2011, Editrice Kurtis

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1 J. Endocrinol. Invest. : -, 2011 DOI: 10.2/902 The role of visfatin in the pathogenesis of gestational diabetes mellitus D.E. Gok 1, M. Yazici 1, G. Uckaya 1, S.E. Bolu 1, Y. Basaran 2, T. Ozgurtas, S. Kilic, and M. Kutlu 1 1Department of Endocrinology; 2 Department of Internal Medicine; Department of Biochemistry; Department of Epidemiology, Gulhane Military Medicine Faculty, Ankara, Turkey ABSTRACT. Aim: The objective of the present study was to evaluate the role of visfatin in gestational diabetes mellitus. Materials and methods: Forty-five pregnant women at 2 to 28 weeks gestation were assigned to coume an initial screening test using a 1-h 0-g glucose load, and then a -h 100-g glucose load. The study group coisted of 2 patients who were diagnosed with gestational diabetes mellitus and the control group coisted of 22 healthy pregnant women. We studied the levels of visfatin and the other parameters of inflammation, glucose and lipid metabolism between the 2 th and 28 th week of gestation and also between the th and 10 th week after delivery. Results: INTRODUCTION Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance with oet or first recognition during pregnancy. The definition applies regardless of whether iulin replacement therapy or only diet modification is used for treatment or whether the condition persists after pregnancy. The prevalence may range from 1 to 1% of pregnancies, depending on the population studied. GDM represents nearly 90% of all pregnancies complicated by diabetes (1). Women with GDM have an increased risk for the subsequent development of Type 2 diabetes mellitus (T2DM) (2). Adipose tissue produces several adipocytokines such as visfatin, leptin, adiponectin, resistin, tumor necrosis factor α (TNF-α) and interleukin- (IL-), which modulate iulin seitivity and appear to play an important role in the pathogenesis of iulin resistance, diabetes, dyslipidemia, inflammation, and atherosclerosis (). Visfatin is a 2 kda cytokine that exerts iulin mimicking effects through activation of an iulin receptor, although in a manner distinct from that of iulin. Glucose lowering effect of visfatin is dose-dependent and is not due to changes in plasma iulin levels. Like iulin, visfatin induces triglyceride (TG) accumulation in preadypocytes from both fat depots and accelerates TG synthesis from glucose. In summary, several lines of evidence indicate that visfatin shares properties with iulin both in vivo and in vitro (). Fukuhara et al. identified the relatiohip between serum Plasma visfatin and glucose levels at 0 min after a 0-g and a 100-g glucose load between the 2 th and 28 th week of gestation were significantly higher in the gestational diabetes group than in the control group. There were no statistical differences in visfatin levels between the groups at -10 weeks post-partum. Conclusion: Visfatin levels were significantly elevated in women with gestational diabetes mellitus and during the course of pregnancy and increased visfatin concentratio were reduced within to 10 weeks after delivery. (J. Endocrinol. Invest. : -, 2011) 2011, Editrice Kurtis visfatin levels and adiposity, and found that visfatin expression in visceral fat is increased in obese subjects and plasma concentratio of visfatin correlated much more strongly with the amount of visceral fat than that of subcutaneous adipose tissue (). It has been reported that plasma visfatin concentratio were elevated in iulin-resistant states, such as obesity, T2DM () and GDM (2, ). On the contrary, decreased visfatin concentratio have also been reported in patients with GDM (, ). Because of the relatively small number of studies, there is not enough evidence in the literature demotrating the exact role of visfatin in the pathogenesis of GDM. To evaluate the role of visfatin, which could be a good predictive marker for GDM, we measured plasma visfatin levels in 2 women with GDM and in 22 healthy pregnant controls between the 2 th and 28 th week of gestation and also between the th and 10 th week after delivery. Szamatowicz et al. found