diabetes research and clinical practice 104 (2014) 171–175
Contents available at ScienceDirect
Diabetes Research and Clinical Practice journ al h ome pa ge : www .elsevier.co m/lo cate/diabres
Maternal serum and fetal cord blood irisin levels in gestational diabetes mellitus Mehmet Aytac Yuksel a,*, Mahmut Oncul a, Abdullah Tuten a, Metehan Imamoglu a, Abdullah Serdar Acikgoz a, Mine Kucur b, Riza Madazli a a b
Department of Obstetrics and Gynecology, Cerrahpasa School of Medicine, Istanbul University, Istanbul, Turkey Department of Biochemistry, Cerrahpasa School of Medicine, Istanbul University, Istanbul, Turkey
article info
abstract
Article history:
Aim: To investigate the relationship between maternal and cord blood irisin in gestational
Received 28 August 2013
diabetes mellitus (GDM).
Received in revised form
Methods: Twenty women with GDM and 20 pregnant women with uncomplicated pregnancies
10 November 2013
were recruited for this case–control study. Maternal serum irisin and cord blood irisin levels
Accepted 21 December 2013
were measured by enzyme-linked immunosorbent assay kit at the time of birth. The associa-
Available online 3 January 2014
tion of maternal serum and cord blood irisin levels with metabolic parameters was analyzed. Results: Women with GDM had significantly lower mean serum irisin levels compared to
Keywords:
control group (258.3 127.9 vs. 393 178.9 ng/ml, p < 0.05). Mean cord blood irisin levels for
Gestational diabetes mellitus
GDM and control groups were not significantly different (357.2 248.0 vs. 333.2 173.4 ng/
Irisin
ml, p > 0.05). No significant differences were found in terms of maternal age, gestational
Cord blood
week at birth, BMI at birth, birth weight, neonatal height, systolic and diastolic blood
Maternal
pressure between the groups as well (p > 0.05). Serum irisin level was negatively correlated with BMI at birth and HOMA-IR (r =
0.401, p = 0.010; r =
0.395, p = 0.012, respectively). No
correlations between irisin levels and others parameters were found in both groups. Conclusions: Maternal serum irisin levels of patients with GDM are significantly lower compared with non-GDM controls. However, no significant difference was found between cord blood irisin levels of patients with GDM and healthy pregnant women. # 2014 Elsevier Ireland Ltd. All rights reserved.
1.
Introduction
GDM (gestational diabetes mellitus) has been defined as any degree of glucose intolerance with onset or first recognition during pregnancy [1]. GDM, which affects 16–20% of all pregnancies has serious adverse perinatal outcomes and increases long-term risk for the development of obesity, type 2 diabetes and cardiovascular disease in both the mother and
the offspring [2]. Insulin resistance plays an important role in the pathogenesis of GDM and despite extensive research, the mechanisms underlying insulin resistance are not fully understood [2]. Since it is the largest organ in the body, skeletal muscle accounts for the majority of glucose uptake in response to insulin, and is quantitatively the most important site of insulin resistance. During the past decade, skeletal muscle has also been identified as a secretory organ and cytokines and
* Corresponding author at: Department of Obstetrics and Gynecology, Cerrahpasa School of Medicine, Istanbul University, Fatih, Istanbul 34098, Turkey. Tel.: +90 532 601 60 58; fax: +90 2124143000. E-mail address: [email protected] (M.A. Yuksel). 0168-8227/$ – see front matter # 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.diabres.2013.12.025
172
diabetes research and clinical practice 104 (2014) 171–175
other peptides produced and secreted by myocytes are classified as myokines [3]. These myokines function as endocrine hormones and regulate the function of various distant organs. Irisin has recently been identified as an exercise-induced hormone secreted by skeletal muscle and has been proposed to mediate the beneficial effects of exercise on metabolism [4]. Sedentary lifestyle is a major risk factor for type 2 diabetes mellitus. Randomized controlled trials have demonstrated that physical activity improves glucose tolerance and reduces the risk of type 2 diabetes mellitus [5]. Therefore, it has been speculated that physical exercise may exert its beneficial effects on energy metabolism through secreted factors from myocytes such as irisin [3]. Recent studies have shown that circulating irisin levels were significantly lower in patients with type 2 diabetes compared to people without diabetes [6,7]. Liu and co-workers demonstrated that irisin might be positively correlated with most of the well-known markers of insulin resistance in people without diabetes [6]. These data show that either the diabetes itself or the metabolic condition that caused progression to type 2 diabetes is accompanied by lower circulating irisin levels in circulation. To date, there are a paucity of data on irisin and human pregnancy. In the current study, our aim was to investigate maternal and cord serum irisin levels in women with GDM and women with uncomplicated pregnancies.
