Serum Concentrations of Betatrophin and Its Association with Indirect Indices of Insulin Resistance and Beta Cell Function in Women with Polycystic Ovary Syndrome

Adamska, Agnieszka; Łebkowska, Agnieszka; Jacewicz, Małgorzata; Krentowska, Anna; Hryniewicka, Justyna; Wołczyński, Sławomir; Górska, Maria; Kowalska, Irina

doi:https://doi.org/10.1155/2017/2316986

International Journal of Endocrinology

On this page

Abstract Introduction Materials and Methods Results Discussion Conclusions Abbreviations Conflicts of Interest Acknowledgments References Copyright Related Articles

Research Article | Open Access

Volume 2017 | Article ID 2316986 | https://doi.org/10.1155/2017/2316986

Serum Concentrations of Betatrophin and Its Association with Indirect Indices of Insulin Resistance and Beta Cell Function in Women with Polycystic Ovary Syndrome

Agnieszka Adamska,¹Agnieszka Łebkowska,¹Małgorzata Jacewicz,¹Anna Krentowska,¹Justyna Hryniewicka,¹Sławomir Wołczyński,²Maria Górska,¹and Irina Kowalska¹

Academic Editor: Amelie Bonnefond

Received21 Jan 2017

Revised27 Apr 2017

Accepted04 May 2017

Published18 Jun 2017

Abstract

Introduction. Data underline the role of betatrophin in glucose homeostasis. Polycystic ovary syndrome (PCOS) is characterized by insulin resistance (IR). The aim of our study was to investigate the relationship of serum betatrophin concentrations with indirect indices of IR and insulin secretion in women with PCOS, compared to the control group. Methods. The study group comprised 43 women with PCOS and 16 controls. IR was assessed by HOMA-IR and Matsuda index. Insulin secretion was evaluated with HOMA-B. An oral glucose tolerance test (OGTT) with estimation of serum betatrophin concentrations was performed. Results. Glucose load resulted in an increase in serum betatrophin concentrations in the control group (). Serum betatrophin concentrations at 120 min of OGTT were lower in women with PCOS than in the control group (). We observed positive correlations between baseline serum betatrophin concentrations and HOMA-IR (, ), negative correlations with Matsuda index (, ), and a positive relationship with HOMA-B (, ) in women with PCOS. Multiple regression analysis revealed that HOMA-B (, ) was an independent factor connected to serum betatrophin levels in PCOS. Conclusions. Serum concentrations of betatrophin are connected with insulin resistance and beta cell function and did not change after glucose load in women with PCOS.

1. Introduction

Polycystic ovary syndrome (PCOS) is a frequent endocrinopathy which affects about 5–10% of reproductive-aged women [1]. Patients with PCOS may present a variety of reproductive and metabolic disturbances, including oligo/anovulation, polycystic ovary in the ultrasound, and hyperandrogenism, as well as insulin resistance [2]. Moreover, it has been shown that beta cell dysfunction is present in PCOS individuals [3]. It is widely known that insulin resistance and impaired beta cell function play a crucial role in the pathogenesis of type 2 diabetes mellitus (T2D). Therefore, women with PCOS, who often show both aforementioned traits, are at higher risk of impaired glucose tolerance, T2D, as well as disturbances in lipid profile [4].

Betatrophin, also called refeeding-induced fat and liver protein (RIFL) [5], lipasin [6], or atypical angiopoietin-like protein 8 (ANGPLT8) [7], is a 22 kDa hormone. In mice, betatrophin is produced by the liver, white adipose tissue (WAT), and brown adipose tissue (BAT), while in humans, it is mainly produced by the liver [6]. It has been shown that betatrophin has a dual role: it affects glucose homeostasis and lipid metabolism [8–12].

In a mouse model of insulin resistance induced by insulin receptor antagonist S961, hepatic and WAT overexpression of betatrophin was observed. This was accompanied by beta cell replication, followed by improved glucose tolerance [8]. The results obtained by these authors suggest that betatrophin can exert a promoting role on beta cell replication. However, these data were not confirmed by Gusarova et al. [13]. They reported that ANGPTL8^−/− mice with insulin resistance induced by a high-fat diet or insulin receptor antagonist S961 had normal beta cell expansion. This indicates that betatrophin is not necessary for beta cell proliferation. Interestingly, in their experiment, a significant reduction of triglyceride (TG) in ANGPTL8^−/− mice in comparison to wild-type mice was observed [13].

