G Model
DSX-368; No. of Pages 3 Diabetes & Metabolic Syndrome: Clinical Research & Reviews xxx (2013) xxx–xxx
Contents lists available at ScienceDirect
Diabetes & Metabolic Syndrome: Clinical Research & Reviews journal homepage: www.elsevier.com/locate/dsx
Original Article
Plasma cystatin-C and risk of developing gestational diabetes mellitus Gholamreza Yousefzadeh a, Sara Pezeshki a, Ahmad Gholamhosseinian a, Mahsa Nazemzadeh a, Mostafa Shokoohi b,* a b
Physiology Research Center, Kerman University of Medical Sciences, Kerman, Iran Research Center for Modeling in Health, Institute for Futures Studies in Health, Kerman University of Medical Sciences, Kerman, Iran
A R T I C L E I N F O
A B S T R A C T
Keywords: Gestational diabetes Cystatin-C Pregnancy
Aims: Cystatin-C, a low molecular weight protein, is effectively applied to evaluate the risk of developing renal insufficiency, cardiovascular disorders, neural defects, and inflammatory states. However, the role of this biomarker to monitor different pregnancy-related complications remains controversial. Materials and methods: In the present study, we compared serum cystatin-C concentration between pregnant women with gestational diabetes mellitus (GDM) and healthy pregnant women to assess value of this biomarker to predict presence of GDM in these women. The study consisted of 60 consecutive pregnant women (30 women suffered GDM and 30 healthy pregnant women) enrolled in Afzalipour hospital in Kerman, Iran in 2012. Fasting blood sample was collected to perform measurements on plasma glucose, lipids, serum creatinine, and C-cystatin. Serum cystatin-C level was quantified using ELISA techniques. Results: Unadjusted comparison of cystatin-C level between the two study group showed no significant discrepancy between them so that the level of this biomarker in GDM group was 593.00 204.81 mg/L and in healthy group was 531.67 87.52 mg/L (P = 0.137); while in multivariable linear model with the presence of associated variables, GDM was a main determinant for increased level of cystatin-C (standardized beta of 0.355, P-value of 0.014). Conclusion: Gestational age was also identified to be another indicator of elevated cystatin-C. In final, our study showed that cystatin-C can be a reliable, useful and promising marker of GDM appearance in pregnant women. ß 2013 Diabetes India. Published by Elsevier Ltd. All rights reserved.
1. Introduction
predictable. Because this protein is naturally removed from blood stream by glomerular filtration in the kidneys, in those with renal insufficiency, elevated level of this protein is expected. Recently, it has been hypothesized that cystatin-C would predict appearance and progression to pre-diabetes and even diabetes states independent of its role to predict renal function. Some trials have shown that the elevated cystatin-C level can be associated with a threefold excess risk of progression to prediabetes [17]. In diabetic nephropathy state, cystatin-C can be effective for detection of high graded nephropathy and would be especially useful for screening high stage chronic kidney disease patients [18]. Some authors have also indicated that the use of cystatin-C for screening and early treatment of incipient diabetic nephropathy appears to be adequate [19]. Moreover, association between the serum level of this marker and different components of metabolic syndrome has been recently investigated [20]. However, the role of cystatin-C to monitor renal function during pregnancy and also its value for predicting different pregnancyrelated events remains controversial. In the present study, we compared serum cystatin-C concentration between pregnant
Cystatin-C, a low molecular weight protein encoded by CST3 gene, is effectively applied to evaluate the risk of renal dysfunction [1,2], and is also recently identified as a biomarker for predicting some neurological defects involving amyloid such as Alzheimer’s disease, new-onset cardiovascular disease [3,4], various cancers [5–7], thyroid dysfunction [8–10], and glucocorticoid therapy [11– 13]. In addition, its concentration can be also increased in HIV infection [14,15], following cigarette smoking, and also in inflammatory conditioned evidenced by elevated C-reactive protein [16]. Wide uses of this protein in clinical settings mainly referred to this fact that all human cells with a nucleus can produce it and therefore, its pathological changes in various states can be
* Corresponding author at: Research Center for Modeling in Health, Institute for Futures Studies in Health, Kerman University of Medical Sciences, Kerman 76175113, Iran. Tel.: +98 341 226 3983; fax: +98 341 226 4079. E-mail address: [email protected] (M. Shokoohi).