that visfatin concentratio correlated significantly with fasting iulin and homeostasis model assessment of iulin resistance (HOMA-IR). Serum visfatin concentratio were elevated in pregnant women, irrespectively of their glucose tolerance status. This elevation may be caused by an additional secretion of visfatin from the placenta, however other possible sources of visfatin should also be taken into account (). Key-words: Visfatin, gestational diabetes mellitus, pregnancy, post partum. Correspondence: Dr. Deniz Engin Gok, Department of Endocrinology, Gulhane Military Medicine Faculty, Etlik, Kecioren, 00 Ankara, Turkey. dengingok@yahoo.com Accepted November 2, First published online March 10, MATERIALS AND METHODS Forty-five pregnant women at 2 to 28 weeks gestation were assigned to coume an initial screening test using a 1-h 0-g glucose load, and then a -h 100-g glucose load. The study group coisted of 2 patients who were diagnosed with GDM and the control group coisted of 22 healthy pregnant women with normal respoe to both 0-g and 100-g glucose oral tolerance tests (OGTT). GDM was diagnosed according to th Workshop Conference of Gestational Diabetes criteria (8). All

2 Visfatin and gestational diabetes mellitus Table 1 - Clinical characteristics of the study and control groups. participants were treated by diet alone. Serum samples for biochemical analysis and visfatin evaluation were obtained from the GDM group and controls between the 2 th and 28 th week of gestation and also between the th and 10 th week of post-partum period. Laboratory analysis GDM Control p (no.=2) (no.=22) Age (yr) 0.9±.2 0.±.8 BMI (kg/m²) 2.±.1 2.±.8 Pregnancies (no.) 1.±1. 2.1±1.8 Weight gain during pregnancy (kg) 11.±. 12.±. Newborn weight (g) ±81 299± 0.01 Data are expressed as mean±sd; : statistically non-significant (p>0.0). BMI: body mass index; GDM: gestational diabetes mellitus. Plasma fasting and post-prandial glucose (FPG and PPG, respectively) (Olympus AU-200, Mishima, Japan), iulin (Roche E-10, Hitachi Corp., Osaka, Japan), C-peptide (Immulite 1000, DPC, UK), glycosylated hemoglobin (HbA 1c ) were analyzed using standard laboratory methods. Visfatin C-terminal was measured by enzyme immunometric assay (Phoenix Pharmaceuticals Inc., Burlingame, CA, USA), with a lower limit of detection of 1.8 ng/ml, measuring range of ng/ml and linear range of ng/ml. Fasting glucose and iulin measures were used to derive estimates of β-cell function and iulin seitivity using the HOMA algorithm (9). All samples from an individual subject were measured in the same assay. Statistics Statistical evaluation was performed using the Statistical Package for the Social Sciences 1.0 (SPSS, Inc., Chicago, IL, USA). Parametric data were expressed as mean±sd. Baseline characteristics of the GDM and control groups were compared by non-parametric test, Mann-Whitney-U test, Wilcoxon signed rank-sum test and χ² test. A p-value of <0.0 was coidered significant. Spearman ρ correlation test was used to investigate the association between visfatin and HbA 1c, FPG, PPG, iulin, HOMA-IR, LDLcholesterol (LDL-C), TG and C-reactive protein levels (CRP). Patient recruitment All clinical investigatio were conducted in accordance with the Guidelines in the Declaration of Helsinki and approved by the Ititutional Review Committee. All subjects were carefully itructed about the aims of the study and written informed coent was obtained from each participant. RESULTS Table 2 - Biochemical characteristics and visfatin levels of the study and control groups th week of gestation 0-g OGTT 0-min plasma glucose (mg/dl) 100-g OGTT 0-min plasma glucose (mg/dl) 0-min plasma glucose (mg/dl) 120-min plasma glucose (mg/dl) 180-min plasma glucose (mg/dl) HbA 1c (%) Iulin (miu/ml) C-peptide (ng/ml) Visfatin (ng/ml) HOMA-IR LDL-C (mg/dl) Triglyceride (mg/dl) CRP (mg/l) Post-partum -10 th week -g OGTT 0-min plasma glucose (mg/dl) 0-min plasma glucose (mg/dl) 120-min plasma glucose (mg/dl) HbA 1c (%) Iulin (miu/ml) C-peptide (ng/ml) Visfatin (ng/ml) HOMA-IR LDL-C (mg/dl) Triglyceride (mg/dl) CRP (mg/l) The clinical characteristics of the patients and controls are summarized in Table 1. There were no significant differences in age, maternal body mass index (BMI) before p 11.1±.2 9.± ±2. 1.2± ±.1.2± ± ±0.8.1± ± ± ±.1 9.9±.8 8.9±8.1 1.± ±2..±0..82±.1 1.±0..8±1. 1.1± ± ±. 8.09± ±1.1 8.± ± ± ±10.8.9±0. 10.±. 2.±0.8.1±1. 2.0± ± ±.0.±2.9 8.± ± ± ±0..± ±1.2.9± ± ±2. 122±.9.±.1 Data are expressed as mean±sd; : statistically non-significant (p>0.0). GDM: gestational diabetes mellitus; OGTT: oral glucose tolerance test; HbA 1c : glycosylated hemoglobin; HOMA-IR: homeostasis model assessment of iulin resistance; LDL-C: LDL cholesterol; CRP: C-reactive protein. <