In humans, the role of betatrophin in glucose metabolism is unclear. Studies that investigated its action in both healthy subjects and patients with diabetes have brought conflicting results so far. Some researchers showed increased levels of serum betatrophin in T2D [14, 15], type 1 diabetes mellitus (T1D) [16], and gestational diabetes [17], whereas other data report decreased serum betatrophin concentrations in obese individuals and T2D patients [11].

Interestingly, it has also been demonstrated that there are no significant differences in serum betatrophin levels between nondiabetic and T2D patients and between the lean and the morbidly obese patients [12]. On the other hand, a comprehensive meta-analysis by Li et al. suggested that circulating betatrophin levels in T2D nonobese patients are higher than those in the nondiabetic control group [9]. Moreover, recent studies showed that plasma concentrations of metabolic markers, for example, betatrophin, as well as hepatocyte growth factor and nesfatin, are elevated in drug-naïve prediabetic and T2D patients in comparison to normoglycemic subjects [18, 19]. It has also been observed that serum betatrophin concentration positively correlated with HbA1c and fasting plasma glucose in the group of patients with diabetes, prediabetic state, and metabolic syndrome [19] and with fasting plasma glucose and HOMA-IR in T2D and nondiabetic subjects [20].

Some data indicate that serum betatrophin concentrations are positively connected with the level of C-peptide in obese nondiabetic subjects [15]. However, this observation was not present in T2D patients [15]. In other studies, serum betatrophin concentrations inversely correlated with the increment of C-peptide in the glucagon stimulation test in T2D patients [21]. This might indicate that the increase in serum betatrophin concentrations is a result of insulin resistance observed in obese nondiabetic subjects.

Apart from its role in glucose homeostasis, betatrophin has an impact on lipid metabolism. In experimental data, betatrophin suppressed adipose triglyceride lipase activity and increased TG accumulation in hepatocytes, adipocytes, and beta cells [22]. In the fasted state, similar serum TG levels in ANGPTL8^−/− mice and wild-type animals were noticed. However, lower serum TG concentrations in response to refeeding in mice lacking the betatrophin gene have been observed [23]. Moreover, starvation decreased betatrophin expression in BAT and WAT [6]. This could suggest that betatrophin influences lipid homeostasis in the refeeding state.

As it was mentioned earlier, betatrophin could be involved in glucose and lipid metabolism, which is often impaired in women with PCOS. Therefore, the aim of the present study was to investigate serum betatrophin concentrations after glucose load and its relationship with indirect indices of insulin resistance and insulin secretion in women with PCOS in comparison to the healthy controls.

2. Materials and Methods

2.1. Subjects

The study group consisted of 59 women—43 patients with PCOS and 16 healthy controls matched for BMI and age. The diagnosis of PCOS was made according to the 2003 Rotterdam ESHRE/ASRM PCOS Consensus Workshop Group diagnostic criteria [24]. We defined PCOS by the presence of at least two out of three criteria: clinical and/or biochemical hyperandrogenism, oligo/anovulation, and polycystic ovaries (>12 follicles measuring 2–9 mm in diameter or ovarian volume > 10 ml in at least one ovary) [24]. Women with PCOS were recruited from the outpatient clinic of the Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok.

Clinical examination, anthropometric measurements, body fat assessment by bioelectrical impedance analysis, oral glucose tolerance test (OGTT) with 75 grams of glucose load, and ultrasonography of ovaries were performed as previously described [2]. Lipids, hormonal profiles (LH, FSH, total testosterone, and PRL), and serum betatrophin concentrations at the baseline and at 120 min of OGTT were estimated. Exclusion criteria included the following: morbid obesity, cardiovascular disease, and hyperlipidemia; other causes of irregular menstrual cycles and/or androgen excess (i.e., hyperprolactinemia, Cushing’s syndrome, late-onset congenital adrenal hyperplasia, or other diseases of the thyroid, adrenal glands, pregnancy, and breastfeeding); type 1 or type 2 diabetes; chronic or acute infection (within the previous 30 days); any other serious medical problem, hormonal contraception, and/or antiandrogen therapy (within the previous 6 months); and the use of medications for obesity, hyperglycemia, dyslipidemia, or hypertension. All participants were nonsmokers. All analyses were carried out after an overnight fast. Studies were performed in the PCOS group 3–5 days after spontaneous menses or independently of cycle phase in the presence of amenorrhea and in regularly cycling women during the early follicular phase (3rd–5th day) of their menstrual cycle. All subjects gave written informed consent. The study protocol was approved by the Ethics Committee of Medical University of Bialystok, Poland, and was concordant with the Declaration of Helsinki.

