital pediatric outpatient clinic in Ismailia. All children had normal blood pressure for age and sex, normal lipid profile and normoalbuminuria. Adiponectin and HbA1c, were measured. Carotid intima media thickness was assessed. Adiponectin level was significantly lower in children with T1 DM (10.1±1.57 mg) than control (11.23±1.14 mg) (p = 0.02). Children with T1D had significantly higher cIMT (0.55±0.06 mm) than control (0.43±0.04 mm) (p = 0.00). Adiponectin level correlated negatively with cIMT (p = 0.01). Adiponectin level had no significant difference in children with good metabolic control (average annual HBA1C <7%) (11.51±0.45 mg) compared to control group (11.23±1.14 mg) (p = 0.15). Adiponectin was significantly higher (11.51±0.45 mg) and cIMT was significantly lower (0.45±0.03 mm) in children with good metabolic control than those with poor metabolic control (9.43±1.38 mg) (0.57±0.05 mm). From the results it can be concluded that glycemic control may have crucial impact to prevent atherosclerotic changes in type 1 diabetic children with short duration of diabetes. Diabetic children with good metabolic control and short duration of diabetes had no significant difference in adiponectin level than healthy children.
Received: June 25, 2011;
Accepted: September 08, 2011;
Published: October 03, 2011
Type 1 diabetes is a known risk factor for arterial atherosclerosis. Individuals
with type 1 diabetes have a two to four fold increase risk of developing atherosclerotic
diseases (Jarvisalo et al., 2001). Pathogenesis
of increased risk of premature heart disease in type 1 diabetes is enigmatic.
Atherosclerosis is regarded as an inflammatory disease. Many studies have established
adipose tissue as an endocrine organ capable of hormone and cytokine production
(Shuldiner et al., 2001). Adiponectin was discovered
in 1995. A large body of evidence indicates that adiponectin has potential antiatherogenic
and anti-inflammatory properties (Frayn et al.,
2003; Xu et al., 2003). Adiponectin mimics
3 major effects of insulin: First it promotes increased glucose uptake and oxidation,
second it reduces the expression of molecules involved in gluconeogenesis in
the liver and the third it increases fatty acid oxidation in muscles through
increasing molecules involved in fatty acid oxidation such as acyl coenzyme
A oxidase (Stern et al., 2007). The molecular
mechanisms of vascular protective effects include inhibition of tumor necrosis
factor α-stimulated adhesion of monocytes to endothelial cells. Adhesion
of monocytes to the vascular endothelium and the consequent transformation into
foam cells may be considered fundamental for the development of vascular diseases
(Luo et al., 2010). Adiponectin inhibits adhesion
of monocytes to endothelium and reduces the production of cytokines by macrophages
phagocytosis. The adiponectin level may be a useful marker of and potential
therapeutic target for coronary artery disease prevention (Costacou
et al., 2005). This study aimed to delineate the relation between
glycemic control and adiponectin level and its impact on carotid Intima Media
Thickness (cIMT) in lean type 1 diabetic children.
MATERIALS AND METHODS
This study was a case-control study. It was performed on 46 of children and
adolescents with type 1 diabetes mellitus attending the Pediatric Endocrinology
Clinic of Suez Canal University, Ismailia. The study was conducted during the
period from 1/4/2009 to 1/11/2009. Forty six healthy children age and sex matched
were included as control group. All children were normotensive, normoalbuminuric
and had no retinopathy. Those who receive regular medications that can affect
carotid intima-media thickness such as aspirin, cholesterol lowering drugs as
well as children with liver and renal diseases were excluded. Height, weight
and body mass index were measured according to the Egyptian growth curves. Pubertal
maturation was assessed (Marshall and Tanner, 1968).
Good glycemic control was defined as average annual HbA1C<7% and poor glycemic
control average HbA1C>9%.