1871-4021/$ – see front matter ß 2013 Diabetes India. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.dsx.2013.10.016
Please cite this article in press as: Yousefzadeh G, et al. Plasma cystatin-C and risk of developing gestational diabetes mellitus. Diab Met Syndr: Clin Res Rev (2013), http://dx.doi.org/10.1016/j.dsx.2013.10.016
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DSX-368; No. of Pages 3 G. Yousefzadeh et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews xxx (2013) xxx–xxx
2
Table 1 Baseline characteristics and clinical data of GDM and non-GDM groups. Characteristics
GDM group (n = 30)
Non-GDM group (n = 30)
P-value
Age, year Gestational age, week Number of parity Body mass index, kg/m2 Systolic BP, mmHg Diastolic BP, mmHg Serum triglyceride, mg/dl Total cholesterol, mg/dl Serum HDL, mg/dl Serum LDL, mg/dl Serum FBS, mg/dl Serum creatinine, mg/dl Serum urea, mg/dl
27.87 4.62 32.27 4.07 1.57 0.77 28.13 3.04 117.33 14.49 77.17 7.95 258.13 89.07 227.37 45.82 46.33 7.98 130.23 49.08 78.83 14.09 0.66 0.15 17.40 4.72
30.07 4.79 29.47 6.26 1.77 0.82 30.50 4.15 116.67 11.01 73.83 6.65 257.07 123.18 218.87 56.15 41.23 12.05 127.03 42.43 95.83 36.51 0.64 0.36 23.83 7.48
0.075 0.044 0.334 0.015 0.842 0.084 0.969 0.523 0.059 0.788 0.021 0.778 126 mg/dl, history of eclampsia or preeclampsia, renal insufficiency, or cardiovascular disorders. The current study protocol was approved by the institutional review boards at the Kerman University of Medical Sciences and all women gave written informed consent. 2.2. Study measurements Demographic and anthropometric parameters were all collected from recorded files on first visits in hospital. A 10 ml fasting blood sample was collected to perform measurements on plasma glucose, lipids, serum creatinine, and C-cystatin. Serum triglyceride, total cholesterol, and high density lipoprotein levels were measured by an enzymatic method using a commercial kit. Low density lipoprotein-cholesterol level was also estimated from measurements of total cholesterol, triacylglycerol, and high density lipoprotein cholesterol (HDL-cholesterol) by means of the Friedewald’s equation. Serum creatinine was also determined by enzymatic method. Cystatin-C level was quantified using ELISA techniques. 2.3. Study analysis Results were presented as mean standard deviation (SD) for quantitative variables and were summarized by absolute frequencies and percentages for categorical variables. Chi-square tests and t tests were used in unadjusted analyses to compare categorical variables or continuous variables, respectively. Multiple linear regression modeling was used to calculate the adjusted beta and standard error for cystatin-C level for women with and without gestational diabetes. Variables associated with cystatin-C level in crude analyses (P 0.20) were included in initial adjustment model. Two tailed P-values of 0.05 or less were considered statistically significant. For the statistical
In order to compare baseline variables between women suffered GDM and healthy women (Table 1); the two groups were comparable in mean age, number of parity, systolic and diastolic blood pressures, serum creatinine level, and lipid profile. However, the former group had higher gestational age, lower body mass index, as well as lower serum urea level. Unadjusted comparison of cystatin-C level between the two study group showed no significant discrepancy between them so that the level of this biomarker in gestational diabetes group was 593.00 204.81 mg/L and in healthy group was 531.67 87.52 mg/L (P = 0.137); while in multivariable linear model (Table 2) with the presence of associated variables, GDM was a main determinant for increased level of cystatin-C (standardized beta of 0.355, P-value of 0.014). Gestational age was also identified to be another indicator for elevated cystatin-C. 4. Discussion In order to several evidences available on association between elevated level of cystatin-C and different pathological states, the present study was conducted to assess this hypothesis that increased level of cystatin-C can be a good index for predicting appearance of GDM in pregnant women. According to some dramatic complications of undiagnosed and uncontrolled GDM in the mother (including development of type 2 diabetes mellitus later in life, development of repeated GDM in future pregnancies, maternal