2.2. Biochemical Analyses

Plasma glucose level was measured immediately by the enzymatic reference method with hexokinase (Cobas c111, Roche Diagnostic Ltd., Switzerland). Serum insulin concentration was assayed by immunoradiometric method (DIAsource ImmunoAssays S.A., Belgium). The minimum detectable concentration was 1 μIU/ml and the intra-assay and interassay coefficients of variation (CVs) were below 2.2% and 6.5%, respectively. In this method, human and animal proinsulins present no cross-reactions.

Serum total cholesterol, HDL-cholesterol, and TG were assessed by the enzymatic methods using commercial kits produced by ANALCO-GBG, Poland. Serum LDL cholesterol was calculated according to Friedewald’s formula.

Serum luteinizing hormone (LH) (sensitivity 0.2 mIU/ml; intra-assay CV 3.9%, interassay CV 3.4%), follicle-stimulating hormone (FSH) (sensitivity 0.1 mIU/ml; intra-assay CV 2.0%, interassay CV 4.4%), and serum prolactin (sensitivity 0.35 ng/ml; intra-assay CV 3.3%, interassay CV 4.5%) were measured by the immunoradiometric method (DIAsource ImmunoAssays S.A., Belgium). Serum total testosterone (sensitivity 0.05 ng/dl; intra-assay CV 4.6%, interassay CV 6.2%) was measured by the radioimmunoassay (DIAsource ImmunoAssays S.A., Belgium). Free-androgen index (FAI) was calculated as serum total testosterone (nmol/l) × 100/SHBG (nmol/l) ratio [25].

Serum betatrophin level was detected by enzyme-linked immunosorbent assays using commercially available reagents (USCN Life Science Inc., Wuhan, China); the detection range was 0.156–10 ng/ml and the sensitivity was less than 0.057 ng/ml. Intra- and interassay coefficients of variation were under 10% and 12%, respectively. Δ betatrophin was calculated as the difference in betatrophin between 0 min and 120 min of OGTT.

2.3. Calculations

Consider as following:

(1)The homeostasis model assessment insulin resistance (HOMA-IR) was calculated according to the formula in [26]:(2)Whole-body insulin sensitivity was calculated by Matsuda index according to the formula in [27]:(3)Islet beta cell function was evaluated by homeostasis model assessment β cell function (HOMA-B) according to the formula in [26]:where FPI is fasting plasma insulin (μIU/ml), FPG is fasting plasma glucose (mmol/l), MPG is mean plasma glucose during OGTT (mmol/l), and MPI is mean plasma insulin during OGTT (μIU/ml).

2.4. Statistical Analysis

The statistics were performed with STATISTICA 10.0 software. The differences between the groups were evaluated with nonparametric Mann–Whitney U test. The relationships between variables were evaluated using Spearman’s rank correlation and multiple linear regression analysis. The level of significance was accepted at .

3. Results

The clinical and biochemical characteristics of the studied groups are presented in Table 1. The PCOS and control women did not differ in age, anthropometric indices, plasma lipid concentrations, baseline plasma glucose concentrations, baseline serum insulin concentrations, HOMA-IR, Matsuda index, and HOMA-B (all ) (Table 1). Women with PCOS had significantly elevated serum LH (), total testosterone concentrations (), and FAI () in comparison to the control group (Table 1).

In the PCOS group, higher plasma concentrations of glucose at 30′ () and 60′ () of OGTT, as well as higher serum insulin concentrations at 60′ () of OGTT, in comparison to those in the control group were observed (Table 1).

Baseline serum betatrophin concentrations did not differ between the studied groups (). Glucose load resulted in an increase in serum betatrophin concentrations only in the control group (). In consequence, serum betatrophin concentrations at 120 min of OGTT were lower in women with PCOS in comparison to the control group () (Table 1).

