J C E M
O N L I N E
B r i e f
R e p o r t — E n d o c r i n e
R e s e a r c h
Circulating Betatrophin Levels Are Increased in Patients With Type 2 Diabetes and Associated With Insulin Resistance Xi Chen,* Puhan Lu,* Wentao He, Jianhua Zhang, Lei Liu, Yan Yang, Zhelong Liu, Junhui Xie, Shiying Shao, Tingting Du, Xianghui Su, Xinrong Zhou, Shuhong Hu, Gang Yuan, Muxun Zhang, Hong Zhang, Liegang Liu, Daowen Wang, and Xuefeng Yu Division of Endocrinology (X.C., P.L., W.H., J.Z., Y.Y., Z.L., J.X., S.S., T.D., X.S., X.Z., S.H., G.Y., M.Z., X.Y.), Department of Internal Medicine, Division of Cardiology (Le.L., D.W.), Department of Internal Medicine, Department of Ophthalmology (H.Z.), Tongji Hospital, and Department of Nutrition and Food Hygiene (Li.L.), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, People’s Republic of China
Context: Betatrophin has recently attracted increasing interests as a potential -cell regenerative therapy in diabetes. However, differences in betatrophin profiles in patients with type 2 diabetes mellitus (T2DM) remain unclear. Objective: The objective of the study was to examine circulating betatrophin levels in subjects with different glucose tolerance status and its correlation with insulin resistance. Design, Setting, and Participants: Serum betatrophin levels were measured using an ELISA in age-, sex-, body mass index-, and blood lipid-matched subjects with normal glucose tolerance (n ⫽ 137), isolated impaired fasting glucose (n ⫽ 69), isolated impaired glucose tolerance (n ⫽ 120), and newly diagnosed T2DM (n ⫽ 112) from the Risk Evaluation of Cancers in Chinese Diabetic Individuals: A Longitudinal study. Results: Serum betatrophin levels were elevated in patients with T2DM compared with subjects with normal glucose tolerance, isolated impaired fasting glucose, or isolated impaired glucose tolerance (798.6 ⫾ 42.5 vs 692.7 ⫾ 29.0, P ⬍ .05, vs 682.7 ⫾ 43.0, P ⬍ .05, vs 646.8 ⫾ 34.3 pg/mL, P ⬍ .01). Betatrophin levels positively correlated with the index of homeostasis model assessment of insulin resistance (partial r ⫽ 0.11); inversely correlated with quantitative insulin sensitivity check index (partial r ⫽ ⫺0.11), the Gutt insulin sensitivity index (partial r ⫽ ⫺0.12), and the Matsuda insulin sensitivity index (partial r ⫽ ⫺0.11) after controlling for age, sex, body mass index, and blood lipid in all participants (all values of P ⬍ .05). Conclusion: Circulating betatrophin levels are increased in patients with T2DM and associated with indexes of insulin resistance. (J Clin Endocrinol Metab 100: E96 –E100, 2015)
B
etatrophin, a novel hormone proposed as a potent stimulator of -cell proliferation, has been found to be significantly increased in liver and white adipose tissue in a mouse model of insulin resistance using the insulin
receptor antagonist S961 (1). A study conducted by Yi et al (1) suggests that hepatic overexpression of betatrophin promotes pancreatic -cells expansion and insulin secretion, with improvements in glucose tolerance. In this re-
ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2015 by the Endocrine Society Received May 11, 2014. Accepted October 6, 2014. First Published Online October 10, 2014
* X.C. and P.L. contributed equally to this work. Abbreviations: BMI, body mass index; FPG, fasting PG; HDL, high-density lipoprotein; HOMA-, homeostasis model assessment of -cell function; HOMA-IR, homeostasis model assessment of insulin resistance; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; ISIG, Gutt insulin sensitivity index; ISIM, Matsuda insulin sensitivity index; LDL, low-density lipoprotein; NGT, normal glucose tolerance; PG, plasma glucose; QUICKI, quantitative insulin sensitivity check index; T2DM, type 2 diabetes mellitus.
E96
jcem.endojournals.org
J Clin Endocrinol Metab, January 2015, 100(1):E96 –E100
doi: 10.1210/jc.2014-2300
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 11 February 2015. at 04:00 For personal use only. No other uses without permission. . All rights reserved.
doi: 10.1210/jc.2014-2300
gard, an important notion has attracted increasing interests is that betatrophin may be involved in the compensatory response to insulin resistance (2). If these findings in mice are successfully translated to the clinic, this would open a new pathway to a possible diabetes therapy (3–5). Recently Espes et al (6) suggested that betatrophin levels were increased in patients with long-standing type 1 diabetes mellitus. However, contradictory results have been reported in patients with type 2 diabetes mellitus (T2DM) (7–9). Therefore, despite promising pictures have been sketched in mice, the results from humans are limited (10). Since the increase of betatrophin was found in Yi’s mouse model of insulin resistance using S961 and other murine models of insulin resistance, such as ob/ob, db/db and pregnant mouse, it seems that betatrophin is increased in face of insulin resistance in mice. As to humans, evidence for betatrophin-insulin resistance association is still lacking. Therefore, the present study aims to evaluate circulating betatrophin levels in subjects with different glucose tolerance status and the factors associated with betatrophin levels, especially whether insulin resistance is associated with betatrophin levels.
Subjects and Methods Subjects The present study participants were recruited from Hubei Province of China during 2011–2012, as one part of the Risk Evaluation of Cancers in Chinese Diabetic Individuals: A Longitudinal study, which was conducted among 259 657 adults, aged 40 years and older in 25 communities across mainland of China (11). In our study, age-, sex-, body mass index (BMI)- and blood lipid-matched subjects with normal glucose tolerance (NGT) (n ⫽ 137), isolated impaired fasting glucose (IFG) (n ⫽ 69), isolated impaired glucose tolerance (IGT) (n ⫽ 120), and newly diagnosed T2DM (n ⫽ 112) were included after excluding those with renal or liver dysfunction, of which none have received antidiabetic or hypolipidemic therapies and 20% have taken antihypertensive agents. The Committee on Human Research at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, approved the study protocol, and all participants provided written informed consents.
