Table of Contents Author Guidelines Submit a Manuscript
Journal of Diabetes Research
Volume 2016, Article ID 4860595, 7 pages
http://dx.doi.org/10.1155/2016/4860595
Review Article

The Rise and the Fall of Betatrophin/ANGPTL8 as an Inducer of β-Cell Proliferation

1Biochemistry and Molecular Biology Unit, Dasman Diabetes Institute, Kuwait City, Kuwait
2Research Division, Dasman Diabetes Institute, Kuwait City, Kuwait

Received 15 June 2016; Revised 16 August 2016; Accepted 17 August 2016

Academic Editor: Daisuke Yabe

Copyright © 2016 Mohamed Abu-Farha 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.

Abstract

Diabetes is a global health problem that is caused by impaired insulin production from pancreatic β-cells. Efforts to regenerate β-cells have been advancing rapidly in the past two decades with progress made towards identifying new agents that induce β-cells regeneration. ANGPTL8, also named betatrophin, has been recently identified as a hormone capable of inducing β-cells proliferation and increasing β-cells mass in rodents. Its discovery has been cherished as a breakthrough and a game changer in the field of β-cells regeneration. Initially, ANGPTL8 has been identified as atypical member of the angiopoietin-like protein family as a regulator of triglyceride in plasma through its interaction with ANGPTL3 and its regulation of lipoprotein lipase activity. In this review, we will review literature on the proposed role of ANGPTL8 in β-cells proliferation, the controversy regarding this role, and the emerging data questioning its involvement in β-cells proliferation. Additionally we will discuss new clinical data that describes its role in diabetes and the putative therapeutic targeting of this protein.

1. Introduction

In the past decade, diabetes has reached an epidemic stage affecting millions of people worldwide [1]. The majority of people are affected by type 2 diabetes (T2D) that is caused by impaired insulin secretion and/or insulin resistance that leads to improper blood glucose metabolism. Obesity associated insulin resistance is one of the main causes behind the progressive decline in insulin production by the pancreatic β-cells that ultimately leads to T2D [13]. Overall, insulin resistance results in increased hepatic glucose production, reduced muscle glucose uptake, and increased level of free fatty acids in plasma under fasting conditions amongst many more physiological changes [1, 3]. To combat insulin resistance, β-cells increase their insulin production to cope with the increased insulin demand before reaching a threshold, where they will not be able to cope with further increase in insulin demand. A myriad of factors are involved in the β-cells failure including aging, oxidative stress, genetic factors, lipotoxicity and glucotoxicity, and inflammation [1, 3]. Various types of medications are used to control plasma glucose level by targeting a number of biochemical pathways involved in decreasing hepatic glucose production, increasing insulin production, and increasing insulin sensitivity or direct insulin injection [1, 3]. In combination with lifestyle intervention these drugs can help diabetic patients reach a reasonable glycemic control; however, reaching a full glycemic control similar to healthy β-cells is very difficult to achieve [1, 2]. As a result, many studies are interested in identifying new and novel mechanisms to induce β-cell proliferation, which is valued as the ultimate treatment for both type 1 and type 2 diabetes. Therefore, numerous strategies and alternative cell sources have been utilized to generate β-like cells.

2. Beta-Cell Regeneration and the Identification of ANGPTL8

Current protocols for β-cell regeneration focus on the use of directed differentiation of embryonic or induced pluripotent stem cells into insulin producing cells. Proliferation of existing β-cells, reprograming nonpancreatic, or dedifferentiation of pancreatic non-beta-cells into beta-like cells approaches are also being experimented [47]. Β-cell mass maintenance is a dynamic process that keeps modifying depending on the metabolic demand throughout life. Β-cell proliferation rates progress during embryonic development, after that cells expansion declines at postnatal stage followed by gradual failing at maturity [47]. Interestingly, studies have detected an increase in β-cell mass during pregnancy and obesity [812], suggesting that new β-cells can form during adulthood. Yet, the main question remains about the mechanism that replenishes the β-cell reservoir; does it occur through preexisting beta-cells proliferation or through the existence of progenitor cells? Current studies have detected an increase in β-cell mitotic activity in response to pancreatic injury or experimental conditioned β-cells genetic ablation suggests that the replication process plays a central role in maintaining β-cell mass [1317]. In human, β-cell neogenesis is not conclusive due to the fact that observations are drawn from pancreatic autopsy and surgical resection [1820]. However, some experimental genetic lineage tracing and transgenic animal model approaches indicate that the progenitor cells are a subpopulation of the pancreatic duct epithelium [18] and/or centroacinar cells [21, 22]. On the other hand, new observations revealed that β-cell neogenesis is not decisive, implying the need for further investigations in the field [2325]. On the other hand, in response to severe β-cell loss, interconversion of pancreatic endocrine cells has been reported in rodents [26, 27]. Several studies in rodents confirm that alteration in glucagon signaling enhanced alpha-cell regeneration, islets enlargement, and transdifferentiation into insulin producing cells [28, 29]. Nevertheless, this mechanism does not contribute to β-cell replenishment in diabetic animal models suggesting a significant role, but not limited, for glucagon in the transdifferentiation mechanism that is yet to be fully clarified [27, 3032].