hypertension) and the fetus (including fetal death, macrosomia, shoulder dystocia, neonatal hypoglycemia), using this biomarker can effectively help to prevent occurrence of these inverse phenomena. To demonstrate this hypothesis, we compared serum cystatin-C level between GDM and healthy pregnant women and showed by a multivariate regression model adjusted for potential confounders that the level of cystatin-C was significantly higher in GDM group. On the other hand, increased level of this biomarker is in line with the appearance of GDM independent to renal function in these pregnant women. Pervious researches mainly focused on predicting renal dysfunction or preeclampsia by measuring cystatin-C in pregnant women [21– 24], but we directly targeted GDM prediction by measuring this biochemical indicator. Only in a study by Qing et al. on Chinese population, early diagnosis value of serum cystatin-C on renal injures of GDM patients was examined that demonstrated a higher level of cystatin-C in patients with GDM were obviously higher than those of the normal group [25]. According to the relationship between the presence of metabolic syndrome and increased level of cystatin-C, association between the level of this marker and
Please cite this article in press as: Yousefzadeh G, et al. Plasma cystatin-C and risk of developing gestational diabetes mellitus. Diab Met Syndr: Clin Res Rev (2013), http://dx.doi.org/10.1016/j.dsx.2013.10.016
G Model
DSX-368; No. of Pages 3 G. Yousefzadeh et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews xxx (2013) xxx–xxx Table 2 Multivariate linear regression analysis for determining role of cystatin-C to predict gestational diabetes mellitus. Characteristics Gestational diabetes Age Gestational age Body mass index, kg/m2 Diastolic BP, mmHg Serum HDL, mg/dl Serum FBS, mg/dl
Standardized beta 0.355 0.075 0.351 0.261 0.089 0.209 0.340
T score 2.544 0.611 2.735 1.0807 0.703 1.677 2.600
P-value 0.014 0.544 0.009 0.076 0.485 0.100 0.012
GDM might be explainable. Surendar et al. indicated that subjects with four or five metabolic abnormalities had the highest cystatinC levels, and with decreasing number of metabolic abnormalities, the cystatin-C levels linearly decreased. They finally showed that levels of cystatin-C could be highly correlated with the number of metabolic abnormalities in Asian Indians [26]. Thus, it seems that the appearance of diabetes mellitus during pregnancy as a main component of metabolic syndrome can be directly influenced by elevated level of cystatin-C. Besides, there are some evidences on association between high insulin resistance and serum concentration of cystatin-C. It has been shown that postprandial insulin secretion might increase cystatin-C and that insulin therapy might suppress an increase in cystatin-C accompanied by an anti-inflammatory effect in diabetic patients [27]. It was also suggested that cystatin-C level was significantly associated with insulin resistance and biomarkers reflecting inflammation independent of renal function [28]. On the other hand, association between GDM and increased level of cystatin-C can be mediated by increasing insulin resistance in pregnant women that should be tested more in further studies. In conclusion, our study showed that cystatin-C can be a reliable, useful and promising marker of GDM appearance in pregnant women. Conflict of interest statement None. Financial disclosures None. References [1] Zerovnik E. The emerging role of cystatins in Alzheimer’s disease. Bioessays 2009;31(June (6)):597–9. [2] Ghidoni R, Benussi L, Glionna M, Desenzani S, Albertini V, Levy E, et al. Plasma cystatin C and risk of developing Alzheimer’s disease in subjects with mild cognitive impairment. J Alzheimers Dis 2010;22(3):985–91. [3] Dupont M, Wu Y, Hazen SL, Tang WH. Cystatin C identifies patients with stable chronic heart failure at increased risk for adverse cardiovascular events. Circ Heart Fail 2012;5(September (5)):602–9 [Epub 16.08.12]. [4] Meng L, Yang Y, Qi LT, Wang XJ, Xu GB, Zhang BW. Elevated serum cystatin C is an independent predictor of cardiovascular events in people with relatively normal renal function. J Nephrol 2012;25(May–June (3)):426–30. [5] Ohara G, Miyazaki K, Kurishima K, Kagohashi K, Ishikawa H, Satoh H, et al. Serum levels of cystatin C in elderly lung cancer patients. Oncol Lett 2012;3(February (2)):303–6.