We found a positive correlation between baseline serum betatrophin concentrations and baseline serum insulin concentration (, ), only in women with PCOS.

We found a negative relationship between Δ betatrophin and serum total testosterone concentration in the entire group (, ).

We subsequently examined the relationship between baseline serum betatrophin and indirect indices of insulin resistance, as well as beta cell function in the studied groups. We observed a positive correlation of baseline betatrophin concentrations with HOMA-IR (, ), a negative correlation with Matsuda index (, ), and a positive relationship with HOMA-B (, ) (Figure 1), only in women with PCOS.

(a)

(b)

In the next step, we created a linear regression model for betatrophin as a dependent variable. The model that best predicted betatrophin in patients with PCOS included HOMA-B as an independent variable (, ). This model explained 22.3% of the variability in betatrophin concentrations ().

4. Discussion

The main observation of the present study is the different responses to glucose load in PCOS women in comparison to the healthy women. The glucose load did not cause any increase in serum betatrophin concentrations during OGTT in the PCOS group, contrary to what was observed in the control group. Additionally, we observed relations between serum betatrophin and indirect measures of insulin resistance, as well as HOMA-B, only in the PCOS group. We also found a negative relationship between Δ betatrophin during OGTT and serum total testosterone concentration in the entire group.

The important observation of the present study is the lack of an increase in serum betatrophin after glucose load during OGTT in the PCOS group, as it was observed in controls. There is no straightforward explanation of this phenomenon. In several murine studies, it was shown that fasting is a negative regulator of betatrophin mRNA expression in BAT, WAT, and liver [6, 7, 28]. In humans, one study examined the impact of meals on serum betatrophin concentrations. The authors evaluated 12 nonobese nondiabetic subjects and observed a statistically significant increase in serum betatrophin concentrations 2 hours after a mixed meal containing carbohydrate, protein, and fat [29]. This indicates that its concentrations in healthy subjects rise in response to food intake, as we did not notice the increase in serum betatrophin concentrations during OGTT in women with PCOS in comparison to the control group. Therefore, we can speculate that its disturbances in this group of patients could first appear in the postprandial state.

Other factors contributing to changes in betatrophin concentrations during glucose load still require identifying. In the present study, we observed an increased level of total testosterone in women with PCOS and an inverse correlation between Δ betatrophin and total testosterone levels in the entire group. Therefore, we can hypothesize that elevated total testosterone concentrations might influence serum betatrophin concentrations in response to glucose load during OGTT in the PCOS group. Similarly, Calan et al. showed that serum betatrophin is related to free-testosterone concentrations in PCOS [30]. Additionally, we can hypothesize that inappropriate response in releasing betatrophin after glucose load could lead to the development of glucose intolerance in women with PCOS.

Another observation of the present study is a finding that baseline serum betatrophin concentrations negatively correlated with indirect indices of insulin sensitivity, for example, Matsuda index, and positively with HOMA-IR and HOMA-B only in patients with PCOS. Moreover, in the linear regression analysis, we observed that baseline serum betatrophin concentration was strongly connected with HOMA-B. Therefore, we can assume that serum betatrophin concentrations depend on insulin secretion from beta cells in women with PCOS. As it was mentioned in the Introduction, it has been shown that serum betatrophin concentration positively correlated with C-peptide and HOMA-IR in obese nondiabetic subjects but not in T2D patients [15]. It could be possible that during the development of insulin resistance, betatrophin is not sufficient to compensate for an increased demand for insulin, as it was observed in T2D [14].

Our results are consistent with those of other researchers who showed a positive correlation between serum betatrophin concentration and HOMA-IR in women with PCOS [30] and in the group consisting of patients with T2D and prediabetes and in the control group [20]. Qu et al. also observed that fasting serum betatrophin concentration positively correlated with HOMA-IR only in women with PCOS [31], but did not estimate HOMA-B and Matsuda index. Additionally, Sahin et al. found that serum betatrophin level variability in the PCOS women was explained by homocysteine, HOMA-IR, and androstenedione levels [32]. Erol et al. reported an elevated serum betatrophin concentration in the PCOS women in comparison to the control group, although they did not evaluate HOMA-IR, Matsuda index, or HOMA-B [33].