2.
Material and methods
The Ethics Committee of our university approved the study protocol (dated February 29, 2013, issue no. 83045809/3709) and all patients were carefully instructed and signed informed consent before recruitment. 20 pregnant women with GDM and 20 controls with uncomplicated pregnancies were recruited for the study. All recruited patients were selected randomly from women admitted to the antenatal clinic of our obstetrics department and had a history of prior cesarean section deliveries and were planned to deliver with cesarean section. This criterion was established to exclude any possible effects of labor on the parameters that evaluated in maternal blood, described below. Exclusion criteria were as follows: chronic hypertension, preeclampsia, diabetes mellitus, polyhydramnios, presence of any acute or chronic disease, fetal anomalies, prior renal disease, liver disease, multiple gestation, history of smoking and chronic alcohol consumption. All women were screened for GDM with 50 g glucose challenge test (GCT) at 24th gestational week. The 50-g GCT was carried out independent of the time of day or any previous meal at about 24 weeks gestation. An oral glucose tolerance test was recommended to all patients with a 1-h test result 140 mg/dl (7.8 mmol/l). Diagnosis of GDM was established according to results of 100-gram oral glucose tolerance test (OGTT). Patients with at least two abnormal values above the cutoff values were determined to be having an abnormal OGTT result: Fasting 95 mg/dl (5.3 mmol/l); 1 h, 180 mg/dl (10.0 mmol/l); 2 h, 155 mg/dl (8.6 mmol/l); 3 h, 140 mg/dl (7.8 mmol/l) [8]. Control subjects had normal responses to GCT. 20 patients with GDM received various treatment (diet therapy, self-monitoring of blood glucose or insulin therapy)
in order to maintain control of blood glucose levels (venous plasma glucose values were targeted to be 105 mg/dl [5.8 mmol/l] or lower before meals and 120 mg/dl [6.7 mmol/l] or lower 2 h after meals). Insulin therapy was administered if blood glucose levels remained above target levels despite strict diet therapy. Venous blood samples were collected in the fasting state before delivery. None of the patients were in labor at the time of sampling. Umbilical cord blood samples were also collected immediately after delivery. Blood samples were collected in tubes and were immediately centrifuged after clotting. The supernatant serum was kept frozen at 80 8C until assay. Serum irisin levels were measured using enzyme immunoassay (EIA). (Catalog # EK-067-16; Phoenix Pharmaceuticals, Belmont, CA, USA). The lowest detectable concentration of irisin was 6.8 ng/ml, with intra- and interassay coefficients of variation were 0.05). Mean maternal serum HOMA-IR, fasting glucose and insulin levels of women with GDM at the time of delivery were significantly higher than the control group (Table 2). Mean maternal serum irisin level of women with GDM was significantly lower than the control group (258.3 127.9 vs. 393 178.9 ng/ml, p: 0.009) (Table 2 and Fig. 1). Irisin levels in cord blood were not statistically different among groups (357.2 248.0 vs. 333.2 173.4 ng/ml, p: 0.735) (Table 2). Among women with GDM, 8 had insulin therapy and 12 were treated with diet alone. Clinical and biochemical characteristics of GDM patients treated with insulin and managed by diet are shown in Table 3. Mean maternal serum
diabetes research and clinical practice 104 (2014) 171–175
173
Table 1 – The clinical characteristics of women diagnosed with gestational diabetes and normal controls.
Age (year) Gestational age at birth (week) Maternal weight (kg) Maternal height (cm) BMI at birth (kg/m2) Birth weight (g) Neonatal height (cm) SBP (mmHg) DBP (mmHg)
GDM (n: 20)
Control (n: 20)
p value
34.8 4.11 37.4 2.7 82.6 11.0 163 6.3 31.4 5.3 3261 755 49.5 4.1 119 16.0 73.5 8.7
33.0 5.35 38.0 1.1 76.4 11.1 164.1 7.8 28.5 4.4 3366 436 50.2 1.6 109.5 10.9 69.0 7.8
0.242 0.862 0.091 0.758 0.174 0.883 0.758 0.060 0.157
Data are presented as mean standard error of mean (SEM). BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure. Statistically significant: p < 0.05.
Table 2 – Biochemical characteristics women diagnosed with gestational diabetes and normal controls.