3
[6] Nu¨ckel H, Langer C, Herget-Rosenthal S, Wichert M, Assert R, Do¨hner H, et al. Prognostic significance of serum cystatin C in multiple myeloma. Int J Hematol 2012;95(May (5)):545–50. [7] Rasouli HA, Moghadam MM, Tabatabaiefar M, Taslimi F, Sheybani KM, Alidoosti A, et al. Comparing cystatin C changes as a measure of renal function before and after radiotherapy in patients with stomach cancer. Acta Med Iran 2012;50(1):43–6. [8] Ozden TA, Tekerek H, Bas¸ F, Darendeliler F. Effect of hypo-and euthyroid status on serum cystatin C levels. J Clin Res Pediatr Endocrinol 2010;2(4):155–8. [9] Kotajima N, Yanagawa Y, Aoki T, Tsunekawa K, Morimura T, Ogiwara T, et al. Influence of thyroid hormones and transforming growth factor-b1 on cystatin C concentrations. J Int Med Res 2010;38(July–August (4)):1365–73. [10] Wiesli P, Schwegler B, Spinas GA, Schmid C. Serum cystatin C is sensitive to small changes in thyroid function. Clin Chim Acta 2003;338(December (1– 2)):87–90. [11] Silva MV, Moscoso Solorzano G, Nishida SK, Kirsztajn GM. Are serum cystatin C levels influenced by steroid doses in lupus nephritis patients? J Bras Nefrol 2011;33(July–September (3)):306–12. [12] Risch L, Herklotz R, Blumberg A, Huber AR. Effects of glucocorticoid immunosuppression on serum cystatin C concentrations in renal transplant patients. Clin Chem 2001;47(November (11)):2055–9. [13] Cimerman N, Brguljan PM, Krasovec M, Suskovic S, Kos J. Serum cystatin C, a potent inhibitor of cysteine proteinases, is elevated in asthmatic patients. Clin Chim Acta 2000;300(October (1–2)):83–95. [14] Gagneux-Brunon A, Mariat C, Delanaye P. Cystatin C in HIV-infected patients: promising but not yet ready for prime time. Nephrol Dial Transplant 2012;27(April (4)):1305–13. [15] Overton ET, Patel P, Mondy K, Bush T, Conley L, Rhame F, et al., Sun Study Investigators. Cystatin C and baseline renal function among HIV-infected persons in the SUN Study. AIDS Res Hum Retroviruses 2012;28(February (2)):148–55. [16] Samouilidou EC, Grapsa E. Relationship of serum cystatin C with C-reactive protein and apolipoprotein A1 in patients on hemodialysis. Ren Fail 2008;30(7):711–5. [17] Donahue RP, Stranges S, Rejman K, Rafalson LB, Dmochowski J, Trevisan M. Elevated cystatin C concentration and progression to pre-diabetes: the Western New York study. Diabetes Care 2007;30(July (7)):1724–9 [Epub 24.04.07]. [18] Suzuki Y, Matsushita K, Seimiya M, Yoshida T, Sawabe Y, Ogawa M, et al. Serum cystatin C as a marker for early detection of chronic kidney disease and grade 2 nephropathy in Japanese patients with type 2 diabetes. Clin Chem Lab Med 2012;50(October (10)):1833–9. http://dx.doi.org/10.1515/cclm-2011-0777. [19] Dhia RB, Hellara I, Harzallah O, Neffati F, Khochtali I, Mahjoub S, et al. Evaluation of the renal function in type 2 diabetes: clearance calculation or cystatin C? Ann Biol Clin (Paris) 2012;70(May–June (3)):287–94. http:// dx.doi.org/10.1684/abc.2012.0702. [20] Qing X, Furong W, Yunxia L, Jian Z, Xuping W, Ling G. Cystatin C and asymptomatic coronary artery disease in patients with metabolic syndrome and normal glomerular filtration rate. Cardiovasc Diabetol 2012;11(September):108. [21] Babay Z, Al-Wakeel J, Addar M, Mittwalli A, Tarif N, Hammad D, et al. Serum cystatin C in