Overall, β-cell mass enrichment, through proliferation/neogenesis or interconversion, is regulated through a network of internal and external biochemical pathways. During the past several decades, studies were directed towards understanding the molecular mechanisms that influence β-cell mass. Several hormones were reported to amplify β-cell number including growth hormone [33], prolactin [34], placental lactogen [35], serotonin [36], glucagon like peptide-1 (GLP1) [37], insulin-like growth factor I (IGF-1) [38], and their prospective receptors, best reviewed in [39]. During pregnancy, the somatolactogenic hormones maintain normal glucose hemostasis through tyrosine signaling cascade activation, which causes a rise in intracellular Ca2+ and enhancement of insulin secretion [40]. On the other hand, GLP1 and IGF-1 increase cytosolic Ca2+ through protein kinase A (PKA) and mitogen-activated protein kinase (MAPK) signal transduction pathway, respectively [41, 42]. Recently, ghrelin has been reported to enhance β-cell mass [43], despite its antiapoptotic activity mediated by activated phosphatidylinositol 3-kinase (PI3K)/Akt and ERK1/2 signaling [44]. The epidermal growth factor betacellulin is also reported to mediate β-cell neogenesis through the activation of ErbB-1 and ErbB-2 receptors and the upregulation of IRS1 [45].

One of the most recently identified inducers of β-cell proliferation was a liver and adipose tissues secreted protein named betatrophin. It increases β-cell replication and β-cell mass in insulin resistance mouse model [49]. This hormone was identified after the authors injected mice with S961 peptide, an insulin receptor antagonist, generating an insulin resistance mouse model [49]. Using microarray technology the authors were able to identify genes that were upregulated as a result of this injection including betatrophin. Its overexpression was found to increase β-cell proliferation and mass [49]. Betatrophin is one of the names given to C19orf80, which is also called Hepatocellular Carcinoma-Associated Gene TD26, Refeeding Induced Fat and Liver (RIFL) [46], Lipasin [54], and ANGPTL8 [48]. ANGPTL8 will be mostly used hereafter in this review.

3. ANGPTL8 Role in Lipid Metabolism

Prior to its identification as a hormone involved in β-cell proliferation, ANGPTL8 was identified by a number of groups as a nutrient and heat regulated protein as well as a regulator of lipid metabolism [46, 48, 54, 55]. Ren et al. were one of the first to show that ANGPTL8 or RIFL, as they referred to it, was induced in 3T3-L1 cells during adipogenesis and its knockdown leads to reduction in adipogenesis [46]. A summary of selected studies is given in Table 1. ANGPTL8 effect on adipogenesis was also shown in primary mouse and human adipocytes [46]. They further looked at its transcript expression level in different mouse tissues showing its highest expression level in white and brown adipose tissues as well as the liver similar to what was later shown by the other groups [46, 48, 54, 55]. ANGPTL8 expression was induced in both adipose tissues and liver by feeding as well as insulin treatment [46]. Similarly, its level was higher in ob/ob obesity mouse model compared to wild type [46]. Quagliarini et al. gave this protein the name ANGPTL8 based on its sequence similarity to members of the angiopoietin-like protein family and showed that it interacted with ANGPTL3 and regulated TG plasma level in mice [48]. They also showed that a nonsynonymous SNP (R59W) was associated with lower LDL and HDL cholesterol without affecting the TG level [48]. We have recently reported that this variant was associated with increased fasting plasma glucose in an Arab population [56]. Concomitantly, Zhang showed that ANGPTL8 had sequence similarity to members of the angiopoietin-like protein family and referred to it as Lipasin due to its inhibition of lipoprotein lipase (LPL) activity [54]. Collectively, the previous studies demonstrated that ANGPTL8 was involved in regulating TG plasma level through its interaction with ANGPTL3 and inhibition of LPL activity [46, 48, 54, 55].

Table 1: Selected early studies investigating the role of ANGPTL8 in obesity and diabetes.