3 D.E. Gok, M. Yazici, G. Uckaya, et al. Serum visfatin (ng/ml) GDM Control Fig. 1 - Visfatin levels in the gestational diabetes mellitus (GDM) and control groups (p=) th weeks -10 th weeks of gestation of post partum Fig. 2 - Significantly higher visfatin levels at gestation period than post-partum period (p=0.00). Serum visfatin (ng/ml) pregnancy, gestational weight gain or number of pregnancies between the groups. Birth weight of the newbor was significantly higher in the GDM group (p=0.01). In the GDM group, 2 women had a past history of GDM and 1 had first-degree relatives with T2DM (.2%). In the control group, only participants had first-degree relatives with T2DM (2.%) (p<0.0). The biochemical parameters and visfatin levels of the study population are shown in Table 2. The GDM group had significantly higher plasma glucose levels at 0 min after a 0-g and a 100-g glucose load between the 2 th and 28 th week of gestation than the control group (p=). There were no statistical differences in HbA 1c, fasting plasma iulin or C-peptide levels between the groups. However, a marked increase in visfatin concentratio was noted in the GDM group (.1±1.1ng/ml), compared with the control subjects (.1±1. ng/ml, p=) (Fig. 1). All participants underwent a 2-h -g OGTT between the th and 10 th week after delivery. Plasma glucose levels at 0 min were significantly higher in the GDM group than in the control group (1.±2.2 vs 108.±21. mg/dl, p=0.00). There were no significant differences in HbA 1c, fasting plasma iulin, C-peptide, TG, CRP and visfatin levels between the groups (Table 2) (Fig. 2). Compared with the gestation, FPG levels in the postpartum period were significantly higher in the GDM group (1.1±20. vs 8.9±.8 mg/dl, p=0.00). On the contrary, plasma visfatin levels (.1±1.1 vs.8±1. ng/ml, p=), PPG (129±28. vs 9.±9. mg/dl, p=), plasma fasting iulin (11.±.1 vs.82±.1 miu/ml, p=) and C-peptide (2.12±0.8 vs 1.±0. ng/ml, p=0.01) levels were significantly lower after delivery. Furthermore, the control group had significantly lower iulin levels (10.±. vs.±1. miu/ml, p=) but FPG, PPG, HbA 1c, C-peptide and serum visfatin levels did not differ significantly after delivery (Table ). The association between parameters related to glucose metabolism (HbA 1c, FPG, PPG, iulin, HOMA-IR, LDL- C, and TG), inflammation (CRP) and visfatin was investigated using Spearman ρ correlation test. No significant correlatio were found between plasma visfatin levels and these parameters in the GDM and control groups between the 2 th and 28 th week of gestation (Table ). However, significant correlatio were found between FPG and HOMA-IR in the GDM group and between HbA 1c and PPG in the control group after delivery (Table ). DISCUSSION Visfatin has iulin mimicking effects through activation of an iulin receptor, although in a manner distinct Table - Biochemical characteristics of the study and control groups at pregnancy and after delivery period. Pregnancy Post-partum Pregnancy Post-partum Visfatin (ng/ml).1±1.1.8±1. b.1±1. a.9±1. FPG (mg/dl) 1.1± ±.8 b 80.±. 9.8±8.8 PPG (mg/dl) 129±28. 9.±9. b 101± ±. HbA 1c (%).2±0..±0..9±0..10±0. Iulin (miu/ml) 11.1±.1.82±.1 b 10.±..±1. a C-peptide (ng/ml) 2.12±0.8 1.±0. b 2.± ±1.2 Data are expressed as mean±sd. a Significant difference between GDM and control groups (p<0.01); b significant difference between pregnancy and post-partum period in the GDM group (p<0.01). GDM: gestational diabetes mellitus; FPG: fasting plasma glucose; PPG: post-prandial glucose; HbA 1c : glycosylated hemoglobin.