Clinical and biochemical evaluation As previously described in the Risk Evaluation of Cancers in Chinese Diabetic Individuals: A Longitudinal study (11), information on sociodemographic characteristics, lifestyle factors, medical history, and family history were collected by trained staff using a standard questionnaire. All participants were asked to fast for at least 10 hours to undergo the oral glucose tolerance test and blood sampling for analysis of various biochemical parameters.
jcem.endojournals.org
E97
Assessment of diabetes and insulin resistance The diagnosis of NGT, isolated IFG, isolated IGT, and T2DM were based on the diagnostic criteria of American Diabetes Association 2006 (12). These included the following: NGT: fasting plasma glucose (FPG) less than 5.6 mmol/L and 2-hour plasma glucose (PG) less than 7.8 mmol/L; isolated IFG: 5.6 mmol/L less than or equal to FPG less than 7.0 mmol/L and 2-hour PG less than 7.8 mmol/L; isolated IGT: FPG less than 5.6 mmol/L and 7.8 mmol/L less than or equal to 2-hour PG less than 11.1 mmol/L; and T2DM: FPG more than or equal to 7.0 mmol/L or 2-hour PG 11.1 mmol/L or greater. B cell function was assessed by homeostasis model assessment of -cell function (HOMA-) (13). Insulin resistance was estimated by the index of homeostasis model assessment of insulin resistance (HOMA-IR) (13), quantitative insulin sensitivity check index (QUICKI) (14), the Gutt insulin sensitivity index (ISIG) (14), and the Matsuda insulin sensitivity index (ISIM) (14). All indexes were calculated according to published formulas (Supplemental Table 1).
Measurement of betatrophin Betatrophin levels in the fasting serum were assessed using ELISA kits (Eiaab Science; catalog number E11644h). The procedures were performed in accordance with the manufacturer’s instructions. All samples were analyzed in duplicate.
Statistical analysis SPSS version 20.0 was used for all analysis. The data were presented as mean ⫾ SEM. Normal distribution of the data was tested using the Kolmogorox-Smirnov test. Variables not normally distributed were natural logarithmically transformed. Comparisons between groups were performed with an ANOVA followed by least significant differences tests. The correlations between variables were assessed using a Pearson correlation analysis by controlling for the covariates. The value of P ⬍ .05 (two tailed) was taken to indicate statistical significance.
Results Circulating betatrophin levels were increased in T2DM The characteristics of subjects with NGT (n ⫽ 137), isolated IFG (n ⫽ 69), isolated IGT (n ⫽ 120), and T2DM (n ⫽ 112) are described in Table 1. There were no significant differences in age, sex, BMI, or lipid profiles between every 2 groups (all P values ⬎ .05). Notably, serum betatrophin levels were significantly elevated in patients with T2DM compared with subjects with NGT, isolated IFG, or isolated IGT (798.6 ⫾ 42.5 vs 692.7 ⫾ 29.0, P ⬍ .05; 798.6 ⫾ 42.5 vs 682.7 ⫾ 43.0, P ⬍ .05; 798.6 ⫾ 42.5 vs 646.8 ⫾ 34.3 pg/mL, P ⬍ .01). However, there were no significant differences of betatrophin levels between each pair of NGT, isolated IFG, and isolated IGT (all P values ⬎ .05). Actually, serum betatrophin levels were increased in type 2 diabetic patients compared with nondiabetic subjects (including NGT, isolated IFG, and isolated IGT) (798.6 ⫾ 42.5 vs 673.7 ⫾ 19.7 pg/mL, P ⬍ .01). Next, we
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 11 February 2015. at 04:00 For personal use only. No other uses without permission. . All rights reserved.
E98
Chen et al
Table 1.
Betatrophin and T2DM
J Clin Endocrinol Metab, January 2015, 100(1):E96 –E100
Clinical and Metabolic Parameters for Subjects With Different Glucose Tolerance
Variable
NGT (n ⴝ 137)
Isolated IFG (n ⴝ 69)
Isolated IGT (n ⴝ 120)
T2DM (n ⴝ 112)
P Value
Age, ya Female, % BMI, kg/m2 FPG, mmol/L 2 hour-PG, mmol/L HbA1c, % HbA1c, mmol/mol Fasting insulin, pmol/L 2 hour-insulin, pmol/L HOMA- HOMA-IR QUICKI ISIG, mg/L2䡠mmol䡠mU䡠min ISIM Total cholesterol, mmol/La Triacylglycerol, mmol/L HDL-cholesterol, mmol/L LDL-cholesterol, mmol/La Betatrophin, pg/mL
60.2 ⫾ 0.7 55 23.0 ⫾ 0.2 4.9 ⫾ 0.04b 5.5 ⫾ 0.08b,d 5.5 ⫾ 0.03 36.91 ⫾ 0.29 30.0 ⫾ 1.8b 159.0 ⫾ 14.4d 84.38 ⫾ 8.80 1.07 ⫾ 0.06b 0.396 ⫾ 0.004b 119.3 ⫾ 3.4b,d 18.1 ⫾ 0.9 4.9 ⫾ 0.07 1.4 ⫾ 0.06 1.5 ⫾ 0.03 2.8 ⫾ 0.06 692.7 ⫾ 29.0
62.5 ⫾ 1.2 54 23.7 ⫾ 0.5 6.6 ⫾ 0.02c,d 6.4 ⫾ 0.10c,d 5.5 ⫾ 0.04 36.8 ⫾ 0.44 61.8 ⫾ 6.0c,d 180.0 ⫾ 14.4d 65.39 ⫾ 6.58 3.01 ⫾ 0.30c,d 0.347 ⫾ 0.007c,d 86.9 ⫾ 4.14c,d 10.2 ⫾ 1.1c 5.0 ⫾ 0.11 1.5 ⫾ 0.09 1.5 ⫾ 0.04 2.8 ⫾ 0.10 682.7 ⫾ 43.0
60.8 ⫾ 0.9 53 23.2 ⫾ 0.3 5.1 ⫾ 0.03b 8.5 ⫾ 0.04b,c 5.6 ⫾ 0.03 37.7 ⫾ 0.32 31.2 ⫾ 1.8b 322.8 ⫾ 21.6b,c 69.59 ⫾ 4.72 1.17 ⫾ 0.07b 0.389 ⫾ 0.004b 68.58 ⫾ 1.98b,c 10.6 ⫾ 0.7c 5.1 ⫾ 0.09 1.4 ⫾ 0.07 1.5 ⫾ 0.03 2.9 ⫾ 0.07 646.8 ⫾ 34.3
60.7 ⫾ 0.9 48 23.4 ⫾ 0.3 8.7 ⫾ 0.2b,c,d 15.3 ⫾ 0.3b,c,d 7.7 ⫾ 0.1b,c,d 60.1 ⫾ 1.49b,c,d 47.4 ⫾ 4.8c,d,e 181.8 ⫾ 12.0d 36.64 ⫾ 6.68c,d,e 3.09 ⫾ 0.30c,d 0.345 ⫾ 0.004c,d 47.7 ⫾ 1.44b,c,d 7.4 ⫾ 0.5c,d,e 5.0 ⫾ 0.10 1.5 ⫾ 0.08 1.4 ⫾ 0.04 2.9 ⫾ 0.07 798.6 ⫾ 42.5d,e,f
.43 .72 .71 ⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001 .601 .60 .25 .62 .01
Abbreviation: HbA1c, glycated hemoglobin. All values are given as mean ⫾ SEM. a
Data normally distributed.