4. Role of ANGPTL8 in β-Cell Proliferation

The identification of ANGPTL8 or betatrophin as a novel β-cell mitogen by Yi et al. has attracted tremendous attention from the scientific community as well as the media. It was hailed as a next-generation drug for diabetes. In their paper, Yi and his coworkers showed that S961 induced insulin resistance and was able to upregulate the expression of ANGPTL8 gene in the liver and adipose tissue. This upregulation of ANGPTL8 expression by insulin resistance was hypothesized to be a mechanism to increase insulin production through increasing β-cell proliferation. Overexpression of ANGPTL8 resulted in a 17-fold increase in β-cell proliferation and a threefold increase in β-cell mass [49]. As a result, mice overexpressing ANGPTL8 had improved glucose tolerance and lower fasting blood glucose [49]. ANGPTL8 level was also increased in ob/ob and db/db mouse models and during gestation in mice. Accordingly, it has been concluded by the authors that ANGPTL8 was capable of inducing β-cell mass and improving glucose tolerance and potentially augmenting or replacing insulin injections [49]. Even though the data was very promising, further validation such as testing the regenerative effect of betatrophin on aged and diabetic mice and human studies demonstrating the beneficial effect of ANGPTL8 on human pancreatic β-cells are deemed necessary [57, 58].

These conclusions were questioned by other studies that showed mice lacking ANGPTL8 had normal glucose and insulin tolerance [59]. Using ANGPTL8 knockout mouse model, Wang et al. showed that ANGPTL8 was required to direct free fatty acid into adipose tissue for storage after food intake through regulating the activity of LPL. However, lack of ANGPTL8 did not affect glucose and insulin tolerance and did not show significant changes in glucose homeostasis [59]. Even though their data failed to show a role for ANGPTL8 in glucose homeostasis they did not rule out the possibility that supraphysiological concentrations of ANGPTL8 might be able to induce β-cell proliferation at the potential cost of inducing hypertriglyceridemia [59].

In order to test the effect of ANGPTL8 on human β-cells, Jiao et al. treated immune-deficient NOD-Scid mice with S961 to induce insulin resistance and ANGPTL8 expression [60]. Treating these mice with S961 resulted in a significant increase in ANGPTL8 expression as well as β-cell replication in the native as well as the ectopically transplanted mice islets under the kidney capsule. However, treatment did not cause any increase in β-cell proliferation using human transplanted islets [60]. Even though they did not address whether mouse produced ANGPTL8 was capable of binding to its unidentified receptor on the human β-cells, they showed that the increased ANGPTL8 level was not capable of inducing β-cell proliferation in humans [60]. Furthermore, Gusarova et al. tested the effect of ANGPTL8 knockout on β-cell proliferation and reported that β-cell proliferation was not affected by the lack of ANGPTL8 in response to diet induced insulin resistance or the S961 insulin receptor antagonist treatment. They also showed that increased ANGPTL8 expression did not increase β-cell mass or improved glucose homeostasis [50]. However, they further confirmed that TG level was reduced in knockout mice and increased by ANGPTL8 overexpression [50]. Later on, Yi et al. have showed that they were not able to reproduce their original data and cited huge variation of the effect of ANGPTL8 injection on β-cell proliferation. In conclusion, it has been shown that ANGPTL8 induction of β-cell proliferation in mice was not reproducible and its deletion did not affect β-cell proliferation as suggested earlier. These reports raise major concerns regarding new inducers of β-cell proliferation and ask for more stringent measures to ensure their accuracy. Some of these measures include testing these mitogenic substances on human islets to test for β-cell proliferation. Additionally, therapeutically relevant levels of human β-cell proliferation ought to be achieved before rushing into conclusions as previously suggested [61].

5. ANGPTL8 Role in Diabetes

Irrespective of its role in β-cell proliferation, initial studies on ANGPTL8 reported that it was induced by insulin [46, 49]. Other human studies also showed that ANGPTL8 was positively associated with insulin [52, 6264]. On the other hand, its plasma level in diabetes has been measured in multiple cohorts [5153, 62, 6472]. Initial mice studies showed that ANGPTL8 level was increased in ob/ob mice as well as the diabetic mouse model db/db   [49]. In humans, Espes et al. showed that circulation level of ANGPTL8 was increased in T1D subjects [51]. Nonetheless, ANGPTL8 level did not correlate with an increase in C-peptide level in T1D [51]. Similarly, in another study, Espes et al. also showed that ANGPTL8 level was increased in T2D subjects. Other studies showed that ANGPTL8 level was increased in T2D as well [64, 67, 68, 70].