pregnant women: reference values, reliable and superior diagnostic accuracy. Clin Exp Obstet Gynecol 2005;32(3):175–9. [22] Franceschini N, Qiu C, Barrow DA, Williams MA. Cystatin C and preeclampsia: a case–control study. Ren Fail 2008;30(1):89–95. [23] Strevens H, Wide-Swensson D, Torffvit O, Grubb A. Serum cystatin C for assessment of glomerular filtration rate in pregnant and non-pregnant women. Indications of altered filtration process in pregnancy. Scand J Clin Lab Invest 2002;62(2):141–7. [24] Akbari A, Lepage N, Keely E, Clark HD, Jaffey J, MacKinnon M, et al. Cystatin-C and beta trace protein as markers of renal function in pregnancy. BJOG 2005;112(May (5)):575–8. [25] Qing O, Jian L, Qing-feng S, Yi-ping L, Yu-chun W, Xi-fang T. Clinical significance of cystatin C and uromicroproteins in evaluation of renal function of gestational diabetes mellitus patients. Shandong Med 2011;28. [26] Surendar J, Indulekha K, Aravindhan V, Ganesan A, Mohan V. Association of Cystatin-C with metabolic syndrome in normal glucose-tolerant subjects (CURES-97). Diabetes Technol Ther 2010;12(November (11)):907–12. [27] Yokoyama H, Inoue T, Node K. Effect of insulin-unstimulated diabetic therapy with miglitol on serum cystatin C level and its clinical significance. Diabetes Res Clin Pract 2009;83(January (1)):77–82. http://dx.doi.org/10.1016/j.diabres.2008.09.049. [28] Lee SH, Park SA, Ko SH, Yim HW, Ahn YB, Yoon KH, et al. Insulin resistance and inflammation may have an additional role in the link between cystatin C and cardiovascular disease in type 2 diabetes mellitus patients. Metabolism 2010;59(February (2)):241–6.
Please cite this article in press as: Yousefzadeh G, et al. Plasma cystatin-C and risk of developing gestational diabetes mellitus. Diab Met Syndr: Clin Res Rev (2013), http://dx.doi.org/10.1016/j.dsx.2013.10.016
DSX-368; No. of Pages 3 Diabetes & Metabolic Syndrome: Clinical Research & Reviews xxx (2013) xxx–xxx
Contents lists available at ScienceDirect
Diabetes & Metabolic Syndrome: Clinical Research & Reviews journal homepage: www.elsevier.com/locate/dsx
Original Article
Plasma cystatin-C and risk of developing gestational diabetes mellitus Gholamreza Yousefzadeh a, Sara Pezeshki a, Ahmad Gholamhosseinian a, Mahsa Nazemzadeh a, Mostafa Shokoohi b,* a b
Physiology Research Center, Kerman University of Medical Sciences, Kerman, Iran Research Center for Modeling in Health, Institute for Futures Studies in Health, Kerman University of Medical Sciences, Kerman, Iran
A R T I C L E I N F O
A B S T R A C T
Keywords: Gestational diabetes Cystatin-C Pregnancy
Aims: Cystatin-C, a low molecular weight protein, is effectively applied to evaluate the risk of developing renal insufficiency, cardiovascular disorders, neural defects, and inflammatory states. However, the role of this biomarker to monitor different pregnancy-related complications remains controversial. Materials and methods: In the present study, we compared serum cystatin-C concentration between pregnant women with gestational diabetes mellitus (GDM) and healthy pregnant women to assess value of this biomarker to predict presence of GDM in these women. The study consisted of 60 consecutive pregnant women (30 women suffered GDM and 30 healthy pregnant women) enrolled in