b
Compared with IFG, P ⬍ .01.
c
Compared with NGT, P ⬍ .01.
d
Compared with IGT, P ⬍ .01.
e
Compared with IFG, P ⬍ .05.
f
Compared with NGT, P ⬍ .05.
studied correlations between betatrophin and other nonglucose-related variables including age, BMI, and lipid profiles in nondiabetic and type 2 diabetic subjects, respectively. The results showed that betatrophin levels significantly correlated with age both in nondiabetic (r ⫽ 0.48, P ⬍ .001) and diabetic (r ⫽ 0.43, P ⬍ .001) subjects. Moreover, betatrophin also correlated with total cholesterol (r ⫽ ⫺0.26, P ⬍ .01), low-density lipoprotein (LDL)cholesterol (r ⫽ ⫺0.26, P ⬍ .01), and high-density lipoprotein (HDL)-cholesterol (r ⫽ ⫺0.23, P ⫽ .01) in diabetic patients but not in nondiabetic subjects (all P values ⬎ .05). There was no association between betatrophin and BMI in either nondiabetic (r ⫽ ⫺0.03, P ⫽ .57) or diabetic (r ⫽ ⫺0.15, P ⫽ .13) subjects. Betatrophin correlates with indexes of insulin resistance Next, we studied correlations between betatrophin levels and glucose-related variables in all participants by using Pearson correlation analysis. We observed that after controlling for age, sex, and BMI, betatrophin levels positively correlated with FPG (r ⫽ 0.10), 2-hour PG (r ⫽ 0.11), and HOMA-IR (r ⫽ 0.10) but negatively correlated with QUICKI (r ⫽ ⫺0.10), ISIG (r ⫽ ⫺0.11), and ISIM (r ⫽ ⫺0.10) (all P values ⬍ .05) (Table 2). When further controlling with blood lipid (total cholesterol), the correla-
tions between betatrophin levels and blood glucose (FPG and 2 hour PG) and insulin resistance-related variables (HOMA-IR, QUICKI, ISIG, and ISIM) were still unchanged (Table 2). In sensitivity analyses, if we use LDLcholesterol instead of total cholesterol for controlling blood lipid, the correlations were the same (data not shown).
Discussion Because the newly emerging role of betatrophin in -cell regeneration has yet to be reproduced in the human model and there are few studies available on the topic in general, here we measured serum betatrophin concentrations in subjects with NGT, isolated IFG, isolated IGT, and T2DM, and found that betatrophin levels were significantly increased in patients with T2DM compared with nondiabetic subjects. Additionally, our results not only replicated the finding that betatrophin was associated with lipid profile but also showed that betatrophin was correlated with indexes of insulin resistance. Of note, the mean levels of betatrophin reported by Fenzl et al (7) (⬃1600 pg/mL) is approximately doubled compared with those of ours (⬃700 pg/mL), and they have claimed that betatrophin levels are unaltered between
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 11 February 2015. at 04:00 For personal use only. No other uses without permission. . All rights reserved.
doi: 10.1210/jc.2014-2300
Table 2.
jcem.endojournals.org
E99
Partial Correlations Between Betatrophin Levels and Glucose-Related Variables in All Study Participants Betatrophin (Age,a Sex, and BMI Adjusted)
Betatrophin
FPG Two-hour PG HbA1c Fasting insulin Two-hour insulin HOMA- HOMA-IR QUICKI ISIG ISIM
Betatrophin (Age,a Sex, BMI, and Total Cholesterola Adjusted)
r
P Value
Partial r
P Value
Partial r
P Value
0.073 0.092 0.012 ⫺0.018 ⫺0.002 ⫺0.087 0.018 ⫺0.011 ⫺0.092 ⫺0.042
.129 .054 .798 .702 .966 .069 .706 .811 .054 .393
0.100 0.114 0.049 0.062 ⫺0.001 ⫺0.050 0.098 ⫺0.096 ⫺0.108b ⫺0.097
.038 .017 .324 .209 .981 .311 .046 .050 .028b .048
0.106 0.119 0.059 0.069 0.000 ⫺0.050 0.106 ⫺0.105 ⫺0.109c ⫺0.103
.028 .013 .234 .160 .999 .311 .031 .032 .027c .035
Abbreviation: HbA1c, glycated hemoglobin. a
Data normally distributed.
b
Age and sex adjusted.
c
Age, sex, and total cholesterol adjusted.