4 Visfatin and gestational diabetes mellitus Table - Correlatio between parameters related to glucose metabolism, inflammation and visfatin in gestational diabetes mellitus (GDM) patient and control groups between the 2 th and 28 th week of gestation. r* p<0.01 r* p<0.01 HbA 1c (%) FPG (mg/dl) PPG (mg/dl) Iulin (miu/ml) HOMA-IR LDL-C (mg/dl) Triglyceride (mg/dl) CRP (mg/l) *Correlation test performed by using Spearman s ρ correlatio. HbA 1c : glycosylated hemoglobin; FPG: fasting plasma glucose; PPG: post-prandial glucose; HOMA-IR: homeostasis model assessment of iulin resistance; LDL-C: LDL cholesterol; CRP: C-reactive protein. Table - Correlatio between parameters related to glucose metabolism, inflammation and visfatin in gestational diabetes mellitus (GDM) patient and control groups between the th and 10 th week after delivery. from that of iulin. Elevated plasma visfatin levels have been reported in iulin-resistant states, such as obesity, T2DM () and GDM (2, ). On the contrary, it has also been reported that women with GDM have decreased plasma visfatin concentratio (, ). In the present study, we found an increase in the fasting plasma visfatin concentratio associated with deterioration of glucose tolerance, especially among women with GDM who had higher levels of glycemia. The importance of early detection and prompt inteive treatment of GDM is universally recognized. Di Gianni et al. reported that 1-h OGTT hyperglycemia could be coidered a more severe condition. Their results indicated that the prevalence of one abnormal value during OGTT and GDM was high in pregnant women with a positive glucose challenge test; women with one abnormal value were clinically indistinguishable from patients with GDM, and both groups were different from the women with normal glucose tolerance test. They suggested that particularly 1-h post-ogtt hyperglycemia defines whether inteive treatment should be recommended for these women as well (10). In the present study, plasma glucose levels at 0 min after a 0-g and a 100-g glucose load between the 2 th and 28 th week of gestation were significantly higher in the GDM group than in the control group. Although the GDM group had significantly higher LDL-C levels, there were no statistical differences in HbA 1c, fasting plasma iulin, C-peptide, HOMA-IR, TG and CRP levels between the groups. The GDM group had also statistically higher HOMA-IR and LDL-C levels after delivery, but TG and CRP levels did not differ significantly. A marked increase in visfatin concentratio was also noted in the GDM group when compared with the controls. Therefore, it appears that higher visfatin levels in the GDM group could be associated with deterioration of glucose tolerance. Furthermore, elevated visfatin levels in the GDM group were reduced within to 10 weeks after delivery. Kryzanowska et al. reported that visfatin was elevated in women with GDM and that it was increased during the course of pregnancy as well as after delivery. They studied visfatin levels at 2 weeks after parturition (2). Lewandowski et al. reported that there was a progressive increase in glucose and iulin at 120 min of the OGTT, which was accompanied by an increase in visfatin levels in GDM and intermediate groups (11). Chen et al. demotrated that plasma visfatin levels correlated with waist-to-hip ratio. On the other hand, they reported that plasma visfatin did not correlate with BMI and other biochemical markers (). Mastorakos et al. reported that there was a significant progressive increase in iulin resistance and decrease in iulin seitivity from the first to the third trimester. Plasma visfatin levels were found to increase during pregnancy between the first and second trimesters, in parallel with β-cell