Afzalipour hospital in Kerman, Iran in 2012. Fasting blood sample was collected to perform measurements on plasma glucose, lipids, serum creatinine, and C-cystatin. Serum cystatin-C level was quantified using ELISA techniques. Results: Unadjusted comparison of cystatin-C level between the two study group showed no significant discrepancy between them so that the level of this biomarker in GDM group was 593.00 204.81 mg/L and in healthy group was 531.67 87.52 mg/L (P = 0.137); while in multivariable linear model with the presence of associated variables, GDM was a main determinant for increased level of cystatin-C (standardized beta of 0.355, P-value of 0.014). Conclusion: Gestational age was also identified to be another indicator of elevated cystatin-C. In final, our study showed that cystatin-C can be a reliable, useful and promising marker of GDM appearance in pregnant women. ß 2013 Diabetes India. Published by Elsevier Ltd. All rights reserved.
1. Introduction
predictable. Because this protein is naturally removed from blood stream by glomerular filtration in the kidneys, in those with renal insufficiency, elevated level of this protein is expected. Recently, it has been hypothesized that cystatin-C would predict appearance and progression to pre-diabetes and even diabetes states independent of its role to predict renal function. Some trials have shown that the elevated cystatin-C level can be associated with a threefold excess risk of progression to prediabetes [17]. In diabetic nephropathy state, cystatin-C can be effective for detection of high graded nephropathy and would be especially useful for screening high stage chronic kidney disease patients [18]. Some authors have also indicated that the use of cystatin-C for screening and early treatment of incipient diabetic nephropathy appears to be adequate [19]. Moreover, association between the serum level of this marker and different components of metabolic syndrome has been recently investigated [20]. However, the role of cystatin-C to monitor renal function during pregnancy and also its value for predicting different pregnancyrelated events remains controversial. In the present study, we compared serum cystatin-C concentration between pregnant
Cystatin-C, a low molecular weight protein encoded by CST3 gene, is effectively applied to evaluate the risk of renal dysfunction [1,2], and is also recently identified as a biomarker for predicting some neurological defects involving amyloid such as Alzheimer’s disease, new-onset cardiovascular disease [3,4], various cancers [5–7], thyroid dysfunction [8–10], and glucocorticoid therapy [11– 13]. In addition, its concentration can be also increased in HIV infection [14,15], following cigarette smoking, and also in inflammatory conditioned evidenced by elevated C-reactive protein [16]. Wide uses of this protein in clinical settings mainly referred to this fact that all human cells with a nucleus can produce it and therefore, its pathological changes in various states can be
* Corresponding author at: Research Center for Modeling in Health, Institute for Futures Studies in Health, Kerman University of Medical Sciences, Kerman 76175113, Iran. Tel.: +98 341 226 3983; fax: +98 341 226 4079. E-mail address: [email protected] (M. Shokoohi).