Lipid profile: Venous blood samples were taken in the morning, after an
overnight fast (10-12 h). Serum total cholesterol and triglyceride concentrations
were measured using standard enzymatic methods (Kuksis and
Myher, 1984). Glycosylated hemoglobin (HbA1c) was determined by quantitative
colorimetric determination of glycoheamoglobin in whole blood (Gabbay
et al., 1977). Adiponectin was measured by Enzyme Linked Immunosorbent
Assay (ELISA). AviBion Human adiponectin enzyme-linked immunosorbent assay kits
were used for monitoring serum adiponectin level.
Carotid artery studies: Doppler ultrasound on carotid artery using a
Philips HD11, linear array probe 12 MHZ. The estimation of cIMT was done at
radiology department, Suez Canal University Hospital. The child was in supine
position. The same experienced doctor scanned all the children and he used the
same equipment. He was blinded to study subjects concerning their clinical and
laboratory characteristics. All studies were done following a predetermined,
standardized scanning protocol for the right and left carotid arteries, using
images of the far wall of the distal common carotid arteries and carotid bulbs
according to the Mannheim common carotid IMT consensus (Touboul
et al., 2007). Each CCA segment was measured. Four measurements of
the intima-media thickness were averaged, in order to give the mean common carotid
intima-media thickness for each side.
Ethical consideration: This study was performed with parental consent.
Data analysis: All the data were collected and were statistically analyzed using SPSS 14 program. Numerical data were expressed as Mean±SD. Non-numerical data were expressed as percentage. The mean was compared using the unpaired Students t test. The p-value <0.05 was considered statistically significant. Between-group comparisons were made using ANOVA to analyze differences between cases and controls. Pearson correlation was calculated to determine univariate relationships. Multiple regression analysis was performed to determine predictive variables for carotid IMT.
All subjects were matched for age, sex and BMI as shown in Table 1. Adiponectin level was significantly lower in children with diabetes (10.1±1.57 mg) than control group their annual HbA1c <7% (11.23±1.14 mg) (p>0.03). Diabetic children had significantly higher cIMT (0.56±0.06 mm) than control group (0.43±0.04 mg) (p<0.001) (Table 1).
Adiponectin level was significantly lower (8.9±0.9 mg) in children with
pubertal than those with prepubertal onset of diabetes (10.68±1.41 mg)
(p<0.0001). Carotid intima media thickness was significantly higher (0.59±0.03
mm) in children with pubertal onset of diabetes than those with prepubertal
onset of diabetes (0.53±0.07 mm) (p<0.003) (Table 1).
||Correlation between adiponectin and cIMT in children with
||Adiponectin level and cIMT in children with T1D and control
|Values are Mean±SD, n = 46
Adiponectin level is significantly lower in diabetic children with poor metabolic (9.43±1.38 mg) control than those with good metabolic control (11.51±0.45 mg) (p<0.004). Carotid intima media thickness is significantly higher in diabetic children with poor metabolic control (0.57±0.05 mm) than those with good metabolic control (0.45±0.03 mm) (p<0.01). Diabetic children with good metabolic control (their annual HbA1c <7%) had no significant difference in adiponectin level compared to control (11.51±0.45 mg) and (11.23±1.14 mg) (p<0.82) (Table 2).
Carotid intima media thickness correlated negatively with adiponectin (p<0.007) (Fig. 1) and age at onset of diabetes (r -0.74, p<0.001). It correlated positively with age (r 0.88, p<0.005), duration of diabetes (r 0.75, p<0.001) and HbA1c (r 0.81, p<0.002).
Multivariate regression model including cIMT as dependent variable and Adiponectin, age, age at onset, duration, BMI and HbA1c as independent variables adjusted for blood pressure, height and total cholesterol level, the most fitting factor that can predict cIMT was adiponectin (p<0.01), Duration of T1D (<p0.001) and BMI (p<0.0001). Multivariate regression were constructed to determine factors predict adiponectin levels as dependent variable and BMI, HbA1c and duration of diabetes as independent variables. HbA1c represent a strong and independent determinant of adiponectin level (p<0.0005), followed by duration of diabetes (p<0.01) and BMI (p<0.03).