nondiabetic and type 2 diabetic participants. These may be due to the different sample size in the study by Fenzl et al (7) (n ⫽ 37) from ours (n ⫽ 438) and the subjects in the study by Fenzl et al with higher BMI and a different ethnicity. More importantly, the diabetic patients in the study by Fenzl et al had taken oral hypoglycemic drugs (metformin ⫾ sulfonylureas), which would potentially affect the levels of betatrophin because the main effect of metformin is to reduce insulin resistance. Very recently another two independent groups have published their results showing that betatrophin levels are increased in patients with T2DM (8, 9), which are consistent with ours. Moreover, we found a correlation between betatrophin and indexes of insulin resistance, including HOMA-IR, QUICKI, ISIG, and ISIM. However, it is not clear whether increased betatrophin expression is a compensatory response or only a marker of insulin resistance. Notably, increased circulating betatrophin levels were found only in patients with T2DM but not in prediabetic subjects who already have insulin resistance (15). It is possible that betatrophin would be increased only when the degree of insulin resistance reaches a certain threshold as a compensatory response. However, we cannot exclude that the elevated betatrophin levels may be associated with other unknown factors of diabetes, which may affect insulin resistance. Further studies are needed to delineate the mechanisms of betatrophin in T2DM and insulin resistance. Beyond glucose metabolism, we also found that betatrophin levels significantly associated with lipid profile. Previous studies in mice have shown that overexpression of betatrophin increases triacylglycerol levels (16, 17), whereas betatrophin deficiency reduces triacylglycerol
concentrations (18, 19). These results are in line with our positive correlation of betatrophin with triacylglycerol (r ⫽ 0.18, P ⫽ .062), although the P value does not reach a statistically significant level. Interestingly, we found negative correlations between betatrophin and total cholesterol, LDL-cholesterol, and HDL-cholesterol, which are consistent with the result from Espes et al (9) but opposite to what Fenzl et al (7) have reported. The reason for the discrepancy is unclear and may be due to difference in study design, sample size, medicine status, and patient selection. In addition, studies in mice have suggested that the mechanisms of betatrophin in lipid control are very complicated. It may interact with other gene products, such as angiopoietin-like 3, to coregulate the lipid metabolism (17). The strengths of our study were that the subjects included were newly diagnosed type 2 diabetic patients without any antidiabetic treatment, whose betatrophin levels probably better reflected the natural profiles of betatrophin. Nevertheless, the sample size of our study was larger than the previous study. Furthermore, the use of indexes derived from both fasting and 2-hour post-oral glucose tolerance test to assess insulin resistance is also advantageous. Limitations of the study were that we investigated betatrophin levels only in a Chinese population. The results from our study need to be confirmed in other ethnicities in the future. Also, because of our cross-sectional design, we cannot determine the cause and effect between betatrophin and insulin resistance in the present study. In conclusion, we have found that the levels of circulating betatrophin are increased in T2DM and that betatrophin levels correlate to markers of insulin resistance.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 11 February 2015. at 04:00 For personal use only. No other uses without permission. . All rights reserved.
E100
Chen et al
Betatrophin and T2DM
Further studies are needed to elucidate the role of betatrophin in the development of T2DM and whether betatrophin could have clinical applications in the development of new antidiabetic drugs.
Acknowledgments Author contributions included the following: X.C., P.L., W.H., and X.Y. contributed to the study design. X.C., P.L., J.Z., Le.L., Y.Y., Z.L., J.X., S.S., T.D., X.S., X.Z., S.H., G.Y., M.Z., H.Z., Li.L., D.W., and X.Y. contributed to the data acquisition. X.C. and P.L. analyzed the data. X.C., P.L., Le.L., and X.Y. wrote the manuscript. X.Y. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Address all correspondence and requests for reprints to: Xuefeng Yu, MD, PhD, Professor of Medicine, Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People’s Republic of China. Email: [email protected]. This work was supported by grants from the National Nature Science Foundation of China (Grant 30772207); Wuhan Planning Project of Science and Technology (Grant 201060938360 – 04), Wuhan Science and Technology Bureau; and the Chinese Society of Endocrinology and the National Clinical Research Center for Metabolic Diseases. Disclosure Summary: The authors have nothing to disclose.
References 1. Yi P, Park JS, Melton DA. Betatrophin: a hormone that controls pancreatic beta cell proliferation. Cell. 2013;153:747–758. 2. Araujo TG, Oliveira AG, Saad MJ. Insulin-resistance-associated compensatory mechanisms of pancreatic  cells: a current opinion. Front Endocrinol. 2013;4:146. 3. Kugelberg E. Diabetes: betatrophin-inducing -cell expansion to treat diabetes mellitus? Nat Rev Endocrinol. 2013;9:379.
J Clin Endocrinol Metab, January 2015, 100(1):E96 –E100
4. Raghow R. Betatrophin: a liver-derived hormone for the pancreatic -cell proliferation. World J Diabetes. 2013;4:234 –237. 5. Lickert H. Betatrophin fuels  cell proliferation: first step toward regenerative therapy? Cell Metab. 2013;18:5– 6. 6. Espes D, Lau J, Carlsson PO. Increased circulating levels of betatrophin in individuals with long-standing type 1 diabetes. Diabetologia. 2014;57:50 –53. 7. Fenzl A, Itariu BK, Kosi L, et al. Circulating betatrophin correlates with atherogenic lipid profiles but not with glucose and insulin levels in insulin-resistant individuals. Diabetologia. 2014;57:1204 –1208. 8. Fu Z, Berhane F, Fite A, Seyoum B, Abou-Samra AB, Zhang R. Elevated circulating lipasin/betatrophin in human type 2 diabetes and obesity. Scientific Rep. 2014;4:5013. 9. Espes D, Martinell M, Carlsson PO. Increased circulating beatatrophin concentrations in patients with type 2 diabetes. Int J Endocrinol. 2014:323407. 10. Stewart AF. Betatrophin versus bitter-trophin and the elephant in the room: time for a new normal in -cell regeneration research. Diabetes. 2014;63:1198 –1199. 11. Lu J, Bi Y, Wang T, et al. The relationship between insulin-sensitive obesity and cardiovascular diseases in a Chinese population: results of the REACTION study. Int J Cardiol. 2014;172:388 –394. 12. American Diabetes Association. Standards of medical care in diabetes—2006 (Position Statement). Diabetes Care 2006;29(suppl 1): S4 –S42. 13. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and -cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412– 419. 14. Monzillo LU, Hamdy O. Evaluation of insulin sensitivity in clinical practice and in research settings. Nutr Rev. 2003;61:397– 412. 15. Tabak AG, Herder C, Rathmann W, Brunner EJ, Kivimaki M. Prediabetes: a high-risk state for diabetes development. Lancet. 2012; 379:2279 –2290. 16. Zhang R. Lipasin, a novel nutritionally-regulated liver-enriched factor that regulates serum triglyceride levels. Biochem Biophys Res Commun. 2012;424:786 –792. 17. Quagliarini F, Wang Y, Kozlitina J, et al. Atypical angiopoietin-like protein that regulates ANGPTL3. Proc Natl Acad Sci USA. 2012; 109:19751–19756. 18. Ren G, Kim JY, Smas CM. Identification of RIFL, a novel adipocyteenriched insulin target gene with a role in lipid metabolism. Am J Physiol Endocrinol Metab. 2012;303:E334 –E351. 19. Wang Y, Quagliarini F, Gusarova V, et al. Mice lacking ANGPTL8 (Betatrophin) manifest disrupted triglyceride metabolism without impaired glucose homeostasis. Proc Natl Acad Sci USA. 2013;110: 16109 –16114.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 11 February 2015. at 04:00 For personal use only. No other uses without permission. . All rights reserved.