Contradictory results have been recently reported by other researchers, who found a negative correlation between fasting serum betatrophin concentration and HOMA-IR [34–36]. Song et al. also observed a negative relationship between serum betatrophin concentration and HOMA-B in the PCOS women [34]. Different results obtained by the cited authors could be derived from differences in anthropometrical measurements of the studied groups. We examined Caucasian women with mean BMI 24.5 ± 3.1 kg/m², whereas Song et al. studied Chinese women with mean BMI 25.4 ± 5.0 kg/m² [34]. Additionally, our group of women with PCOS was younger (25.3 ± 4.5 yr versus 28.9 ± 4.9 yr). As betatrophin action could reflect a compensatory response in insulin resistant state and is proposed as a marker of insulin resistance, it is important to take these indices into consideration while comparing the results of different studies [20]. Moreover, we cannot exclude the influence of ethnic origin on serum betatrophin concentrations and different phenotypes of PCOS included in the quoted studies. However, the role of this hormone in the pathogenesis of insulin resistance in PCOS women is not established yet.

The main limitation of the present study is the relatively small sample size, especially in the control group.

5. Conclusions

On the basis of the obtained results, we concluded that serum concentrations of betatrophin are connected with insulin resistance and beta cell function and did not change after glucose load in women with PCOS.

Abbreviations

ANGPLT8:	Atypical angiopoietin-like protein 8
BAT:	Brown adipose tissue
BMI:	Body mass index
CV:	Coefficient of variation
FAI:	Free-androgen index
FFM:	Fat-free mass
FM:	Fat mass
FSH:	Follicle-stimulating hormone
HOMA-B:	Homeostasis model assessment β cell function
HOMA-IR:	Homeostasis model assessment insulin resistance
IR:	Insulin resistance
LH:	Luteinizing hormone
OGTT:	Oral glucose tolerance test
PCOS:	Polycystic ovary syndrome
RIFL:	Refeeding-induced fat and liver protein
SHBG:	Sex hormone-binding globulin
T1D:	Type 1 diabetes mellitus
T2D:	Type 2 diabetes mellitus
TG:	Triglycerides
WAT:	White adipose tissue.

Conflicts of Interest

The authors declare that they have no conflict of interest.

Acknowledgments

This study was funded by a grant from the Medical University of Bialystok (Grant no. N/ST/ZB/15/010/1150).