The effect of increasing hyperglycemia on the risk of CVD mortality is more
profound in type 1 than in type 2 diabetic subjects (Juutilainen
et al., 2008). In experimental studies, adiponectin has been shown
to exert anti-inflammatory anti-atherosclerotic and insulin sensitizing effects
and to inhibit neointimal thickening and vascular smooth muscle cell proliferation
in mechanically injured arteries (Goldstein and Scalia,
2004). The thickness of cIMT is an excellent surrogate marker of cardiovascular
risk (Barchetta et al., 2009).
|| Adiponectin level and cIMT in children with good and poor
metabolic control children with T1D and control group
|Values are Mean±SD
The prevalence of subclinical atherosclerosis as estimated by cIMT is significantly
increased in T1D youth relative to controls (Nadeau and
An increase of 0.2 mm of cIMT was associated with a 28% increase in the likelihood
of incident stroke. The present study showed significantly increased cIMT in
diabetic children (0.56±0.06 mm) than the control group (0.43±0.04
mm) (p<0.001). Similar results were reported by others (Schwab
et al., 2007; Atwa et al., 2005; Abdelghaffar
et al., 2005; Jarvisalo et al., 2002;
Peppa-Patrikiou et al., 1998). These findings
extend to observations of postmortem studies that have indicated a relation
between early atherosclerotic vascular lesions and diabetic state (McGill
et al., 2000). The prevalence of subclinical atherosclerosis as estimated
by cIMT is significantly increased in T1D youth relative to controls (Krantz
et al., 2004; Jarvisalo et al., 2002).
However, other studies were unable to demonstrate increased carotid thickening
in children with a short and longer duration of diabetes (Gunczler
et al., 2002; Parikh et al., 2000).
Differences in methodology and study population may offer an explanation for
the discrepancy. Chronic state of hyperglycemia may induce atherogenesis by
increasing oxidative stress leading to increased LDL oxidation (Brownlee,
2001) and decreased nitric oxide bioavailability, inducing endothelial dysfunction
(Jarvisalo et al., 2004). The present study showed
positive statistically significant correlation between mean carotid intima media
thickness and both age of diabetic subjects (r = 0.88) (p<0.001) and age
at onset of diabetes (r = 0.71) (p<0.001). Carotid intima media thickness
was (0.534±0.072 mm) in prepubertal onset of diabetes versus (0.59±0.039
mm) in pubertal onset of diabetes with statistically significant difference
(p<0.001). Both Atwa et al. (2005) and Abdelghaffar
et al. (2005) reported statistically significant positive correlation
between mean cIMT and age of diabetic subjects. This suggests, not that the
early ages of onset are protective but rather that the clock does not run as
fast for the years before pubertal onset. Donaghue et
al. (2003) also reported that prepubertal duration of diabetes contributes
less than the pubertal duration to the risk of diabetic complications. The mechanism
behind this effect of age at onset is not clear but it has been speculated that
puberty, characterized by both rapid growth, hormonal changes and worsening
in glycemic control, may accelerate the processes leading to chronic diabetes
complications (Rudberg et al., 1992).
There was statistically significant positive correlation between mean cIMT
and duration of T1D of diabetic subjects (r = 0.75) (p<0.001). Rodriguez
et al. (2007), Atwa et al. (2005),
Abdelghaffar et al. (2005) and Jarvisalo
et al. (2002) also reported positive statistically significant correlation
between mean cIMT and duration of T1D of diabetic subjects. Prolonged exposure
to hyperglycemia is recognized as the primary casual factor in the pathogenesis
of diabetic complications (Laakso, 1999; The
Diabetes Control and Complications Trial Research Group, 1993). There was
statistically significant positive correlation between mean carotid intima media
thickness and HbA1c of diabetic subjects (r = 0.81) (p<0.001). Atwa
et al. (2005) and Abdelghaffar et al.
(2005) also reported statistically significant positive correlation between
mean carotid intima media thickness and HbA1c of diabetic children. This explains
the value of glycemic control in preventing or minimizing macro-vascular complications.