Fasting glucose (mg/dl) HOMA-IR HbA1c (%) Insulin (mU/l) Serum irisin (ng/ml) Cord irisin (ng/ml) Cord glucose (mg/dl)
GDM (n: 20)
Control (n: 20)
p value
90.9 21.1 2.63 1.0 5.7 1.9 12.4 5.1 258.3 127.9 357.2 248.0 70.7 8.6
74.5 12.9 1.44 0.53 5.11 0.36 8.19 2.0 393 178.9 333.2 173.4 67.3 9.8
0.012 0.000 0.367 0.003 0.009 0.735 0.217
Data are presented as mean standard error of mean (SEM). HOMA-IR, homeostatic model assessment of insulin resistance. Statistically significant: p < 0.05.
irisin and cord irisin levels were not significantly different between women with GDM on insulin therapy and those treated with diet alone (p > 0.05) (Table 3). Maternal serum irisin levels were negatively correlated with BMI and HOMA-IR values (r = 0.401, p = 0.010; r = 0.395, p = 0.012, respectively) (Fig. 2). In addition, maternal mean serum irisin levels were not found to be associated with age, gestational week at birth, birth weight, HbA1c, glucose, insulin and cord irisin levels (r = 0.087, p = 0.596; r = 303, p = 0.058; r = 0.150, p = 0.357; r = 0.063, p = 0.764; r = 0.264, p = 0.100; r = 0.236, p = 0.142; r = 0.013, p = 0.936, respectively) (Table 4).
4.
Discussion
Association between irisin and various diseases such as obesity, anorexia nervosa, type 2 diabetes, insulin sensitivity and chronic kidney disease has been studied [6,7,10,11]. However, to the best of our knowledge, this is the first study to investigate the relationship between irisin and pregnancy. Maternal serum irisin levels were significantly lower in pregnant women with GDM compared to control group. This result suggests that serum irisin levels might be introduced as
Data are presented as mean ± standard error of mean (SEM) Fig. 1 – Maternal irisin levels in women with and without GDM.
174
diabetes research and clinical practice 104 (2014) 171–175
Table 3 – The clinical and biochemical characteristics of GDM patients treated with insulin and managed by diet.
Age (year) BMI at birth (kg/m2) Gestational age at birth (week) Birth weight (g) Fasting glucose (mg/dl) HOMA-IR HbA1c (%) Insulin (mU/l) Serum irisin (ng/ml) Cordon irisin (ng/ml) Cordon glucose (mg/dl)
Management by diet (n: 12)
Insulin treatment (n: 8)
p value
34.0 3.91 30.5 4.46 37.3 3.39 3110.0 863.0 87.7 21.5 2.45 0.83 5.53 1.37 12.1 5.07 267.0 110.7 387.0 250.7 68.2 9.38
35.8 4.42 32.8 6.45 37.6 1.76 3487.5 529.3 95.6 20.9 2.89 1.38 6.05 2.48 12.8 5.66 245.3 157.5 312.5 253.5 74.5 6.07
0.258 0.487 0.528 0.395 0.334 0.512 0.954 0.643 0.280 0.396 0.141
Data are presented as mean standard error of mean (SEM). BMI, body mass index; HOMA-IR, homeostatic model assessment of insulin resistance. Statistically significant: p < 0.05.
Table 4 – Correlations between maternal serum irisin levels and all the other parameters in whole groups. Maternal serum irisin levels r Maternal age BMI at birth Gestational week at birth Birth weight HbA1c Glucose Insulin HOMA-IR Cord irisin
0.087 0.401 0.303 0.150 0.063 0.264 0.236 0.395 0.013
p 0.596 0.010* 0.058 0.357 0.764 0.100 0.142 0.012* 0.936
BMI, body mass index; HOMA-IR, homeostatic model assessment of insulin resistance. Statistically significant: p < 0.05. * Significant difference.
a prospective and novel marker for GDM and decreased levels of irisin might be indicative of GDM. There was no significant relationship between GDM and cord irisin levels. Irisin has been proposed to be involved in mediating the beneficial effects of exercise on metabolism [4]. In culture and mouse
models, expression of FNDC5 gene has been proposed to stimulate the production of irisin, thus leading to an increase in uncoupling protein 1 (UCP1) levels which induce browning of subcutaneous adipocytes and thermogenesis [4]. Improvement in glucose tolerance of mice fed a high-fat diet occurs when circulating levels of irisin increased 3–4 fold [4]. Therefore, brown fat has been demonstrated to induce effects against diabetes and obesity in murine models [12] as well as humans [13]. As a PGC-1a activated messenger of myocytes, irisin is involved in the association between sedentary lifestyle and obesity and diabetes [3,4,14,15]. The relationship between irisin and type 2 diabetes has been evaluated in recent studies [6,7]. It has been suggested that lower levels of circulating irisin is associated with diabetes itself or the metabolic condition that caused progression to type 2 diabetes. Previous studies also investigated the role of PGC-1a in the pathogenesis of women with PCOS, type 2 diabetes and their offspring. Studies in humans revealed that PGC-1a expression and its activity were significantly down-regulated in skeletal muscles in type 2 diabetes [16]. Our results show that circulating irisin levels are significantly lower in women with GDM, and these
Fig. 2 – Correlation between maternal serum irisin levels and BMI and HOMA-IR in all patients.