O N L I N E
B r i e f
R e p o r t — E n d o c r i n e
R e s e a r c h
Circulating Betatrophin Levels Are Increased in Patients With Type 2 Diabetes and Associated With Insulin Resistance Xi Chen,* Puhan Lu,* Wentao He, Jianhua Zhang, Lei Liu, Yan Yang, Zhelong Liu, Junhui Xie, Shiying Shao, Tingting Du, Xianghui Su, Xinrong Zhou, Shuhong Hu, Gang Yuan, Muxun Zhang, Hong Zhang, Liegang Liu, Daowen Wang, and Xuefeng Yu Division of Endocrinology (X.C., P.L., W.H., J.Z., Y.Y., Z.L., J.X., S.S., T.D., X.S., X.Z., S.H., G.Y., M.Z., X.Y.), Department of Internal Medicine, Division of Cardiology (Le.L., D.W.), Department of Internal Medicine, Department of Ophthalmology (H.Z.), Tongji Hospital, and Department of Nutrition and Food Hygiene (Li.L.), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, People’s Republic of China
Context: Betatrophin has recently attracted increasing interests as a potential -cell regenerative therapy in diabetes. However, differences in betatrophin profiles in patients with type 2 diabetes mellitus (T2DM) remain unclear. Objective: The objective of the study was to examine circulating betatrophin levels in subjects with different glucose tolerance status and its correlation with insulin resistance. Design, Setting, and Participants: Serum betatrophin levels were measured using an ELISA in age-, sex-, body mass index-, and blood lipid-matched subjects with normal glucose tolerance (n ⫽ 137), isolated impaired fasting glucose (n ⫽ 69), isolated impaired glucose tolerance (n ⫽ 120), and newly diagnosed T2DM (n ⫽ 112) from the Risk Evaluation of Cancers in Chinese Diabetic Individuals: A Longitudinal study. Results: Serum betatrophin levels were elevated in patients with T2DM compared with subjects with normal glucose tolerance, isolated impaired fasting glucose, or isolated impaired glucose tolerance (798.6 ⫾ 42.5 vs 692.7 ⫾ 29.0, P ⬍ .05, vs 682.7 ⫾ 43.0, P ⬍ .05, vs 646.8 ⫾ 34.3 pg/mL, P ⬍ .01). Betatrophin levels positively correlated with the index of homeostasis model assessment of insulin resistance (partial r ⫽ 0.11); inversely correlated with quantitative insulin sensitivity check index (partial r ⫽ ⫺0.11), the Gutt insulin sensitivity index (partial r ⫽ ⫺0.12), and the Matsuda insulin sensitivity index (partial r ⫽ ⫺0.11) after controlling for age, sex, body mass index, and blood lipid in all participants (all values of P ⬍ .05). Conclusion: Circulating betatrophin levels are increased in patients with T2DM and associated with indexes of insulin resistance. (J Clin Endocrinol Metab 100: E96 –E100, 2015)
B
etatrophin, a novel hormone proposed as a potent stimulator of -cell proliferation, has been found to be significantly increased in liver and white adipose tissue in a mouse model of insulin resistance using the insulin
receptor antagonist S961 (1). A study conducted by Yi et al (1) suggests that hepatic overexpression of betatrophin promotes pancreatic -cells expansion and insulin secretion, with improvements in glucose tolerance. In this re-
ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2015 by the Endocrine Society Received May 11, 2014. Accepted October 6, 2014. First Published Online October 10, 2014
* X.C. and P.L. contributed equally to this work. Abbreviations: BMI, body mass index; FPG, fasting PG; HDL, high-density lipoprotein; HOMA-, homeostasis model assessment of -cell function; HOMA-IR, homeostasis model assessment of insulin resistance; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; ISIG, Gutt insulin sensitivity index; ISIM, Matsuda insulin sensitivity index; LDL, low-density lipoprotein; NGT, normal glucose tolerance; PG, plasma glucose; QUICKI, quantitative insulin sensitivity check index; T2DM, type 2 diabetes mellitus.
E96
jcem.endojournals.org
J Clin Endocrinol Metab, January 2015, 100(1):E96 –E100
doi: 10.1210/jc.2014-2300
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 11 February 2015. at 04:00 For personal use only. No other uses without permission. . All rights reserved.
doi: 10.1210/jc.2014-2300
gard, an important notion has attracted increasing interests is that betatrophin may be involved in the compensatory response to insulin resistance (2). If these findings in mice are successfully translated to the clinic, this would open a new pathway to a possible diabetes therapy (3–5). Recently Espes et al (6) suggested that betatrophin levels were increased in patients with long-standing type 1 diabetes mellitus. However, contradictory results have been reported in patients with type 2 diabetes mellitus (T2DM) (7–9). Therefore, despite promising pictures have been sketched in mice, the results from humans are limited (10). Since the increase of betatrophin was found in Yi’s mouse model of insulin resistance using S961 and other murine models of insulin resistance, such as ob/ob, db/db and pregnant mouse, it seems that betatrophin is increased in face of insulin resistance in mice. As to humans, evidence for betatrophin-insulin resistance association is still lacking. Therefore, the present study aims to evaluate circulating betatrophin levels in subjects with different glucose tolerance status and the factors associated with betatrophin levels, especially whether insulin resistance is associated with betatrophin levels.
Subjects and Methods Subjects The present study participants were recruited from Hubei Province of China during 2011–2012, as one part of the Risk Evaluation of Cancers in Chinese Diabetic Individuals: A Longitudinal study, which was conducted among 259 657 adults, aged 40 years and older in 25 communities across mainland of China (11). In our study, age-, sex-, body mass index (BMI)- and blood lipid-matched subjects with normal glucose tolerance (NGT) (n ⫽ 137), isolated impaired fasting glucose (IFG) (n ⫽ 69), isolated impaired glucose tolerance (IGT) (n ⫽ 120), and newly diagnosed T2DM (n ⫽ 112) were included after excluding those with renal or liver dysfunction, of which none have received antidiabetic or hypolipidemic therapies and 20% have taken antihypertensive agents. The Committee on Human Research at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, approved the study protocol, and all participants provided written informed consents.