Using a large sample set of T2D and normal subjects, we have recently reported that ANGPTL8 was increased in T2D subjects [52]. Comparing the level of ANGPTL8 in 556 T2D subjects with that of 1047 nondiabetic subjects we showed that ANGPTL8 level was more than three times higher in T2D subjects [52]. ANGPTL8 level was associated with blood glucose, insulin, and insulin resistance as measured by homeostatic model assessment-insulin resistance (HOMA-IR) in the nondiabetic subjects only. No association was observed with these factors in the T2D subjects [52]. Furthermore, we have showed that ANGPTL8 level was associated with increased C-peptide level in the nondiabetic subjects but not the T2D subjects. Taken together, our data revealed that the increase in ANGPTL8 in T2D was not increasing insulin production in the T2D subjects [62]. On the other hand, other studies showed that ANGPTL8 was not increased in T2D subject and rather decreased [53, 63]. Recently, Li et al. have published a meta-analysis that investigated the association between ANGPTL8 level and T2D based on a total of nine studies [73]. Based on their analysis, ANGPTL8 level was significantly higher in subjects with T2D compared to nondiabetics [73]. Similarly, ANGPTL8 expression level was increased in subjects with gestational diabetes [7477]. ANGPTL8 level was also found to be increased in subjects with metabolic syndrome [71]. One of the main causes for differences in these results has been suggested to be the ELISA kits used. Fu et al. tested both full length ELISA kit from Wuhan EIAAB Science Co. (catalogue number E1164H) and C-terminal ELISA kit recognizing the region from 139 to 198 amino acids from Phoenix Pharmaceuticals (catalogue number EK-051-55) [78]. Both kits were found to be accurate at measuring plasma level of ANGPTL8 and showed high correlation [78]. However, the studies showing decreased plasma level in diabetes used a third kit from ELISA kit manufactured by CUSABIO/Aviscera Bioscience which might have been the cause for the discrepancy [53, 63].

6. Conclusion

Overall, ANGPTL8 role in lipid metabolism is well established, through its interaction with ANGPTL3 and regulation of LPL activity to maintain blood TG content. It is also well established that ANGPTL8 does not play a major role in β-cell proliferation as proposed initially. Its role in diabetes and obesity however remains elusive and further studies are still required to understand its involvement in metabolic diseases. New data is emerging to link ANGPTL8 to other diseases such as cancer and polycystic ovary syndrome [79] will increase our knowledge of the functional role of this hormone. In conclusion, β-cell regeneration remains an ultimate goal in diabetes treatment and detailed understanding of their biology and agents that manipulate their function is required. Nonetheless, human studies as well as more rigorous experimental design are required to test for new agents associated with β-cell regeneration to avoid further setbacks similar to what has been observed with betatrophin.

Competing Interests

The authors declare that they have no competing interests.

Acknowledgments

This work was funded by Kuwait Foundation for the Advancement of Sciences (KFAS) for financial support of this research project (RA-2014-021 and AC14013003).

