ABSTRACT
Aim: to identify the proportion of low adiponectin level and to evaluate the role of low adiponectin level, age, body mass index, and waist circumference on the occurrence of metabolic syndrome in women with insulin resistance.
Methods: the study was done by a cross-sectional survey on adult women aged 30 – 60 years. The study was conducted at Fatmawati Hospital - Jakarta from January to March 2008 with a total sample of 33. The sample was selected consecutively based on the presence of metabolic syndrome according to the IDF 2005 criteria. The examination of plasma adiponectin level was done by ELISA method. Insulin resistance was defined if HOMA IR
>2 (calculated by fasting insulin (μU/mL) x Fasting blood sugar (mmol/L) divided by 22.5). Association of low adiponectin level with insulin resistance was evaluated by calculating the Odds Ratio.
Results: seventeen of 33 subjects with metabolic syndrome have insulin resistance, in which 7 of them (41.18%) show low adiponectin level. While in 16 subjects without insulin resistance, only one subject (6.25%) has low adiponectin level. From 8 subjects with low adiponectin level, 7 of them (87.5%) have insulin resistance. In other words, low adiponectin level is associated with increased risk of insulin resistance (Odds Ratio 10.5, P=0.040 (CI 95% : 1.12-98.91).
Conclusion: low adiponectin concentration increases the risk of developing insulin resistance much more than normal adiponectin level.
Key words: metabolic syndrome, adiponectin, insulin resistance.
Adiponectin Levels and Its Role in Insulin Resistance Among Adult Women with Metabolic Syndrome
Nanang Soebijanto*, Sarwono Waspadji**
* Department of Internal Medicine, Fatmawati Hospital, Jl. RS Fatmawati, Jakarta 12430, Indonesia.
**Department of Internal Medicine, Faculty of Medicine, University of Indonesia - dr.Cipto Mangunkusumo Hospital, Jakarta, Indonesia.
Correspondence mail to: nsoebi@yahoo.com.
INTRODUCTION
Metabolic syndrome is defined by the National Cholesterol Education Program - Adult Treatment Program III (NCEP-ATP III) – 2001 as a cluster of lipid and metabolic abnormalities that increases the risk factor of coronary disease, consisting of central obesity, atherogenic dyslipidemia, hypertension and abnormalities of plasma glucose level.1-3 Obesity has reached epidemic globally, and all the evidence suggests that the situation seems to get worse. In developed countries the prevalence of obesity is high and is increasing but in some developing countries a more extreme situation exists.2
The metabolic syndrome is an abnormality with insulin resistance as a major characteristic. Insulin resistance is defined as a state that requires more insulin to obtain the biological effects as achieved by a lower amount of insulin in the normal state. Obesity is characterized by excessive body fat and has been known to be related with the occurrence of insulin resistance. Adipose tissue is an active endocrine and paracrine organ that releases a large number of cytokines and bioactive mediators that influence not only body weight homeostasis but also play the roles in inflammation, coagulation, fibrinolysis, insulin resistance, diabetes, atherosclerosis and some form of cancer.2-6 Adiponectin is a hormone produced exclusively by adipocyte besides many kinds of bioactive factors.
Adiponectin has a negative correlation with insulin resistance. Adiponectin plasma decreases in obesity, especially in visceral obesity, and in this condition the insulin resistance increases.4,7 Renaldi et al, in their study showed that hypoadiponectin and insulin resistance were risk factors for metabolic syndrome development.7
Relationship between adiponectin and insulin resistance is well known, but data in Indonesia are still very rare. The novelty of this study is to give additional information on association of adiponectin and insulin resistance in adult women with metabolic syndrome.
The purpose of the study was to find out the proportion of low adiponectin levels in adult women with metabolic syndrome and insulin resistance. In addition, the role of low adiponectin level, age, BMI and waist circumference on the occurrence of insulin resistance was also evaluated.
METHODS
The study was performed as a cross-sectional survey on adult women with the age of 30-60 years.
The sample is selected consecutively, using the IDF 2005 criteria of metabolic syndrome. Central obesity is defined from the measurement of waist circumfer- ence of women that is >80 cm and 2 of the 4 factors mentioned in IDF 2005 criteria (the trygliceride
>150mg/dL, HDL cholesterol in women <50mg/dL, the blood pressure >130/80 mmHg and the fasting blood sugar >150mg/dL). Laboratory examination was done at Prodia Clinical Laboratory in Fatmawati Hospital and in another Prodia Clinical Laboratory in Jakarta from January to March 2008 after subjects signed the informed consent. The protocol of the study had been approved by the Ethic Committee of Fatmawati Hospital.