1871-4021/$ – see front matter ß 2013 Diabetes India. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.dsx.2013.10.016
Please cite this article in press as: Yousefzadeh G, et al. Plasma cystatin-C and risk of developing gestational diabetes mellitus. Diab Met Syndr: Clin Res Rev (2013), http://dx.doi.org/10.1016/j.dsx.2013.10.016
G Model
DSX-368; No. of Pages 3 G. Yousefzadeh et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews xxx (2013) xxx–xxx
2
Table 1 Baseline characteristics and clinical data of GDM and non-GDM groups. Characteristics
GDM group (n = 30)
Non-GDM group (n = 30)
P-value
Age, year Gestational age, week Number of parity Body mass index, kg/m2 Systolic BP, mmHg Diastolic BP, mmHg Serum triglyceride, mg/dl Total cholesterol, mg/dl Serum HDL, mg/dl Serum LDL, mg/dl Serum FBS, mg/dl Serum creatinine, mg/dl Serum urea, mg/dl
27.87 4.62 32.27 4.07 1.57 0.77 28.13 3.04 117.33 14.49 77.17 7.95 258.13 89.07 227.37 45.82 46.33 7.98 130.23 49.08 78.83 14.09 0.66 0.15 17.40 4.72
30.07 4.79 29.47 6.26 1.77 0.82 30.50 4.15 116.67 11.01 73.83 6.65 257.07 123.18 218.87 56.15 41.23 12.05 127.03 42.43 95.83 36.51 0.64 0.36 23.83 7.48
0.075 0.044 0.334 0.015 0.842 0.084 0.969 0.523 0.059 0.788 0.021 0.778 126 mg/dl, history of eclampsia or preeclampsia, renal insufficiency, or cardiovascular disorders. The current study protocol was approved by the institutional review boards at the Kerman University of Medical Sciences and all women gave written informed consent. 2.2. Study measurements Demographic and anthropometric parameters were all collected from recorded files on first visits in hospital. A 10 ml fasting blood sample was collected to perform measurements on plasma glucose, lipids, serum creatinine, and C-cystatin. Serum triglyceride, total cholesterol, and high density lipoprotein levels were measured by an enzymatic method using a commercial kit. Low density lipoprotein-cholesterol level was also estimated from measurements of total cholesterol, triacylglycerol, and high density lipoprotein cholesterol (HDL-cholesterol) by means of the Friedewald’s equation. Serum creatinine was also determined by enzymatic method. Cystatin-C level was quantified using ELISA techniques. 2.3. Study analysis Results were presented as mean standard deviation (SD) for quantitative variables and were summarized by absolute frequencies and percentages for categorical variables. Chi-square tests and t tests were used in unadjusted analyses to compare categorical variables or continuous variables, respectively. Multiple linear regression modeling was used to calculate the adjusted beta and standard error for cystatin-C level for women with and without gestational diabetes. Variables associated with cystatin-C level in crude analyses (P 0.20) were included in initial adjustment model. Two tailed P-values of 0.05 or less were considered statistically significant. For the statistical
In order to compare baseline variables between women suffered GDM and healthy women (Table 1); the two groups were comparable in mean age, number of parity, systolic and diastolic blood pressures, serum creatinine level, and lipid profile. However, the former group had higher gestational age, lower body mass index, as well as lower serum urea level. Unadjusted comparison of cystatin-C level between the two study group showed no significant discrepancy between them so that the level of this biomarker in gestational diabetes group was 593.00 204.81 mg/L and in healthy group was 531.67 87.52 mg/L (P = 0.137); while in multivariable linear model (Table 2) with the presence of associated variables, GDM was a main determinant for increased level of cystatin-C (standardized beta of 0.355, P-value of 0.014). Gestational age was also identified to be another indicator for elevated cystatin-C. 4. Discussion In order to several evidences available on association between elevated level of cystatin-C and different pathological states, the present study was conducted to assess this hypothesis that increased level of cystatin-C can be a good index for predicting appearance of GDM in pregnant women. According to some dramatic complications of undiagnosed and uncontrolled GDM in the mother (including development of type 2 diabetes mellitus later in life, development of repeated GDM in future pregnancies, maternal hypertension) and the fetus (including fetal death, macrosomia, shoulder dystocia, neonatal hypoglycemia), using this biomarker can effectively help to prevent