References

  1. R. A. DeFronzo, E. Ferrannini, L. Groop et al., “Type 2 diabetes mellitus,” Nature Reviews Disease Primers, vol. 1, Article ID 15019, 2015. View at Publisher · View at Google Scholar
  2. J. Tuomilehto, J. Lindström, J. G. Eriksson et al., “Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance,” The New England Journal of Medicine, vol. 344, no. 18, pp. 1343–1350, 2001. View at Publisher · View at Google Scholar
  3. S. O'Rahilly, “Human obesity and insulin resistance: lessons from experiments of nature,” Biochemical Society Transactions, vol. 35, part 1, pp. 33–36, 2007. View at Publisher · View at Google Scholar
  4. A. M. Ackermann and M. Gannon, “Molecular regulation of pancreatic beta-cell mass development, maintenance, and expansion,” Journal of Molecular Endocrinology, vol. 38, no. 1-2, pp. 193–206, 2007. View at Publisher · View at Google Scholar
  5. C. Bernard-Kargar and A. Ktorza, “Endocrine pancreas plasticity under physiological and pathological conditions,” Diabetes, vol. 50, supplement 1, pp. S30–S35, 2001. View at Publisher · View at Google Scholar · View at Scopus
  6. J. Petrik, B. Reusens, E. Arany et al., “A low protein diet alters the balance of islet cell replication and apoptosis in the fetal and neonatal rat and is associated with a reduced pancreatic expression of insulin-like growth factor-II,” Endocrinology, vol. 140, no. 10, pp. 4861–4873, 1999. View at Publisher · View at Google Scholar · View at Scopus
  7. E. Montanya, V. Nacher, M. Biarnes, and J. Soler, “Linear correlation between beta-cell mass and body weight throughout the lifespan in Lewis rats: role of beta-cell hyperplasia and hypertrophy,” Diabetes, vol. 49, no. 8, pp. 1341–1346, 2000. View at Publisher · View at Google Scholar · View at Scopus
  8. R. L. Sorenson, T. C. Brelje, and C. Roth, “Effects of steroid and lactogenic hormones on islets of langerhans: a new hypothesis for the role of pregnancy steroids in the adaptation of islets to pregnancy,” Endocrinology, vol. 133, no. 5, pp. 2227–2234, 1993. View at Google Scholar · View at Scopus
  9. T. C. Brelje, D. W. Scharp, P. E. Lacy et al., “Effect of homologous placental lactogens, prolactins, and growth hormones on islet B-cell division and insulin secretion in rat, mouse, and human islets: implication for placental lactogen regulation of islet function during pregnancy,” Endocrinology, vol. 132, no. 2, pp. 879–887, 1993. View at Google Scholar · View at Scopus
  10. J. Domínguez-Bendala, L. Inverardi, and C. Ricordi, “Regeneration of pancreatic beta-cell mass for the treatment of diabetes,” Expert Opinion on Biological Therapy, vol. 12, no. 6, pp. 731–741, 2012. View at Publisher · View at Google Scholar
  11. A. K. Linnemann, M. Baan, and D. B. Davis, “Pancreatic beta-cell proliferation in obesity,” Advances in Nutrition, vol. 5, no. 3, pp. 278–288, 2014. View at Publisher · View at Google Scholar
  12. J. J. Meier, A. E. Butler, Y. Saisho et al., “β-cell replication is the primary mechanism subserving the postnatal expansion of β-cell mass in humans,” Diabetes, vol. 57, no. 6, pp. 1584–1594, 2008. View at Publisher · View at Google Scholar
  13. Y. Dor, J. Brown, O. I. Martinez, and D. A. Melton, “Adult pancreatic β-cells are formed by self-duplication rather than stem-cell differentiation,” Nature, vol. 429, no. 6987, pp. 41–46, 2004. View at Publisher · View at Google Scholar · View at Scopus
  14. S. Georgia and A. Bhushan, “β cell replication is the primary mechanism for maintaining postnatal β cell mass,” Journal of Clinical Investigation, vol. 114, no. 7, pp. 963–968, 2004. View at Publisher · View at Google Scholar
  15. T. Nir, D. A. Melton, and Y. Dor, “Recovery from diabetes in mice by beta cell regeneration,” The Journal of Clinical Investigation, vol. 117, no. 9, pp. 2553–2561, 2007. View at Publisher · View at Google Scholar
  16. P. Wang, N. M. Fiaschi-Taesch, R. C. Vasavada, D. K. Scott, A. García-Ocaña, and A. F. Stewart, “Diabetes mellitus—advances and challenges in human β-cell proliferation,” Nature Reviews Endocrinology, vol. 11, no. 4, pp. 201–212, 2015. View at Publisher · View at Google Scholar
  17. D. Saunders and A. C. Powers, “Replicative capacity of β-cells and type 1 diabetes,” Journal of Autoimmunity, vol. 71, pp. 59–68, 2016. View at Publisher · View at Google Scholar
  18. S. Bonner-Weir, W. C. Li, L. Ouziel-Yahalom, L. Guo, G. C. Weir, and A. Sharma, “β-cell growth and regeneration: replication is only part of the story,” Diabetes, vol. 59, no. 10, pp. 2340–2348, 2010. View at Publisher · View at Google Scholar