Excluded from the study were women who suffer from acute infection (hsCRP >10mg/L) and those taking anti inflammation drug(s). Insulin resistance was defined by using HOMA IR formula that is fasting insulin (μU/mL) x Fasting blood sugar (mmol/L) divided by 22.5. Insulin resistance was determined when HOMA IR is >2.8-13 The examination of the adiponectin is done by using ELISA method. The normal value of adiponectin in woman according to Prodia Clinical Laboratory is 3.58 – 9.66 ug/mL.
Sample size was calculated by using single proportion formula (N = Zα2 PQ / d2) where P was taken 50% and precision was set at 20%, thereby 25 samples were needed. By estimating 20% of drop out, then 33 samples were recruited. For bivariate analysis, we used rule of thumb, in which 4 variables (adiponectin, BMI, age and waist circumference) would be evaluated. Odds ratio was calculated to estimate the risk of insulin resistance in low adiponectin level.
In addition correlation between HOMA IR and
adiponectin level was calculated by Spearman correlation. The data were analyzed by using STATA 9.2 software.
RESULTS
The characteristic of the study subjects can be seen in Table 1. Most of the subjects (78.7%) aged above 41 years.
Laboratory data of the study subjects can be seen in Table 2.
The proportion of insulin resistance and adiponectin concentration of study subject is as follows:
From Table 3, it can be seen that from the 33 samples, 51.52% is considered as insulin resistance.
Observed from the adiponectin concentration, 24.24%
of sample has low adiponectin value.
Table 1. Subjects’ characteristics
Variables N (%) Mean SD
Age (years) - 30 – 40 - 41 – 50 - 51 – 60
7 (21.2) 14 (42.4) 12 (36.3)
47.4 7.51
BMI 28.7 3.81
Height (cm) 155.3 4.99
BW (kg) 69.2 10.34
Waist circumference (cm) 92.8 9.83
Systolic BP (mmHg) 125.5 12.01
Diastolic BP (mmHg) 84.0 9.24
Tabel 2. Laboratory data of the study subjects
Variables Mean SD
Adiponectin (ug/mL) 4.9 2.11
Trygliceride (mg/dL) 199.9 100.46
HDL Chol (mg/dL) 44.9 6.48
Insulin (µU/mL) 9.9 5.77
Fasting B Sugar mol/L 4.9 0.68
HOMA IR 2.2 1.44
Table 3. Proportion of insulin resistance and adiponectin concentration of study subjects
Characteristics N Proportion
Insulin Resistance - Negative
- Positive 16
17
48.48 51.52 Adiponectin Concentration
- High - Normal - Low
1 24 8
3.03 72.73 24.24
From Table 4 it can be seen that from 17 samples with insulin resistance 41.18% had low adiponectin concentration and present mostly in the age of 41-50 years (41.17%). 7 of 8 subjects with low adiponectin level (87.5%) had insulin resistance. Bivariate analysis shows the significantly higher probability of the occurrence of insulin resistance in subjects with low adiponectin level (Odds Ratio of 10.5, CI 95% : 1.12- 98.91). Whereas age, BMI and waist circumference as confounding factors did not affect the occurrence of insulin resistance, as seen by the P value >0.05.
There is a correlation between HOMA IR and adiponectin level. (r = - 0.3483, R = 0.121 and P value
= 0.047).
DISCUSSION
In this study, from the 33 subjects who have metabolic syndrome, 17 subjects are indicated as insulin resistance and 16 people are without insulin resistance. It was found that not all people having metabolic syndrome indicated as having insulin resistance, although many studies mentioned that there
Figure 1. Correlation between HOMA IR and adiponectin concentration Table 4. Association between adiponectin level, age, BMI, waist circumference and insulin resistance
Insulin Resistance NEGATIVE
Insulin Resistance POSITIVE N Proportion N Proportion
OR CI 95% P
Adiponectin Level - Normal and High
- Low 15
1
93.75 6.25
10 7
58.82 41.18
1
10.5 1.12-98.91 0.040 Age (years)
- 30 – 40 - 41 – 50 - 51 – 60
3 7 6
18.75 43.75 37.50
4 7 6
23.53 41.17 35.29
1 0.75 0.75
0.12-4.66 0.11-4.89
0.758 0.764 BMI
- 23 - < 25 - 25 - < 30 - > 30
3 10
3
18.75 62.50 18.75
2 7 8
11.76 41.17 47.06
1 1.05
4
0.14-8.02 0.43-37.11
0.962 0.223 Waist circumf (cm)
- 80 – 95 - > 95 – 110 - > 110
13 2 1
81.25 12.50 6.25
10 5 2
58.82 29.41 11.76
1 3.25
2.6
0.52-20.37 0.21-32.90
0.208 0.461
is a close relationship between metabolic syndrome and insulin resistance.