diabetes research and clinical practice 104 (2014) 171–175
data are consistent with the available data. Therefore, it is reasonable to hypothesize that lower level of circulating irisin observed in our study might be secondary to impaired PGC-1a expression and function in muscles in patients with GDM. The effects of irisin on energy metabolism is controversial [17]. Liu et al. have reported a positive correlation between circulating irisin levels and BMI values in people without diabetes. However, the same study also showed no association between irisin expression from myocytes and BMI, fasting insulin and fasting blood glucose (FBG) in patients with diabetes [6]. Positive correlations between circulating irisin levels and BMI in people without diabetes were shown in the studies of Stengel et al. and Huh et al. [10,18]. In contrast, a very recent study suggested that circulating irisin correlated negatively with BMI, waist–hip ratio and fat mass in men. Even after adjustment for age, waist–hip ratio and insulin sensitivity; circulating irisin was still lower in overweight and obese men without diabetes [19]. Our study showed that maternal serum irisin levels were negatively correlated with BMI and insulin resistance. Reasons for these discrepancies could be the gender-differences, but this paradox might also the result of a disassociation between FNDC5 expression and circulating irisin under some conditions. Irisin in fetal cord blood has not been evaluated so far. We found no significant difference in cord blood irisin levels of patients with GDM compared to control group. In fact, we have no data about the placental absorption of maternal irisin. In addition to this, normal maternal glucose levels were successfully achieved in women with GDM in this study. These facts may explain fetal irisin levels. Indeed, further evaluation of fetal irisin in GDM patients with uncontrolled glycemic profiles may contribute to an elaboration of fetal irisin and its association with GDM. The inability to measure the effect of fetal insulin concentrations on fetal irisin levels and the relatively small population can be listed as the limitations of the study. Therefore, further studies are needed to investigate the role of irisin in the pathogenesis of GDM. In conclusion, maternal serum irisin levels are lower in the patients with GDM. It remains possible that GDM may affect PGC-1a expression or functions in muscles. Furthermore, maternal plasma irisin levels are negatively associated with BMI and insulin resistance.
Conflict of interest
[2]
[3]
[4]
[5] [6]
[7]
[8] [9]
[10]
[11]
[12]
[13] [14] [15] [16] [17]
[18]
No conflict of interest.
references
[1] ACOG Practice Bulletin. Clinical management guidelines for obstetrician-gynecologists. Number 30, September 2001
[19]
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(replaces Technical Bulletin Number 200, December 1994). Gestational diabetes. Obstet Gynecol 2001;98:525–38. Catalano PM, Kirwan JP, Haugel-de Mouzon S, King J. Gestational diabetes and insulin resistance: role in shortand long-term implications for mother and fetus. J Nutr 2003;133:1674S–83S. Pedersen BK, Febbraio M.A.. Muscles exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol 2012;8:457–65. Bostrom P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, et al. A PGC1-alpha-dependent myokine that drives brownfat-like development of white fat and thermogenesis. Nature 2012;481:463–8. Hojlund K, Bostrom P. Irisin in obesity and type 2 diabetes. J Diabetes Complications 2013;27:303–4. Liu JJ, Wong MD, Toy WC, Tan CS, Liu S, Ng XW, et al. Lower circulating irisin is associated with type 2 diabetes mellitus. J Diabetes Complications 2013;27:365–9. Choi YK, Kim MK, Bae KH, Seo HA, Jeong JY, Lee WK, et al. Serum irisin levels in new-onset type 2 diabetes. Diabetes Res Clin Pract 2013;100:96–101. Carpenter MW, Coustan DR. Criteria for screening tests for gestational diabetes. Am J Obstet Gynecol 1982;144:768–73. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412–9. Stengel A, Hofmann T, Goebel-Stengel M, Elbelt U, Kobelt P, Klapp BF. Circulating levels of irisin in patients with anorexia nervosa and different stages of obesity— correlation with body mass index. Peptides 2013; 39:125–30. Wen MS, Wang CY, Lin SL, Hung KC. Decrease in irisin in patients with chronic kidney disease. PLoS One 2013;8:e64025. Seale P, Conroe HM, Estall J, Kajimura S, Frontini A, Ishibashi J, et al. Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J Clin Invest 2011;121:96–105. Enerback S. Human brown adipose tissue. Cell Metab 2010;11:248–52. Kelly DP. Medicine. Irisin, light my fire. Science 2012;336:42–3. Villarroya F. Irisin, turning up the heat. Cell Metab 2012;15:277–8. Liang H, Ward WF. PGC-1alpha: a key regulator of energy metabolism. Adv Physiol Educ 2006;30:145–51. Timmons JA, Baar K, Davidsen PK, Atherton PJ. Is irisin a human exercise gene? Nature 2012;488:E9–10. discussion E-1. Huh JY, Panagiotou G, Mougios V, Brinkoetter M, Vamvini MT, Schneider BE, et al. FNDC5 and irisin in humans: I. Predictors of circulating concentrations in serum and plasma and II. mRNA expression and circulating concentrations in response to weight loss and exercise. Metabolism 2012;61:1725–38. Moreno-Navarrete JM, Ortega F, Serrano M, Guerra E, Pardo G, Tinahones F, et al. Irisin is expressed and produced by human muscle and adipose tissue in association with obesity and insulin resistance. J Clin Endocrinol Metab 2013;98:E769–78.
Contents available at ScienceDirect
Diabetes Research and Clinical Practice journ al h ome pa ge : www .elsevier.co m/lo cate/diabres
Maternal serum and fetal cord blood irisin levels in gestational diabetes mellitus Mehmet Aytac Yuksel a,*, Mahmut Oncul a, Abdullah Tuten a, Metehan Imamoglu a, Abdullah Serdar Acikgoz a, Mine Kucur b, Riza Madazli a a b
Department of Obstetrics and Gynecology, Cerrahpasa School of Medicine, Istanbul University, Istanbul, Turkey Department of Biochemistry, Cerrahpasa School of Medicine, Istanbul University, Istanbul, Turkey
article info
abstract
Article history:
Aim: To investigate the relationship between maternal and cord blood irisin in gestational
Received 28 August 2013
diabetes mellitus (GDM).
Received in revised form
Methods: Twenty women with GDM and 20 pregnant women with uncomplicated pregnancies
10 November 2013
were recruited for this case–control study. Maternal serum irisin and cord blood irisin levels
Accepted 21 December 2013
were measured by enzyme-linked immunosorbent assay kit at the time of birth. The associa-
Available online 3 January 2014
tion of maternal serum and cord blood irisin levels with metabolic parameters was analyzed. Results: Women with GDM had significantly lower mean serum irisin levels compared to
Keywords:
control group (258.3 127.9 vs. 393 178.9 ng/ml, p < 0.05). Mean cord blood irisin levels for
Gestational diabetes mellitus
GDM and control groups were not significantly different (357.2 248.0 vs. 333.2 173.4 ng/
Irisin
ml, p > 0.05). No significant differences were found in terms of maternal age, gestational
Cord blood
week at birth, BMI at birth, birth weight, neonatal height, systolic and diastolic blood
Maternal
pressure between the groups as well (p > 0.05). Serum irisin level was negatively correlated with BMI at birth and HOMA-IR (r =
0.401, p = 0.010; r =
0.395, p = 0.012, respectively). No
correlations between irisin levels and others parameters were found in both groups. Conclusions: Maternal serum irisin levels of patients with GDM are significantly lower compared with non-GDM controls. However, no significant difference was found between cord blood irisin levels of patients with GDM and healthy pregnant women. # 2014 Elsevier Ireland Ltd. All rights reserved.
1.