  19. K. Juhl, S. Bonner-Weir, and A. Sharma, “Regenerating pancreatic β-cells: plasticity of adult pancreatic cells and the feasibility of in-vivo neogenesis,” Current Opinion in Organ Transplantation, vol. 15, no. 1, pp. 79–85, 2010. View at Publisher · View at Google Scholar
  20. S. Bonner-Weir, L. Guo, W.-C. Li et al., “Islet neogenesis: a possible pathway for beta-cell replenishment,” Review of Diabetic Studies, vol. 9, no. 4, pp. 407–416, 2012. View at Publisher · View at Google Scholar · View at Scopus
  21. M. Rovira, S. G. Scott, A. S. Liss, J. Jensen, S. P. Thayer, and S. D. Leach, “Isolation and characterization of centroacinar/terminal ductal progenitor cells in adult mouse pancreas,” Proceedings of the National Academy of Sciences, vol. 107, no. 1, pp. 75–80, 2010. View at Publisher · View at Google Scholar
  22. F. Delaspre, R. L. Beer, M. Rovira et al., “Centroacinar cells are progenitors that contribute to endocrine pancreas regeneration,” Diabetes, vol. 64, no. 10, pp. 3499–3509, 2015. View at Publisher · View at Google Scholar
  23. X. Xiao, Z. Chen, C. Shiota et al., “No evidence for β cell neogenesis in murine adult pancreas,” Journal of Clinical Investigation, vol. 123, no. 5, pp. 2207–2217, 2013. View at Publisher · View at Google Scholar
  24. M. M. Rankin, C. J. Wilbur, K. Rak, E. J. Shields, A. Granger, and J. A. Kushner, “β-Cells are not generated in pancreatic duct ligation-induced injury in adult mice,” Diabetes, vol. 62, no. 5, pp. 1634–1645, 2013. View at Publisher · View at Google Scholar
  25. C. Cavelti-Weder, M. Shtessel, J. E. Reuss et al., “Pancreatic duct ligation after almost complete β-cell loss: exocrine regeneration but no evidence of β-cell regeneration,” Endocrinology, vol. 154, no. 12, pp. 4493–4502, 2013. View at Publisher · View at Google Scholar · View at Scopus
  26. F. Thorel, V. Népote, I. Avril et al., “Conversion of adult pancreatic α-cells to β-cells after extreme β-cell loss,” Nature, vol. 464, no. 7292, pp. 1149–1154, 2010. View at Publisher · View at Google Scholar
  27. C. Talchai, S. Xuan, H. V. Lin, L. Sussel, and D. Accili, “Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure,” Cell, vol. 150, no. 6, pp. 1223–1234, 2012. View at Publisher · View at Google Scholar · View at Scopus
  28. P. Collombat and A. Mansouri, “Turning on the β-cell identity in the pancreas,” Cell Cycle, vol. 8, no. 21, pp. 3450–3451, 2009. View at Publisher · View at Google Scholar · View at Scopus
  29. S. Kordowich, A. Mansouri, and P. Collombat, “Reprogramming into pancreatic endocrine cells based on developmental cues,” Molecular and Cellular Endocrinology, vol. 315, no. 1-2, pp. 11–18, 2010. View at Publisher · View at Google Scholar
  30. L. Ye, M. A. Robertson, D. Hesselson, D. Y. Stainier, and R. M. Anderson, “Glucagon is essential for alpha cell transdifferentiation and beta cell neogenesis,” Development, vol. 142, no. 8, pp. 1407–1417, 2015. View at Publisher · View at Google Scholar
  31. A. Mansouri, “Development and regeneration in the endocrine pancreas,” ISRN Endocrinology, vol. 2012, Article ID 640956, 12 pages, 2012. View at Publisher · View at Google Scholar
  32. R. Piran, S. H. Lee, C. R. Li, A. Charbono, L. M. Bradley, and F. Levine, “Pharmacological induction of pancreatic islet cell transdifferentiation: relevance to type I diabetes,” Cell Death and Disease, vol. 5, no. 7, Article ID e1357, 2014. View at Publisher · View at Google Scholar
  33. J. H. Nielsen, S. Linde, B. S. Welinder, N. Billestrup, and O. D. Madsen, “Growth hormone is a growth factor for the differentiated pancreatic β-cell,” Molecular Endocrinology, vol. 3, no. 1, pp. 165–173, 1989. View at Publisher · View at Google Scholar
  34. B. N. Friedrichsen, E. D. Galsgaard, J. H. Nielsen, and A. Møldrup, “Growth hormone- and prolactin-induced proliferation of insulinoma cells, INS-1, depends on activation of STAT5 (signal transducer and activator of transcription 5),” Molecular Endocrinology, vol. 15, no. 1, pp. 136–148, 2001. View at Publisher · View at Google Scholar · View at Scopus
  35. N. Billestrup and J. H. Nielsen, “The stimulatory effect of growth hormone, prolactin, and placental lactogen on β-cell proliferation is not mediated by insulin-like growth factor-I,” Endocrinology, vol. 129, no. 2, pp. 883–888, 1991. View at Publisher · View at Google Scholar · View at Scopus
  36. H. Kim, Y. Toyofuku, F. C. Lynn et al., “Serotonin regulates pancreatic beta cell mass during pregnancy,” Nature Medicine, vol. 16, no. 7, pp. 804–808, 2010. View at Publisher · View at Google Scholar