Abdominal obesity is one of the criteria of metabolic syndrome that is not the manifestation of insulin resistance, but an anthropometric variable that has a strong association with insulin resistance compared with generalized obesity. European Group for the Study of Insulin Resistance (EGIR) concluded (on the basis of over 1100 direct measures of insulin–
mediated glucose disposal) that only about 25% of obese individuals could be classified as having insulin resistance. Not all overweight subjects are insulin resistance, nor all insulin resistance individuals are overweight.14
In this study, there were many subjects without insulin resistance which strengthen the assumption that the insulin resistance is not the main cause of metabolic syndrome. Some studies show that hyperleptinemia also plays the roles in metabolic syndrome. Moreover many factors such as subclinical inflammation, production of reactive oxygen species, decrease of the first phase insulin secretion, endothelial dysfunction and acetylation – stimulating protein (ASP) also play a role.15,16
Adipose tissue secretes a wide range of bioactive substances from fatty acids, lipoprotein lipase, steroid hormones, growth factors, angiotensinogen, acetylation stimulating proteins and prostaglandins, to a group of cytokines or cytokines-like molecules such as leptin, tumor necrosis factor-α (TNF-α), interleukin- 6 (IL-6), plasminogen activator inhibitor (PAI-1), adiponectin, resistin and peroxisome proliferator – activated receptor γ (PPAR-γ) regulated angiopoietin- related protein (PGAR).5,17 The bioactive substances modulate adipose tissue itself and other tissue functions in response to neural (sympathetic), hormonal and nutrient (mainly fatty acid) stimuli.5
Adiponectin is an adipokine that is specifically and abundantly expressed in adipose tissue. It has been shown to directly or indirectly affect insulin sensitivity through modulation of insulin signaling and the molecules involved in glucose and lipid metabolism.17-19 Plasma adiponectin level has been reported to be reduced in obese human, particularly those with visceral obesity and to correlate inversely with insulin resistance. Asdie et al. in their study to determine the relationship between serum adiponectin and glucose intolerance in obese people found that there was a significant correlation between low level of adiponectin with body mass index, fasting and 2 hours post prandial glucose, triglyceride, HDL cholesterol and
HOMA IR.7 Hypoadiponectin has also been demon- strated to be independently associated with the metabolic syndrome. Plasma adiponectin level is affected by multiple factors including gender, aging and lifestyle. Female humans have higher plasma adiponectin levels than males, suggesting that sexual hormones regulate the production of adiponectin, although it is controversial how these hormones are involved in the regulation of plasma adiponectin levels.20
In the study of Isobe et al, it was shown that adiponectin level increased linearly with aging in males, whereas it increased dramatically in females until their 50s.21 Therefore, it maybe the reason why not all women having metabolic syndrome and insulin resistance have low adiponectin concentration.
Our data on the adiponectin concentration in the group of insulin resistance, revealed that the proportion of low adiponectin concentration was 41.18% but in the group without insulin resistance was 6.25%. In this study various confounders that may influenced the insulin resistance such as age, BMI and waist circumference were also considered. However, Table 4 shows that these confounders do not statistically affect the presence or absence of insulin resistance. It is found that individual with low adiponectin concentration has the risk to have insulin resistance 10.5 times greater than individual who has normal or high adiponectin concentration. Furthermore, from this study we could learn that the probability for the occurrence of insulin resistance in adult women with metabolic syndrome and low adiponectin concentra- tion is 88%. Thus, low adiponectin concentration may be a predictor for the occurrence of insulin resistance.
Adiponectin has important clinical impact because the hypoadiponectinemia is not only related to the decreased of insulin sensitivity but also associated with less favorable plasma lipid profiles, increased levels of inflammatory markers and increased risk for the development of cardiovascular diseases.4
CONCLUSION
Insulin resistance in adult women with metabolic syndrome was found in 51.52% of the subjects. In the individual with insulin resistance, the proportion of low adiponectin level was 41.18%. The low adiponectin concentration tended to have the risk of insulin resistance 10.5 times greater than with normal adiponectin level. Adult women with metabolic syndrome and low adiponectin concentration had a 87.5% probability for the occurrence of insulin
resistance.
We suggest that a case control studies be conducted to determine the implications of metabolic syndrome in hypoadiponectin associated with insulin resistance and cardiovascular risk.
ACKNOWLEDGMENT
We are grateful to Prodia Clinical Laboratory for their participation testing in laboratory for all of the study subjects, and also to dr. Endang Pudjiningsih, M.Epid., dr. Sabarinah Prasetyo MSc, Anggi Nurjanah SKM, for statistical analysis and dr.Nafrialdi, PhD for his help in the manuscript writing.
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