The study showed significant negative correlation between mean carotid intima
media thickness and serum adiponectin level of diabetic subjects (r = -0.74)
(p<0.002). Adiponectin infiltrates in the subendothelial space of injured
vascular walls and suppress the expression of adhesion molecules on endothelial
cells, thus inhibiting subinflammatory processes that occur during early phases
of atherosclerosis. It also inhibits the production and action of TNF α
and suppresses transformation of macrophages into foam cells that is the link
between vascular inflammation and atherosclerosis. The cellular antiatherosclerotic
effect of adiponectin is documented by its capacity to inhibit growth factors
in smooth vascular musculature and reduction of macrophage migration (Ekmekci
and Ekmekci, 2006). So, the ability of adiponectin to act as an antiinflammatory
and antiatherogenic factor has made this novel adipocytokine a promising therapeutic
tool for the future (Karboska et al., 2003).
Cardiovascular disease is the most frequent cause of death in T1D, with 10-fold
increased CVD-related and all-cause mortality compared with the general population
(Laing et al., 2003; Dorman
et al., 1984), despite modern advances in glycemic control and CVD
risk factor modification (Rewers, 2008; Soedamah-Muthu
et al., 2006). Other studies showed that adiponectin suppresses various
mechanisms contributing to atherogenesis (Ouchi et al.,
2001, 2003, 2004; Arita
et al., 2002) and present results are consistent with this background.
This may explain the negative correlation between mean carotid intima media
thickness and serum adiponectin level of diabetic children in our study. The
study showed that lean diabetic group had significantly lower serum adiponectin
level compared with control subjects. Adiponectin level in diabetic group was
(10.1±1.57) versus (11.23±1.14) in control group (p<0.001).
Studies in T1D in children are limited and the results were controversial. Celi
et al. (2006) found that circulating adiponectin concentrations
were higher in the prepubertal diabetic children compared with healthy children.
Morales et al. (2004) found that there was no
significant difference between adiponectin levels in T1D children compared with
control. It was (10.2 μg mL-1) in diabetic children versus (10.6
μg mL-1) in control. Martos-Moreno et
al. (2006) found that adiponectin levels in prepubertal children with
newly diagnosed T1D were similar at diagnosis to controls, after one month adiponectin
level increased and normalizing at the fourth month. Abu
El-Yazid et al. (2008) showed that serum adiponectin are lower in
diabetic patient compared to control group. This difference in adiponectin levels
in children with type 1 diabetes in various studies may be due to differences
in ethnic groups, methodology, population size, mean age of study population
and difference in diabetic control. The lower adiponectin level in the present
study may be explained by that all children were normoalbuminuric along with
ethnic variation. Adiponectin can be glycosylated and hydroxylated, consequently,
a modified adiponectin could lead to diminished negative feedback and thus to
increased adiponectin concentrations. In the present study there was statistically
significant negative correlation between adiponectin level and both age of onset
of diabetes of diabetic subjects (r = -0.78) (p<0.0001) and age of diabetic
subjects (r = -0.89) (p<0.002). Pozza et al. (2007)
findings is in agreement with our results, found that plasma adiponectin level
(mean 9.1±3.1 μg mL-1) was negatively correlated with
age of diabetic subjects (p<0.04). Present study showed statistically significant
negative correlation between adiponectin level and duration of T1D (r = -0.83)
(p<0.001). While Galler et al. (2007) found
that adiponectin level was not affected by duration of diabetes. Present study
showed significant negative correlation between adiponectin level and BMI of
diabetic subjects (r = -0.72) (p<0.004). Galler et
al. (2007) found that plasma adiponectin level was negatively correlated
with BMI. There was statistically significant negative correlation between adiponectin
level and HbA1c of diabetic subjects (r = -0.89) (p<0.001). In agreement
with our results, Celi et al. (2006) found that
circulating adiponectin concentrations were higher in the prepubertal diabetic
children and were positively associated with HbA1c. While, Galler
et al. (2007) failed to find significant difference of adiponectin
levels regarding gender, diabetes duration or HbA1c.
Glycemic control may have crucial impact to prevent atherosclerotic changes
in type 1 diabetic children with short duration of diabetes. Diabetic children
with good metabolic control and short duration of diabetes had no significant
difference in adiponectin level than healthy children.
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