Clinical and biochemical evaluation As previously described in the Risk Evaluation of Cancers in Chinese Diabetic Individuals: A Longitudinal study (11), information on sociodemographic characteristics, lifestyle factors, medical history, and family history were collected by trained staff using a standard questionnaire. All participants were asked to fast for at least 10 hours to undergo the oral glucose tolerance test and blood sampling for analysis of various biochemical parameters.
jcem.endojournals.org
E97
Assessment of diabetes and insulin resistance The diagnosis of NGT, isolated IFG, isolated IGT, and T2DM were based on the diagnostic criteria of American Diabetes Association 2006 (12). These included the following: NGT: fasting plasma glucose (FPG) less than 5.6 mmol/L and 2-hour plasma glucose (PG) less than 7.8 mmol/L; isolated IFG: 5.6 mmol/L less than or equal to FPG less than 7.0 mmol/L and 2-hour PG less than 7.8 mmol/L; isolated IGT: FPG less than 5.6 mmol/L and 7.8 mmol/L less than or equal to 2-hour PG less than 11.1 mmol/L; and T2DM: FPG more than or equal to 7.0 mmol/L or 2-hour PG 11.1 mmol/L or greater. B cell function was assessed by homeostasis model assessment of -cell function (HOMA-) (13). Insulin resistance was estimated by the index of homeostasis model assessment of insulin resistance (HOMA-IR) (13), quantitative insulin sensitivity check index (QUICKI) (14), the Gutt insulin sensitivity index (ISIG) (14), and the Matsuda insulin sensitivity index (ISIM) (14). All indexes were calculated according to published formulas (Supplemental Table 1).
Measurement of betatrophin Betatrophin levels in the fasting serum were assessed using ELISA kits (Eiaab Science; catalog number E11644h). The procedures were performed in accordance with the manufacturer’s instructions. All samples were analyzed in duplicate.
Statistical analysis SPSS version 20.0 was used for all analysis. The data were presented as mean ⫾ SEM. Normal distribution of the data was tested using the Kolmogorox-Smirnov test. Variables not normally distributed were natural logarithmically transformed. Comparisons between groups were performed with an ANOVA followed by least significant differences tests. The correlations between variables were assessed using a Pearson correlation analysis by controlling for the covariates. The value of P ⬍ .05 (two tailed) was taken to indicate statistical significance.
Results Circulating betatrophin levels were increased in T2DM The characteristics of subjects with NGT (n ⫽ 137), isolated IFG (n ⫽ 69), isolated IGT (n ⫽ 120), and T2DM (n ⫽ 112) are described in Table 1. There were no significant differences in age, sex, BMI, or lipid profiles between every 2 groups (all P values ⬎ .05). Notably, serum betatrophin levels were significantly elevated in patients with T2DM compared with subjects with NGT, isolated IFG, or isolated IGT (798.6 ⫾ 42.5 vs 692.7 ⫾ 29.0, P ⬍ .05; 798.6 ⫾ 42.5 vs 682.7 ⫾ 43.0, P ⬍ .05; 798.6 ⫾ 42.5 vs 646.8 ⫾ 34.3 pg/mL, P ⬍ .01). However, there were no significant differences of betatrophin levels between each pair of NGT, isolated IFG, and isolated IGT (all P values ⬎ .05). Actually, serum betatrophin levels were increased in type 2 diabetic patients compared with nondiabetic subjects (including NGT, isolated IFG, and isolated IGT) (798.6 ⫾ 42.5 vs 673.7 ⫾ 19.7 pg/mL, P ⬍ .01). Next, we
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 11 February 2015. at 04:00 For personal use only. No other uses without permission. . All rights reserved.
E98
Chen et al
Table 1.
Betatrophin and T2DM
J Clin Endocrinol Metab, January 2015, 100(1):E96 –E100
Clinical and Metabolic Parameters for Subjects With Different Glucose Tolerance
Variable
NGT (n ⴝ 137)
Isolated IFG (n ⴝ 69)
Isolated IGT (n ⴝ 120)
T2DM (n ⴝ 112)
P Value
Age, ya Female, % BMI, kg/m2 FPG, mmol/L 2 hour-PG, mmol/L HbA1c, % HbA1c, mmol/mol Fasting insulin, pmol/L 2 hour-insulin, pmol/L HOMA- HOMA-IR QUICKI ISIG, mg/L2䡠mmol䡠mU䡠min ISIM Total cholesterol, mmol/La Triacylglycerol, mmol/L HDL-cholesterol, mmol/L LDL-cholesterol, mmol/La Betatrophin, pg/mL
60.2 ⫾ 0.7 55 23.0 ⫾ 0.2 4.9 ⫾ 0.04b 5.5 ⫾ 0.08b,d 5.5 ⫾ 0.03 36.91 ⫾ 0.29 30.0 ⫾ 1.8b 159.0 ⫾ 14.4d 84.38 ⫾ 8.80 1.07 ⫾ 0.06b 0.396 ⫾ 0.004b 119.3 ⫾ 3.4b,d 18.1 ⫾ 0.9 4.9 ⫾ 0.07 1.4 ⫾ 0.06 1.5 ⫾ 0.03 2.8 ⫾ 0.06 692.7 ⫾ 29.0
62.5 ⫾ 1.2 54 23.7 ⫾ 0.5 6.6 ⫾ 0.02c,d 6.4 ⫾ 0.10c,d 5.5 ⫾ 0.04 36.8 ⫾ 0.44 61.8 ⫾ 6.0c,d 180.0 ⫾ 14.4d 65.39 ⫾ 6.58 3.01 ⫾ 0.30c,d 0.347 ⫾ 0.007c,d 86.9 ⫾ 4.14c,d 10.2 ⫾ 1.1c 5.0 ⫾ 0.11 1.5 ⫾ 0.09 1.5 ⫾ 0.04 2.8 ⫾ 0.10 682.7 ⫾ 43.0
60.8 ⫾ 0.9 53 23.2 ⫾ 0.3 5.1 ⫾ 0.03b 8.5 ⫾ 0.04b,c 5.6 ⫾ 0.03 37.7 ⫾ 0.32 31.2 ⫾ 1.8b 322.8 ⫾ 21.6b,c 69.59 ⫾ 4.72 1.17 ⫾ 0.07b 0.389 ⫾ 0.004b 68.58 ⫾ 1.98b,c 10.6 ⫾ 0.7c 5.1 ⫾ 0.09 1.4 ⫾ 0.07 1.5 ⫾ 0.03 2.9 ⫾ 0.07 646.8 ⫾ 34.3
60.7 ⫾ 0.9 48 23.4 ⫾ 0.3 8.7 ⫾ 0.2b,c,d 15.3 ⫾ 0.3b,c,d 7.7 ⫾ 0.1b,c,d 60.1 ⫾ 1.49b,c,d 47.4 ⫾ 4.8c,d,e 181.8 ⫾ 12.0d 36.64 ⫾ 6.68c,d,e 3.09 ⫾ 0.30c,d 0.345 ⫾ 0.004c,d 47.7 ⫾ 1.44b,c,d 7.4 ⫾ 0.5c,d,e 5.0 ⫾ 0.10 1.5 ⫾ 0.08 1.4 ⫾ 0.04 2.9 ⫾ 0.07 798.6 ⫾ 42.5d,e,f
.43 .72 .71 ⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001 .601 .60 .25 .62 .01
Abbreviation: HbA1c, glycated hemoglobin. All values are given as mean ⫾ SEM. a
Data normally distributed.