Introduction
GDM (gestational diabetes mellitus) has been defined as any degree of glucose intolerance with onset or first recognition during pregnancy [1]. GDM, which affects 16–20% of all pregnancies has serious adverse perinatal outcomes and increases long-term risk for the development of obesity, type 2 diabetes and cardiovascular disease in both the mother and
the offspring [2]. Insulin resistance plays an important role in the pathogenesis of GDM and despite extensive research, the mechanisms underlying insulin resistance are not fully understood [2]. Since it is the largest organ in the body, skeletal muscle accounts for the majority of glucose uptake in response to insulin, and is quantitatively the most important site of insulin resistance. During the past decade, skeletal muscle has also been identified as a secretory organ and cytokines and
* Corresponding author at: Department of Obstetrics and Gynecology, Cerrahpasa School of Medicine, Istanbul University, Fatih, Istanbul 34098, Turkey. Tel.: +90 532 601 60 58; fax: +90 2124143000. E-mail address: [email protected] (M.A. Yuksel). 0168-8227/$ – see front matter # 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.diabres.2013.12.025
172
diabetes research and clinical practice 104 (2014) 171–175
other peptides produced and secreted by myocytes are classified as myokines [3]. These myokines function as endocrine hormones and regulate the function of various distant organs. Irisin has recently been identified as an exercise-induced hormone secreted by skeletal muscle and has been proposed to mediate the beneficial effects of exercise on metabolism [4]. Sedentary lifestyle is a major risk factor for type 2 diabetes mellitus. Randomized controlled trials have demonstrated that physical activity improves glucose tolerance and reduces the risk of type 2 diabetes mellitus [5]. Therefore, it has been speculated that physical exercise may exert its beneficial effects on energy metabolism through secreted factors from myocytes such as irisin [3]. Recent studies have shown that circulating irisin levels were significantly lower in patients with type 2 diabetes compared to people without diabetes [6,7]. Liu and co-workers demonstrated that irisin might be positively correlated with most of the well-known markers of insulin resistance in people without diabetes [6]. These data show that either the diabetes itself or the metabolic condition that caused progression to type 2 diabetes is accompanied by lower circulating irisin levels in circulation. To date, there are a paucity of data on irisin and human pregnancy. In the current study, our aim was to investigate maternal and cord serum irisin levels in women with GDM and women with uncomplicated pregnancies.
2.
Material and methods
The Ethics Committee of our university approved the study protocol (dated February 29, 2013, issue no. 83045809/3709) and all patients were carefully instructed and signed informed consent before recruitment. 20 pregnant women with GDM and 20 controls with uncomplicated pregnancies were recruited for the study. All recruited patients were selected randomly from women admitted to the antenatal clinic of our obstetrics department and had a history of prior cesarean section deliveries and were planned to deliver with cesarean section. This criterion was established to exclude any possible effects of labor on the parameters that evaluated in maternal blood, described below. Exclusion criteria were as follows: chronic hypertension, preeclampsia, diabetes mellitus, polyhydramnios, presence of any acute or chronic disease, fetal anomalies, prior renal disease, liver disease, multiple gestation, history of smoking and chronic alcohol consumption. All women were screened for GDM with 50 g glucose challenge test (GCT) at 24th gestational week. The 50-g GCT was carried out independent of the time of day or any previous meal at about 24 weeks gestation. An oral glucose tolerance test was recommended to all patients with a 1-h test result 140 mg/dl (7.8 mmol/l). Diagnosis of GDM was established according to results of 100-gram oral glucose tolerance test (OGTT). Patients with at least two abnormal values above the cutoff values were determined to be having an abnormal OGTT result: Fasting 95 mg/dl (5.3 mmol/l); 1 h, 180 mg/dl (10.0 mmol/l); 2 h, 155 mg/dl (8.6 mmol/l); 3 h, 140 mg/dl (7.8 mmol/l) [8]. Control subjects had normal responses to GCT. 20 patients with GDM received various treatment (diet therapy, self-monitoring of blood glucose or insulin therapy)
in order to maintain control of blood glucose levels (venous plasma glucose values were targeted to be 105 mg/dl [5.8 mmol/l] or lower before meals and 120 mg/dl [6.7 mmol/l] or lower 2 h after meals). Insulin therapy was administered if blood glucose levels remained above target levels despite strict diet therapy. Venous blood samples were collected in the fasting state before delivery. None of the patients were in labor at the time of sampling. Umbilical cord blood samples were also collected immediately after delivery. Blood samples were collected in tubes and were immediately centrifuged after clotting. The supernatant serum was kept frozen at 80 8C until assay. Serum irisin levels were measured using enzyme immunoassay (EIA). (Catalog # EK-067-16; Phoenix Pharmaceuticals, Belmont, CA, USA). The lowest detectable concentration of irisin was 6.8 ng/ml, with intra- and interassay coefficients of variation were 0.05). Mean maternal serum HOMA-IR, fasting glucose and insulin levels of women with GDM at the time of delivery were significantly higher than the control group (Table 2). Mean maternal serum irisin level of women with GDM was significantly lower than the control group (258.3 127.9 vs. 393 178.9 ng/ml, p: 0.009) (Table 2 and Fig. 1). Irisin levels in cord blood were not statistically different among groups (357.2 248.0 vs. 333.2 173.4 ng/ml, p: 0.735) (Table 2). Among women with GDM, 8 had insulin therapy and 12 were treated with diet alone. Clinical and biochemical characteristics of GDM patients treated with insulin and managed by diet are shown in Table 3. Mean maternal serum
diabetes research and clinical practice 104 (2014) 171–175
173
Table 1 – The clinical characteristics of women diagnosed with gestational diabetes and normal controls.