References

E. Diamanti-Kandarakis and A. Dunaif, “Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications,” Endocrine Reviews, vol. 33, no. 6, pp. 981–1030, 2012.
View at: Publisher Site | Google Scholar
I. Kowalska, M. Straczkowski, A. Nikolajuk et al., “Serum visfatin in relation to insulin resistance and markers of hyperandrogenism in lean and obese women with polycystic ovary syndrome,” Human Reproduction, vol. 22, no. 7, pp. 1824–1829, 2007.
View at: Publisher Site | Google Scholar
A. Dunaif and D. T. Finegood, “Beta-cell dysfunction independent of obesity and glucose intolerance in the polycystic ovary syndrome,” The Journal of Clinical Endocrinology and Metabolism, vol. 81, no. 3, pp. 942–947, 1996.
View at: Publisher Site | Google Scholar
S. A. Arslanian, V. D. Lewy, and K. Danadian, “Glucose intolerance in obese adolescents with polycystic ovary syndrome: roles of insulin resistance and beta-cell dysfunction and risk of cardiovascular disease,” The Journal of Clinical Endocrinology and Metabolism, vol. 86, no. 1, pp. 66–71, 2001.
View at: Publisher Site | Google Scholar
G. Ren, J. Y. Kim, and C. M. Smas, “Identification of RIFL, a novel adipocyte-enriched insulin target gene with a role in lipid metabolism,” American Journal of Physiology. Endocrinology and Metabolism, vol. 303, no. 3, pp. E334–E351, 2012.
View at: Publisher Site | Google Scholar
R. Zhang, “Lipasin, a novel nutritionally-regulated liver-enriched factor that regulates serum triglyceride levels,” Biochemical Biophysical Research Communications, vol. 424, no. 4, pp. 786–792, 2012.
View at: Publisher Site | Google Scholar
F. Quagliarini, Y. Wang, J. Kozlitina et al., “Atypical angiopoietin-like protein that regulates ANGPTL3,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 48, pp. 19751–19756, 2012.
View at: Publisher Site | Google Scholar
P. Yi, J. S. Park, and D. A. Melton, “Betatrophin: a hormone that controls pancreatic β cell proliferation,” Cell, vol. 153, no. 4, pp. 747–758, 2013.
View at: Publisher Site | Google Scholar
S. Li, D. Liu, L. Li et al., “Circulating betatrophin in patients with type 2 diabetes: a meta-analysis,” Journal of Diabetes Research, vol. 2016, Article ID 6194750, p. 9, 2016.
View at: Publisher Site | Google Scholar
H. Hu, W. Sun, S. Yu et al., “Increased circulating levels of betatrophin in newly diagnosed type 2 diabetic patients,” Diabetes Care, vol. 37, no. 10, pp. 2718–2722, 2014.
View at: Publisher Site | Google Scholar
J. Gomez-Ambrosi, E. Pascual, V. Catalan et al., “Circulating betatrophin concentrations are decreased in human obesity and type 2 diabetes,” The Journal of Clinical Endocrinology and Metabolism, vol. 99, no. 10, pp. E2004–E2009, 2014.
View at: Publisher Site | Google Scholar
A. Fenzl, B. K. Itariu, L. Kosi et al., “Circulating betatrophin correlates with atherogenic lipid profiles but not with glucose and insulin levels in insulin-resistant individuals,” Diabetologia, vol. 57, no. 6, pp. 1204–1208, 2014.
View at: Publisher Site | Google Scholar
V. Gusarova, C. A. Alexa, E. Na et al., “ANGPTL8/betatrophin does not control pancreatic beta cell expansion,” Cell, vol. 159, no. 3, pp. 691–696, 2014.
View at: Publisher Site | Google Scholar
M. Abu-Farha, J. Abubaker, I. Al-Khairi et al., “Higher plasma betatrophin/ANGPTL8 level in type 2 diabetes subjects does not correlate with blood glucose or insulin resistance,” Scientific Reports, vol. 5, p. 10949, 2015.
View at: Publisher Site | Google Scholar
M. Abu-Farha, J. Abubaker, F. Noronha et al., “Lack of associations between betatrophin/ANGPTL8 level and C-peptide in type 2 diabetic subjects,” Cardiovascular Diabetology, vol. 14, no. 1, p. 112, 2015.
View at: Publisher Site | Google Scholar
D. Espes, J. Lau, and P. O. Carlsson, “Increased circulating levels of betatrophin in individuals with long-standing type 1 diabetes,” Diabetologia, vol. 57, no. 1, pp. 50–53, 2014.
View at: Publisher Site | Google Scholar
L. K. Trebotic, P. Klimek, A. Thomas et al., “Circulating betatrophin is strongly increased in pregnancy and gestational diabetes mellitus,” PloS One, vol. 10, no. 9, article e0136701, 2015.
View at: Publisher Site | Google Scholar
A. Akour, V. Kasabri, N. Boulatova et al., “Levels of metabolic markers in drug-naive prediabetic and type 2 diabetic patients,” Acta Diabetologica, vol. 54, no. 2, pp. 163–170, 2017.
View at: Publisher Site | Google Scholar
A. Al-Rawashdeh, V. Kasabri, N. Bulatova et al., “The correlation between plasma levels of oxytocin and betatrophin in non-diabetic and diabetic metabolic syndrome patients: a cross sectional study from Jordan,” Diabetes and Metabolic Syndrome, vol. 11, no. 1, pp. 59–67, 2017.