b
Compared with IFG, P ⬍ .01.
c
Compared with NGT, P ⬍ .01.
d
Compared with IGT, P ⬍ .01.
e
Compared with IFG, P ⬍ .05.
f
Compared with NGT, P ⬍ .05.
studied correlations between betatrophin and other nonglucose-related variables including age, BMI, and lipid profiles in nondiabetic and type 2 diabetic subjects, respectively. The results showed that betatrophin levels significantly correlated with age both in nondiabetic (r ⫽ 0.48, P ⬍ .001) and diabetic (r ⫽ 0.43, P ⬍ .001) subjects. Moreover, betatrophin also correlated with total cholesterol (r ⫽ ⫺0.26, P ⬍ .01), low-density lipoprotein (LDL)cholesterol (r ⫽ ⫺0.26, P ⬍ .01), and high-density lipoprotein (HDL)-cholesterol (r ⫽ ⫺0.23, P ⫽ .01) in diabetic patients but not in nondiabetic subjects (all P values ⬎ .05). There was no association between betatrophin and BMI in either nondiabetic (r ⫽ ⫺0.03, P ⫽ .57) or diabetic (r ⫽ ⫺0.15, P ⫽ .13) subjects. Betatrophin correlates with indexes of insulin resistance Next, we studied correlations between betatrophin levels and glucose-related variables in all participants by using Pearson correlation analysis. We observed that after controlling for age, sex, and BMI, betatrophin levels positively correlated with FPG (r ⫽ 0.10), 2-hour PG (r ⫽ 0.11), and HOMA-IR (r ⫽ 0.10) but negatively correlated with QUICKI (r ⫽ ⫺0.10), ISIG (r ⫽ ⫺0.11), and ISIM (r ⫽ ⫺0.10) (all P values ⬍ .05) (Table 2). When further controlling with blood lipid (total cholesterol), the correla-
tions between betatrophin levels and blood glucose (FPG and 2 hour PG) and insulin resistance-related variables (HOMA-IR, QUICKI, ISIG, and ISIM) were still unchanged (Table 2). In sensitivity analyses, if we use LDLcholesterol instead of total cholesterol for controlling blood lipid, the correlations were the same (data not shown).
Discussion Because the newly emerging role of betatrophin in -cell regeneration has yet to be reproduced in the human model and there are few studies available on the topic in general, here we measured serum betatrophin concentrations in subjects with NGT, isolated IFG, isolated IGT, and T2DM, and found that betatrophin levels were significantly increased in patients with T2DM compared with nondiabetic subjects. Additionally, our results not only replicated the finding that betatrophin was associated with lipid profile but also showed that betatrophin was correlated with indexes of insulin resistance. Of note, the mean levels of betatrophin reported by Fenzl et al (7) (⬃1600 pg/mL) is approximately doubled compared with those of ours (⬃700 pg/mL), and they have claimed that betatrophin levels are unaltered between
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 11 February 2015. at 04:00 For personal use only. No other uses without permission. . All rights reserved.
doi: 10.1210/jc.2014-2300
Table 2.
jcem.endojournals.org
E99
Partial Correlations Between Betatrophin Levels and Glucose-Related Variables in All Study Participants Betatrophin (Age,a Sex, and BMI Adjusted)
Betatrophin
FPG Two-hour PG HbA1c Fasting insulin Two-hour insulin HOMA- HOMA-IR QUICKI ISIG ISIM
Betatrophin (Age,a Sex, BMI, and Total Cholesterola Adjusted)
r
P Value
Partial r
P Value
Partial r
P Value
0.073 0.092 0.012 ⫺0.018 ⫺0.002 ⫺0.087 0.018 ⫺0.011 ⫺0.092 ⫺0.042
.129 .054 .798 .702 .966 .069 .706 .811 .054 .393
0.100 0.114 0.049 0.062 ⫺0.001 ⫺0.050 0.098 ⫺0.096 ⫺0.108b ⫺0.097
.038 .017 .324 .209 .981 .311 .046 .050 .028b .048
0.106 0.119 0.059 0.069 0.000 ⫺0.050 0.106 ⫺0.105 ⫺0.109c ⫺0.103
.028 .013 .234 .160 .999 .311 .031 .032 .027c .035
Abbreviation: HbA1c, glycated hemoglobin. a
Data normally distributed.
b
Age and sex adjusted.
c
Age, sex, and total cholesterol adjusted.