Age (year) Gestational age at birth (week) Maternal weight (kg) Maternal height (cm) BMI at birth (kg/m2) Birth weight (g) Neonatal height (cm) SBP (mmHg) DBP (mmHg)
GDM (n: 20)
Control (n: 20)
p value
34.8 4.11 37.4 2.7 82.6 11.0 163 6.3 31.4 5.3 3261 755 49.5 4.1 119 16.0 73.5 8.7
33.0 5.35 38.0 1.1 76.4 11.1 164.1 7.8 28.5 4.4 3366 436 50.2 1.6 109.5 10.9 69.0 7.8
0.242 0.862 0.091 0.758 0.174 0.883 0.758 0.060 0.157
Data are presented as mean standard error of mean (SEM). BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure. Statistically significant: p < 0.05.
Table 2 – Biochemical characteristics women diagnosed with gestational diabetes and normal controls.
Fasting glucose (mg/dl) HOMA-IR HbA1c (%) Insulin (mU/l) Serum irisin (ng/ml) Cord irisin (ng/ml) Cord glucose (mg/dl)
GDM (n: 20)
Control (n: 20)
p value
90.9 21.1 2.63 1.0 5.7 1.9 12.4 5.1 258.3 127.9 357.2 248.0 70.7 8.6
74.5 12.9 1.44 0.53 5.11 0.36 8.19 2.0 393 178.9 333.2 173.4 67.3 9.8
0.012 0.000 0.367 0.003 0.009 0.735 0.217
Data are presented as mean standard error of mean (SEM). HOMA-IR, homeostatic model assessment of insulin resistance. Statistically significant: p < 0.05.
irisin and cord irisin levels were not significantly different between women with GDM on insulin therapy and those treated with diet alone (p > 0.05) (Table 3). Maternal serum irisin levels were negatively correlated with BMI and HOMA-IR values (r = 0.401, p = 0.010; r = 0.395, p = 0.012, respectively) (Fig. 2). In addition, maternal mean serum irisin levels were not found to be associated with age, gestational week at birth, birth weight, HbA1c, glucose, insulin and cord irisin levels (r = 0.087, p = 0.596; r = 303, p = 0.058; r = 0.150, p = 0.357; r = 0.063, p = 0.764; r = 0.264, p = 0.100; r = 0.236, p = 0.142; r = 0.013, p = 0.936, respectively) (Table 4).
4.
Discussion
Association between irisin and various diseases such as obesity, anorexia nervosa, type 2 diabetes, insulin sensitivity and chronic kidney disease has been studied [6,7,10,11]. However, to the best of our knowledge, this is the first study to investigate the relationship between irisin and pregnancy. Maternal serum irisin levels were significantly lower in pregnant women with GDM compared to control group. This result suggests that serum irisin levels might be introduced as
Data are presented as mean ± standard error of mean (SEM) Fig. 1 – Maternal irisin levels in women with and without GDM.
174
diabetes research and clinical practice 104 (2014) 171–175
Table 3 – The clinical and biochemical characteristics of GDM patients treated with insulin and managed by diet.
Age (year) BMI at birth (kg/m2) Gestational age at birth (week) Birth weight (g) Fasting glucose (mg/dl) HOMA-IR HbA1c (%) Insulin (mU/l) Serum irisin (ng/ml) Cordon irisin (ng/ml) Cordon glucose (mg/dl)
Management by diet (n: 12)
Insulin treatment (n: 8)
p value
34.0 3.91 30.5 4.46 37.3 3.39 3110.0 863.0 87.7 21.5 2.45 0.83 5.53 1.37 12.1 5.07 267.0 110.7 387.0 250.7 68.2 9.38
35.8 4.42 32.8 6.45 37.6 1.76 3487.5 529.3 95.6 20.9 2.89 1.38 6.05 2.48 12.8 5.66 245.3 157.5 312.5 253.5 74.5 6.07
0.258 0.487 0.528 0.395 0.334 0.512 0.954 0.643 0.280 0.396 0.141
Data are presented as mean standard error of mean (SEM). BMI, body mass index; HOMA-IR, homeostatic model assessment of insulin resistance. Statistically significant: p < 0.05.