View at: Publisher Site | Google Scholar
X. Chen, P. Lu, W. He et al., “Circulating betatrophin levels are increased in patients with type 2 diabetes and associated with insulin resistance,” The Journal of Clinical Endocrinology and Metabolism, vol. 100, no. 1, pp. E96–100, 2015.
View at: Publisher Site | Google Scholar
S. Tokumoto, Y. Hamamoto, K. Fujimoto et al., “Correlation of circulating betatrophin concentrations with insulin secretion capacity, evaluated by glucagon stimulation tests,” Diabetic Medicine, vol. 32, no. 5, pp. 653–656, 2015.
View at: Publisher Site | Google Scholar
Y. Zhang, S. Li, W. Donelan et al., “Angiopoietin-like protein 8 (betatrophin) is a stress-response protein that down-regulates expression of adipocyte triglyceride lipase,” Biochimica et Biophysica Acta, vol. 1861, no. 2, pp. 130–137, 2016.
View at: Publisher Site | Google Scholar
Y. Wang, F. Quagliarini, V. Gusarova et al., “Mice lacking ANGPTL8 (betatrophin) manifest disrupted triglyceride metabolism without impaired glucose homeostasis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 40, pp. 16109–16114, 2013.
View at: Publisher Site | Google Scholar
Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, “Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome,” Fertility and Sterility, vol. 81, no. 1, pp. 19–25, 2004.
View at: Publisher Site | Google Scholar
A. Vermeulen, L. Verdonck, and J. M. Kaufman, “A critical evaluation of simple methods for the estimation of free testosterone in serum,” The Journal of Clinical Endocrinology and Metabolism, vol. 84, no. 10, pp. 3666–3672, 1999.
View at: Publisher Site | Google Scholar
D. R. Matthews, J. P. Hosker, A. S. Rudenski, B. A. Naylor, D. F. Treacher, and R. C. Turner, “Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man,” Diabetologia, vol. 28, no. 7, pp. 412–419, 1985.
View at: Publisher Site | Google Scholar
M. Matsuda and R. A. DeFronzo, “Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp,” Diabetes Care, vol. 22, no. 9, pp. 1462–1470, 1999.
View at: Publisher Site | Google Scholar
Z. Fu, F. Yao, A. B. Abou-Samra, and R. Zhang, “Lipasin, thermoregulated in brown fat, is a novel but atypical member of the angiopoietin-like protein family,” Biochemical Biophysical Research Communications, vol. 430, no. 3, pp. 1126–1131, 2013.
View at: Publisher Site | Google Scholar
Z. Fu, F. Berhane, A. Fite, B. Seyoum, A. B. Abou-Samra, and R. Zhang, “Elevated circulating lipasin/betatrophin in human type 2 diabetes and obesity,” Scientific Reports, vol. 4, p. 5013, 2014.
View at: Publisher Site | Google Scholar
M. Calan, O. Yilmaz, T. Kume et al., “Elevated circulating levels of betatrophin are associated with polycystic ovary syndrome,” Endocrine, vol. 53, no. 1, pp. 271–279, 2016.
View at: Publisher Site | Google Scholar
Q. Qu, D. Zhao, F. Zhang, H. Bao, and Q. Yang, “Serum betatrophin levels are increased and associated with insulin resistance in patients with polycystic ovary syndrome,” Journal of International Medical Research, vol. 45, no. 1, pp. 193–202, 2017.
View at: Publisher Site | Google Scholar
G. Sahin Ersoy, T. Altun Ensari, D. Vatansever, V. Emirdar, and O. Cevik, “Novel adipokines WISP1 and betatrophin in PCOS: relationship to AMH levels, atherogenic and metabolic profile,” Gynecological Endocrinology, vol. 33, no. 2, pp. 119–123, 2017.
View at: Publisher Site | Google Scholar
O. Erol, M. K. Özel, H. Y. Ellidağ, T. Toptaş, A. U. Derbent, and N. Yılmaz, “Assessment of circulating betatrophin concentrations in lean glucose-tolerant women with polycystic ovary syndrome,” Journal of Obstetrics and Gynaecology, pp. 1–6, 2017.
View at: Publisher Site | Google Scholar
S. Song, J. Wang, C. Guo, and T. Jiang, “Elevated serum levels of betatrophin in patients with polycystic ovary syndrome and the influential factors,” Zhong Nan Da Xue Xue Bao Yi Xue Ban, vol. 41, no. 9, pp. 969–974, 2016.
View at: Publisher Site | Google Scholar
L. Li, F. Zhang, J. Cui et al., “Association of betatrophin with metabolic characteristics in overweight/obese and lean women with PCOS,” Gynecological Endocrinology, vol. 33, no. 3, pp. 238–243, 2017.
View at: Publisher Site | Google Scholar
G. Erbag, M. Eroglu, H. Turkon et al., “Relationship between betatrophin levels and metabolic parameters in patients with polycystic ovary syndrome,” Cellular and Molecular Biology (Noisy-le-grand, France), vol. 62, no. 5, pp. 20–24, 2016.
View at: Google Scholar

Copyright

Copyright © 2017 Agnieszka Adamska et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

1338

Downloads

1064

Citations