nondiabetic and type 2 diabetic participants. These may be due to the different sample size in the study by Fenzl et al (7) (n ⫽ 37) from ours (n ⫽ 438) and the subjects in the study by Fenzl et al with higher BMI and a different ethnicity. More importantly, the diabetic patients in the study by Fenzl et al had taken oral hypoglycemic drugs (metformin ⫾ sulfonylureas), which would potentially affect the levels of betatrophin because the main effect of metformin is to reduce insulin resistance. Very recently another two independent groups have published their results showing that betatrophin levels are increased in patients with T2DM (8, 9), which are consistent with ours. Moreover, we found a correlation between betatrophin and indexes of insulin resistance, including HOMA-IR, QUICKI, ISIG, and ISIM. However, it is not clear whether increased betatrophin expression is a compensatory response or only a marker of insulin resistance. Notably, increased circulating betatrophin levels were found only in patients with T2DM but not in prediabetic subjects who already have insulin resistance (15). It is possible that betatrophin would be increased only when the degree of insulin resistance reaches a certain threshold as a compensatory response. However, we cannot exclude that the elevated betatrophin levels may be associated with other unknown factors of diabetes, which may affect insulin resistance. Further studies are needed to delineate the mechanisms of betatrophin in T2DM and insulin resistance. Beyond glucose metabolism, we also found that betatrophin levels significantly associated with lipid profile. Previous studies in mice have shown that overexpression of betatrophin increases triacylglycerol levels (16, 17), whereas betatrophin deficiency reduces triacylglycerol
concentrations (18, 19). These results are in line with our positive correlation of betatrophin with triacylglycerol (r ⫽ 0.18, P ⫽ .062), although the P value does not reach a statistically significant level. Interestingly, we found negative correlations between betatrophin and total cholesterol, LDL-cholesterol, and HDL-cholesterol, which are consistent with the result from Espes et al (9) but opposite to what Fenzl et al (7) have reported. The reason for the discrepancy is unclear and may be due to difference in study design, sample size, medicine status, and patient selection. In addition, studies in mice have suggested that the mechanisms of betatrophin in lipid control are very complicated. It may interact with other gene products, such as angiopoietin-like 3, to coregulate the lipid metabolism (17). The strengths of our study were that the subjects included were newly diagnosed type 2 diabetic patients without any antidiabetic treatment, whose betatrophin levels probably better reflected the natural profiles of betatrophin. Nevertheless, the sample size of our study was larger than the previous study. Furthermore, the use of indexes derived from both fasting and 2-hour post-oral glucose tolerance test to assess insulin resistance is also advantageous. Limitations of the study were that we investigated betatrophin levels only in a Chinese population. The results from our study need to be confirmed in other ethnicities in the future. Also, because of our cross-sectional design, we cannot determine the cause and effect between betatrophin and insulin resistance in the present study. In conclusion, we have found that the levels of circulating betatrophin are increased in T2DM and that betatrophin levels correlate to markers of insulin resistance.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 11 February 2015. at 04:00 For personal use only. No other uses without permission. . All rights reserved.
E100
Chen et al
Betatrophin and T2DM
Further studies are needed to elucidate the role of betatrophin in the development of T2DM and whether betatrophin could have clinical applications in the development of new antidiabetic drugs.
Acknowledgments Author contributions included the following: X.C., P.L., W.H., and X.Y. contributed to the study design. X.C., P.L., J.Z., Le.L., Y.Y., Z.L., J.X., S.S., T.D., X.S., X.Z., S.H., G.Y., M.Z., H.Z., Li.L., D.W., and X.Y. contributed to the data acquisition. X.C. and P.L. analyzed the data. X.C., P.L., Le.L., and X.Y. wrote the manuscript. X.Y. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Address all correspondence and requests for reprints to: Xuefeng Yu, MD, PhD, Professor of Medicine, Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People’s Republic of China. Email: [email protected]. This work was supported by grants from the National Nature Science Foundation of China (Grant 30772207); Wuhan Planning Project of Science and Technology (Grant 201060938360 – 04), Wuhan Science and Technology Bureau; and the Chinese Society of Endocrinology and the National Clinical Research Center for Metabolic Diseases. Disclosure Summary: The authors have nothing to disclose.
References 1. Yi P, Park JS, Melton DA. Betatrophin: a hormone that controls pancreatic beta cell proliferation. Cell. 2013;153:747–758. 2. Araujo TG, Oliveira AG, Saad MJ. Insulin-resistance-associated compensatory mechanisms of pancreatic  cells: a current opinion. Front Endocrinol. 2013;4:146. 3. Kugelberg E. Diabetes: betatrophin-inducing -cell expansion to treat diabetes mellitus? Nat Rev Endocrinol. 2013;9:379.
J Clin Endocrinol Metab, January 2015, 100(1):E96 –E100
4. Raghow R. Betatrophin: a liver-derived hormone for the pancreatic -cell proliferation. World J Diabetes. 2013;4:234 –237. 5. Lickert H. Betatrophin fuels  cell proliferation: first step toward regenerative therapy? Cell Metab. 2013;18:5– 6. 6. Espes D, Lau J, Carlsson PO. Increased circulating levels of betatrophin in individuals with long-standing type 1 diabetes. Diabetologia. 2014;57:50 –53. 7. Fenzl A, Itariu BK, Kosi L, et al. Circulating betatrophin correlates with atherogenic lipid profiles but not with glucose and insulin levels in insulin-resistant individuals. Diabetologia. 2014;57:1204 –1208. 8. Fu Z, Berhane F, Fite A, Seyoum B, Abou-Samra AB, Zhang R. Elevated circulating lipasin/betatrophin in human type 2 diabetes and obesity. Scientific Rep. 2014;4:5013. 9. Espes D, Martinell M, Carlsson PO. Increased circulating beatatrophin concentrations in patients with type 2 diabetes. Int J Endocrinol. 2014:323407. 10. Stewart AF. Betatrophin versus bitter-trophin and the elephant in the room: time for a new normal in -cell regeneration research. Diabetes. 2014;63:1198 –1199. 11. Lu J, Bi Y, Wang T, et al. The relationship between insulin-sensitive obesity and cardiovascular diseases in a Chinese population: results of the REACTION study. Int J Cardiol. 2014;172:388 –394. 12. American Diabetes Association. Standards of medical care in diabetes—2006 (Position Statement). Diabetes Care 2006;29(suppl 1): S4 –S42. 13. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and -cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412– 419. 14. Monzillo LU, Hamdy O. Evaluation of insulin sensitivity in clinical practice and in research settings. Nutr Rev. 2003;61:397– 412. 15. Tabak AG, Herder C, Rathmann W, Brunner EJ, Kivimaki M. Prediabetes: a high-risk state for diabetes development. Lancet. 2012; 379:2279 –2290. 16. Zhang R. Lipasin, a novel nutritionally-regulated liver-enriched factor that regulates serum triglyceride levels. Biochem Biophys Res Commun. 2012;424:786 –792. 17. Quagliarini F, Wang Y, Kozlitina J, et al. Atypical angiopoietin-like protein that regulates ANGPTL3. Proc Natl Acad Sci USA. 2012; 109:19751–19756. 18. Ren G, Kim JY, Smas CM. Identification of RIFL, a novel adipocyteenriched insulin target gene with a role in lipid metabolism. Am J Physiol Endocrinol Metab. 2012;303:E334 –E351. 19. Wang Y, Quagliarini F, Gusarova V, et al. Mice lacking ANGPTL8 (Betatrophin) manifest disrupted triglyceride metabolism without impaired glucose homeostasis. Proc Natl Acad Sci USA. 2013;110: 16109 –16114.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 11 February 2015. at 04:00 For personal use only. No other uses without permission. . All rights reserved.