Table 4 – Correlations between maternal serum irisin levels and all the other parameters in whole groups. Maternal serum irisin levels r Maternal age BMI at birth Gestational week at birth Birth weight HbA1c Glucose Insulin HOMA-IR Cord irisin
0.087 0.401 0.303 0.150 0.063 0.264 0.236 0.395 0.013
p 0.596 0.010* 0.058 0.357 0.764 0.100 0.142 0.012* 0.936
BMI, body mass index; HOMA-IR, homeostatic model assessment of insulin resistance. Statistically significant: p < 0.05. * Significant difference.
a prospective and novel marker for GDM and decreased levels of irisin might be indicative of GDM. There was no significant relationship between GDM and cord irisin levels. Irisin has been proposed to be involved in mediating the beneficial effects of exercise on metabolism [4]. In culture and mouse
models, expression of FNDC5 gene has been proposed to stimulate the production of irisin, thus leading to an increase in uncoupling protein 1 (UCP1) levels which induce browning of subcutaneous adipocytes and thermogenesis [4]. Improvement in glucose tolerance of mice fed a high-fat diet occurs when circulating levels of irisin increased 3–4 fold [4]. Therefore, brown fat has been demonstrated to induce effects against diabetes and obesity in murine models [12] as well as humans [13]. As a PGC-1a activated messenger of myocytes, irisin is involved in the association between sedentary lifestyle and obesity and diabetes [3,4,14,15]. The relationship between irisin and type 2 diabetes has been evaluated in recent studies [6,7]. It has been suggested that lower levels of circulating irisin is associated with diabetes itself or the metabolic condition that caused progression to type 2 diabetes. Previous studies also investigated the role of PGC-1a in the pathogenesis of women with PCOS, type 2 diabetes and their offspring. Studies in humans revealed that PGC-1a expression and its activity were significantly down-regulated in skeletal muscles in type 2 diabetes [16]. Our results show that circulating irisin levels are significantly lower in women with GDM, and these
Fig. 2 – Correlation between maternal serum irisin levels and BMI and HOMA-IR in all patients.
diabetes research and clinical practice 104 (2014) 171–175
data are consistent with the available data. Therefore, it is reasonable to hypothesize that lower level of circulating irisin observed in our study might be secondary to impaired PGC-1a expression and function in muscles in patients with GDM. The effects of irisin on energy metabolism is controversial [17]. Liu et al. have reported a positive correlation between circulating irisin levels and BMI values in people without diabetes. However, the same study also showed no association between irisin expression from myocytes and BMI, fasting insulin and fasting blood glucose (FBG) in patients with diabetes [6]. Positive correlations between circulating irisin levels and BMI in people without diabetes were shown in the studies of Stengel et al. and Huh et al. [10,18]. In contrast, a very recent study suggested that circulating irisin correlated negatively with BMI, waist–hip ratio and fat mass in men. Even after adjustment for age, waist–hip ratio and insulin sensitivity; circulating irisin was still lower in overweight and obese men without diabetes [19]. Our study showed that maternal serum irisin levels were negatively correlated with BMI and insulin resistance. Reasons for these discrepancies could be the gender-differences, but this paradox might also the result of a disassociation between FNDC5 expression and circulating irisin under some conditions. Irisin in fetal cord blood has not been evaluated so far. We found no significant difference in cord blood irisin levels of patients with GDM compared to control group. In fact, we have no data about the placental absorption of maternal irisin. In addition to this, normal maternal glucose levels were successfully achieved in women with GDM in this study. These facts may explain fetal irisin levels. Indeed, further evaluation of fetal irisin in GDM patients with uncontrolled glycemic profiles may contribute to an elaboration of fetal irisin and its association with GDM. The inability to measure the effect of fetal insulin concentrations on fetal irisin levels and the relatively small population can be listed as the limitations of the study. Therefore, further studies are needed to investigate the role of irisin in the pathogenesis of GDM. In conclusion, maternal serum irisin levels are lower in the patients with GDM. It remains possible that GDM may affect PGC-1a expression or functions in muscles. Furthermore, maternal plasma irisin levels are negatively associated with BMI and insulin resistance.
Conflict of interest
[2]
[3]
[4]
[5] [6]
[7]
[8] [9]
[10]
[11]
[12]
[13] [14] [15] [16] [17]
[18]
No conflict of interest.
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