secretion indices and body fat mass (12). Chan et al. measured visfatin levels in 20 women with GDM at 2-28 weeks of gestation and found that plasma visfatin concentratio were significantly lower in the GDM group (). Haider et al. reported that women with GDM at 2-28 weeks of gestation had lower fasting plasma visfatin and more suppressed visfatin respoe than those with normal glucose tolerance during OGTT (). Akturk et al. showed that plasma visfatin concentratio at -9 weeks of gestation were more markedly decreased in women with GDM than in those with normal glucose tolerance (1). However, none of these controversial studies were re-evaluated after delivery. In the present study, the GDM group had significantly higher visfatin levels during the course of pregnancy and elevated visfatin concentratio were reduced after delivery. This is the first study describing the relatiohip between GDM and visfatin both between the 2 th and 28 th week of gestation and between the th and 10 th week after delivery. Elevated visfatin levels in patients with GDM may suggest the role of increased secretory functio of adipose tissue during pregnancy. Limitatio of this study include the small number of subjects and short-term follow-up after delivery. r* p<0.0 r* p<0.0 HbA 1c (%) < FPG (mg/dl) PPG (mg/dl) Iulin (miu/ml) HOMA-IR LDL-C (mg/dl) Triglyceride (mg/dl) CRP (mg/l) *Correlation test performed by using Spearman s ρ correlatio. HbA 1c : glycosylated hemoglobin; FPG: fasting plasma glucose; PPG: post-prandial glucose; HOMA-IR: homeostasis model assessment of iulin resistance; LDL-C: LDL cholesterol; CRP: C-reactive protein.

5 D.E. Gok, M. Yazici, G. Uckaya, et al. REFERENCES 1. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2008, 1 (Suppl 1): Krzyzanowska K, Krugluger W, Mittermayer F, et al. Increased Visfatin visfatin concentratio in women with gestational diabetes mellitus. Clin Sci (Lond) 200, 110: Chen MP, Chung FM, Chang DM, et al. Elevated plasma level of visfatin/pre-b cell colony-enhancing factor in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 200, 91: Fukuhara A, Matsuda M, Nishizawa M, et al. Visfatin: a protein secreted by visceral fat that mimics the effects of iulin. Science 200, 0: Chan TF, Chen YL, Lee CH, et al. Decreased plasma visfatin concentratio in women with gestational diabetes mellitus. J Soc Gynecol Investig 200, 1: -.. Haider DG, Handisurya A, Storka A, et al. Visfatin respoe to glucose is reduced in women with gestational diabetes mellitus. Diabetes Care 200, 0: Szamatowicz J, Kuzmicki M, Telejko B, et al. Serum visfatin concentration is elevated in pregnant women irrespectively of the presence of gestational diabetes. Ginekol Pol 2009, 80: American Diabetes Association. Clinical practice recommendatio. Gestational diabetes mellitus. Diabetes Care 2002, 2 (Suppl 1): Matthews DR, Hasker JP, Rudeki AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: iulin resistance and beta-cell function from fasting plasma glucose and iulin concentratio in men. Diabetologia 198, 28: Di Cianni G, Seghieri G, Lencioni C, et al. Normal glucose tolerance and gestational diabetes mellitus: what is in between?. Diabetes Care 200, 0: Lewandowski KC, Stojanovic N, Press M, et al. Elevated serum levels of visfatin in gestational diabetes: a comparative study across various degrees of glucose tolerance. Diabetologia 200, 0: Mastorakos G, Valsamakis G, Papatheodorou DC, et al. The role of adipocytokines in iulin resistance in normal pregnancy: visfatin concentratio in early pregnancy predict iulin seitivity. Clin Chem 200, : Akturk M, Altinova AE, Mert I, et al. Visfatin concentration is decreased in women with gestational diabetes mellitus in the third trimester. J Endocrinol Invest 2008, 1: 10-.