  37. J. Buteau, S. Foisy, E. Joly, and M. Prentki, “Glucagon-like peptide 1 induces pancreatic β-cell proliferation via transactivation of the epidermal growth factor receptor,” Diabetes, vol. 52, no. 1, pp. 124–132, 2003. View at Publisher · View at Google Scholar · View at Scopus
  38. S. R. Hügl, M. F. White, and C. J. Rhodes, “Insulin-like growth factor I (IGF-I)-stimulated pancreatic β-cell growth is glucose-dependent synergistic activation of insulin receptor substrate-mediated signal transduction pathways by glucose and IGF-I in INS- 1 cells,” The Journal of Biological Chemistry, vol. 273, no. 28, pp. 17771–17779, 1998. View at Publisher · View at Google Scholar · View at Scopus
  39. Y. Huang and Y. Chang, “Regulation of pancreatic islet beta-cell mass by growth factor and hormone signaling,” Progress in Molecular Biology and Translational Science, vol. 121, pp. 321–349, 2014. View at Publisher · View at Google Scholar
  40. F. Zhang, A. Sjoholm, and Q. Zhang, “Growth hormone signaling in pancreatic β-cells—calcium handling regulated by growth hormone,” Molecular and Cellular Endocrinology, vol. 297, no. 1-2, pp. 50–57, 2009. View at Publisher · View at Google Scholar
  41. C. Widmann, E. Bürki, W. Dolci, and B. Thorens, “Signal transduction by the cloned glucagon-like peptide-1 receptor: comparison with signaling by the endogenous receptors of β cell lines,” Molecular Pharmacology, vol. 45, no. 5, pp. 1029–1035, 1994. View at Google Scholar · View at Scopus
  42. P. N. Nair, D. T. De Armond, M. L. Adamo, W. E. Strodel, and J. W. Freeman, “Aberrant expression and activation of insulin-like growth factor-1 receptor (IGF-1R) are mediated by an induction of IGF-1R promoter activity and stabilization of IGF-1R mRNA and contributes to growth factor independence and increased survival of the pancreatic cancer cell line MIA PaCa-2,” Oncogene, vol. 20, no. 57, pp. 8203–8214, 2001. View at Publisher · View at Google Scholar · View at Scopus
  43. M. Bando, H. Iwakura, H. Ariyasu et al., “Overexpression of intraislet ghrelin enhances β-cell proliferation after streptozotocin-induced β-cell injury in mice,” American Journal of Physiology—Endocrinology and Metabolism, vol. 305, no. 1, pp. E140–E148, 2013. View at Publisher · View at Google Scholar · View at Scopus
  44. R. Granata, F. Settanni, L. Biancone et al., “Acylated and unacylated ghrelin promote proliferation and inhibit apoptosis of pancreatic β-cells and human islets: involvement of 3′,5′-cyclic adenosine monophosphate/protein kinase A, extracellular signal-regulated kinase 1/2, and phosphatidyl inositol 3-kinase/Akt signaling,” Endocrinology, vol. 148, no. 2, pp. 512–529, 2007. View at Publisher · View at Google Scholar · View at Scopus
  45. Y. S. Oh, S. Shin, Y. Lee, E. H. Kim, H. Jun, and K. Maedler, “Betacellulin-induced beta cell proliferation and regeneration is mediated by activation of ErbB-1 and ErbB-2 receptors,” PLoS ONE, vol. 6, no. 8, Article ID e23894, 2011. View at Publisher · View at Google Scholar
  46. 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 Google Scholar
  47. R. Zhang and A. B. Abou-Samra, “Emerging roles of Lipasin as a critical lipid regulator,” Biochemical and Biophysical Research Communications, vol. 432, no. 3, pp. 401–405, 2013. View at Publisher · View at Google Scholar
  48. 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 · View at Google Scholar
  49. P. Yi, J. Park, and D. Melton, “Betatrophin: a hormone that controls pancreatic β cell proliferation,” Cell, vol. 153, no. 4, pp. 747–758, 2013. View at Publisher · View at Google Scholar
  50. V. Gusarova, C. 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 · View at Google Scholar
  51. 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 · View at Google Scholar
  52. 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, article 10949, 2015. View at Publisher · View at Google Scholar · View at Scopus
  53. 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 & Metabolism, vol. 99, no. 10, pp. E2004–E2009, 2014. View at Publisher · View at Google Scholar
  54. R. Zhang, “Lipasin, a novel nutritionally-regulated liver-enriched factor that regulates serum triglyceride levels,” Biochemical and Biophysical Research Communications, vol. 424, no. 4, pp. 786–792, 2012. View at Publisher · View at Google Scholar · View at Scopus
  55. 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 and Biophysical Research Communications, vol. 430, no. 3, pp. 1126–1131, 2013. View at Publisher · View at Google Scholar · View at Scopus
  56. M. Abu-Farha, M. Melhem, J. Abubaker, K. Behbehani, O. Alsmadi, and N. Elkum, “ANGPTL8/Betatrophin R59W variant is associated with higher glucose level in non-diabetic Arabs living in Kuwaits,” Lipids in Health and Disease, vol. 15, article 26, 2016. View at Publisher · View at Google Scholar · View at Scopus