occurrence of these inverse phenomena. To demonstrate this hypothesis, we compared serum cystatin-C level between GDM and healthy pregnant women and showed by a multivariate regression model adjusted for potential confounders that the level of cystatin-C was significantly higher in GDM group. On the other hand, increased level of this biomarker is in line with the appearance of GDM independent to renal function in these pregnant women. Pervious researches mainly focused on predicting renal dysfunction or preeclampsia by measuring cystatin-C in pregnant women [21– 24], but we directly targeted GDM prediction by measuring this biochemical indicator. Only in a study by Qing et al. on Chinese population, early diagnosis value of serum cystatin-C on renal injures of GDM patients was examined that demonstrated a higher level of cystatin-C in patients with GDM were obviously higher than those of the normal group [25]. According to the relationship between the presence of metabolic syndrome and increased level of cystatin-C, association between the level of this marker and
Please cite this article in press as: Yousefzadeh G, et al. Plasma cystatin-C and risk of developing gestational diabetes mellitus. Diab Met Syndr: Clin Res Rev (2013), http://dx.doi.org/10.1016/j.dsx.2013.10.016
G Model
DSX-368; No. of Pages 3 G. Yousefzadeh et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews xxx (2013) xxx–xxx Table 2 Multivariate linear regression analysis for determining role of cystatin-C to predict gestational diabetes mellitus. Characteristics Gestational diabetes Age Gestational age Body mass index, kg/m2 Diastolic BP, mmHg Serum HDL, mg/dl Serum FBS, mg/dl
Standardized beta 0.355 0.075 0.351 0.261 0.089 0.209 0.340
T score 2.544 0.611 2.735 1.0807 0.703 1.677 2.600
P-value 0.014 0.544 0.009 0.076 0.485 0.100 0.012
GDM might be explainable. Surendar et al. indicated that subjects with four or five metabolic abnormalities had the highest cystatinC levels, and with decreasing number of metabolic abnormalities, the cystatin-C levels linearly decreased. They finally showed that levels of cystatin-C could be highly correlated with the number of metabolic abnormalities in Asian Indians [26]. Thus, it seems that the appearance of diabetes mellitus during pregnancy as a main component of metabolic syndrome can be directly influenced by elevated level of cystatin-C. Besides, there are some evidences on association between high insulin resistance and serum concentration of cystatin-C. It has been shown that postprandial insulin secretion might increase cystatin-C and that insulin therapy might suppress an increase in cystatin-C accompanied by an anti-inflammatory effect in diabetic patients [27]. It was also suggested that cystatin-C level was significantly associated with insulin resistance and biomarkers reflecting inflammation independent of renal function [28]. On the other hand, association between GDM and increased level of cystatin-C can be mediated by increasing insulin resistance in pregnant women that should be tested more in further studies. In conclusion, our study showed that cystatin-C can be a reliable, useful and promising marker of GDM appearance in pregnant women. Conflict of interest statement None. Financial disclosures None. References [1] Zerovnik E. The emerging role of cystatins in Alzheimer’s disease. Bioessays 2009;31(June (6)):597–9. [2] Ghidoni R, Benussi L, Glionna M, Desenzani S, Albertini V, Levy E, et al. Plasma cystatin C and risk of developing Alzheimer’s disease in subjects with mild cognitive impairment. J Alzheimers Dis 2010;22(3):985–91. [3] Dupont M, Wu Y, Hazen SL, Tang WH. Cystatin C identifies patients with stable chronic heart failure at increased risk for adverse cardiovascular events. Circ Heart Fail 2012;5(September (5)):602–9 [Epub 16.08.12]. [4] Meng L, Yang Y, Qi LT, Wang XJ, Xu GB, Zhang BW. Elevated serum cystatin C is an independent predictor of cardiovascular events in people with relatively normal renal function. J Nephrol 2012;25(May–June (3)):426–30. [5] Ohara G, Miyazaki K, Kurishima K, Kagohashi K, Ishikawa H, Satoh H, et al. Serum levels of cystatin C in elderly lung cancer patients. Oncol Lett 2012;3(February (2)):303–6.
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Please cite this article in press as: Yousefzadeh G, et al. Plasma cystatin-C and risk of developing gestational diabetes mellitus. Diab Met Syndr: Clin Res Rev (2013), http://dx.doi.org/10.1016/j.dsx.2013.10.016