  57. E. Kugelberg, “Diabetes: betatrophin—inducing β-cell expansion to treat diabetes mellitus?” Nature Reviews Endocrinology, vol. 9, no. 7, pp. 379–379, 2013. View at Publisher · View at Google Scholar
  58. H. Lickert, “Betatrophin fuels β cell proliferation: first step toward regenerative therapy?” Cell Metabolism, vol. 18, no. 1, pp. 5–6, 2013. View at Publisher · View at Google Scholar
  59. 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, vol. 110, no. 40, pp. 16109–16114, 2013. View at Publisher · View at Google Scholar
  60. Y. Jiao, J. Le Lay, M. Yu, A. Naji, and K. H. Kaestner, “Elevated mouse hepatic betatrophin expression does not increase human β-cell replication in the transplant setting,” Diabetes, vol. 63, no. 4, pp. 1283–1288, 2014. View at Publisher · View at Google Scholar
  61. A. F. Stewart, “Betatrophin versus bitter-trophin and the elephant in the room: time for a new normal in β-cell regeneration research,” Diabetes, vol. 63, no. 4, pp. 1198–1199, 2014. View at Publisher · View at Google Scholar · View at Scopus
  62. 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, article 112, 2015. View at Publisher · View at Google Scholar
  63. K. Guo, J. Lu, H. Yu et al., “Serum betatrophin concentrations are significantly increased in overweight but not in obese or type 2 diabetic individuals,” Obesity, vol. 23, no. 4, pp. 793–797, 2015. View at Publisher · View at Google Scholar
  64. 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 · View at Google Scholar
  65. D. Espes, M. Martinell, and P. Carlsson, “Increased circulating betatrophin concentrations in patients with type 2 diabetes,” International Journal of Endocrinology, vol. 2014, 6 pages, 2014. View at Publisher · View at Google Scholar
  66. 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 · View at Google Scholar · View at Scopus
  67. 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, article 5013, 2014. View at Publisher · View at Google Scholar · View at Scopus
  68. 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 & Metabolism, vol. 100, no. 1, pp. E96–E100, 2015. View at Publisher · View at Google Scholar
  69. A. R. Cox, C. J. Lam, C. W. Bonnyman, J. Chavez, J. S. Rios, and J. A. Kushner, “Angiopoietin-like protein 8 (ANGPTL8)/betatrophin overexpression does not increase beta cell proliferation in mice,” Diabetologia, vol. 58, no. 7, pp. 1523–1531, 2015. View at Publisher · View at Google Scholar · View at Scopus
  70. H. Yamada, T. Saito, A. Aoki et al., “Circulating betatrophin is elevated in patients with type 1 and type 2 diabetes,” Endocrine Journal, vol. 62, no. 5, pp. 417–421, 2015. View at Publisher · View at Google Scholar
  71. M. Abu-Farha, J. Abubaker, I. Al-Khairi et al., “Circulating angiopoietin-like protein 8 (betatrophin) association with HsCRP and metabolic syndrome,” Cardiovascular Diabetology, vol. 15, no. 1, article 25, 2016. View at Publisher · View at Google Scholar
  72. M. Abu-Farha, D. Sriraman, P. Cherian et al., “Circulating ANGPTL8/betatrophin is increased in obesity and reduced after exercise training,” PLoS ONE, vol. 11, no. 1, Article ID e0147367, 2016. View at Publisher · View at Google Scholar · View at Scopus
  73. 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, 9 pages, 2016. View at Publisher · View at Google Scholar
  74. O. Erol, H. Y. Ellidağ, H. Ayık, M. K. Özel, A. U. Derbent, and N. Yılmaz, “Evaluation of circulating betatrophin levels in gestational diabetes mellitus,” Gynecological Endocrinology, vol. 31, no. 8, pp. 652–656, 2015. View at Publisher · View at Google Scholar
  75. 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 ID e0136701, 2015. View at Publisher · View at Google Scholar · View at Scopus
  76. N. Wawrusiewicz-Kurylonek, B. Telejko, M. Kuzmicki et al., “Increased maternal and cord blood betatrophin in gestational diabetes,” PLoS ONE, vol. 10, no. 6, Article ID e0131171, 2015. View at Publisher · View at Google Scholar
  77. X. Xie, H. Gao, S. Wu et al., “Increased cord blood betatrophin levels in the offspring of mothers with gestational diabetes,” PLoS ONE, vol. 11, no. 5, Article ID e0155646, 2016. View at Publisher · View at Google Scholar
  78. Z. Fu, A. B. Abou-Samra, and R. Zhang, “An explanation for recent discrepancies in levels of human circulating betatrophin,” Diabetologia, vol. 57, no. 10, pp. 2232–2234, 2014. View at Publisher · View at Google Scholar
  79. 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, vol. 62, no. 5, pp. 20–24, 2016. View at Google Scholar