Effects of Activin A on Pancreatic Ductal Cells in Streptozotocin-Induced Diabetic Rats

Park, Mi-Kyung; Han, Chul Hee; Lee, Kyung‐Hee; Hong, Seung-Hyun; Kim, Hyo Sup; Lee, Young Jin; Jeong, In‐Kyung; Noh, Junghyun; Yang, Tae Young; Lee, Myung-Shik; Kim, Kwang-Won; Lee, Moon‐Kyu

doi:10.1097/01.tp.0000259978.62139.9d

Cited by 18 publications

(12 citation statements)

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“…The signals leading to upregulation of pancreatic β-cell performance during pregnancy are unknown. However, the action of activin A on pancreatic β-cells (14,15), our finding of low FSTL3 levels in the serum of women with GDM, and the previous reports of elevated activin A levels in pregnancies affected by GDM (16,17) underscore a possible role for activin A in the promotion of islet cell hyperplasia and increased insulin secretion during pregnancy.…”

Section: Discussionsupporting

confidence: 61%

“…Further evidence supporting a role for FSTL3 in glucose homeostasis includes the biological activities of activin A and myostatin, which are antagonized by FSTL3. Activin A promotes proliferation of β-cells and secretion of insulin (14,15); activin A levels were found to be elevated in pregnancies affected by GDM in previous studies (16,17). In mouse models, the absence of myostatin promotes insulin sensitivity and protects against weight gain (18,19).…”

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confidence: 94%

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First-Trimester Follistatin-Like-3 Levels in Pregnancies Complicated by Subsequent Gestational Diabetes Mellitus

et al. 2009

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OBJECTIVETo determine whether maternal levels of follistatin-like-3 (FSTL3), an inhibitor of activin and myostatin involved in glucose homeostasis, are altered in the first trimester of pregnancies complicated by subsequent gestational diabetes mellitus (GDM).RESEARCH DESIGN AND METHODSThis was a nested case-control study of subjects enrolled in a prospective cohort of pregnant women with and without GDM (≥2 abnormal values on a 100-g glucose tolerance test at ∼28 weeks of gestation). We measured FSTL3 levels in serum collected during the first trimester of pregnancy. Logistic regression analyses were used to determine the risk of GDM.RESULTSWomen who developed GDM (n = 37) had lower first-trimester serum levels of FSTL3 compared with women who did not (n = 127) (median 10,789 [interquartile range 7,013–18,939] vs. 30,670 [18,370–55,484] pg/ml, P < 0.001). When subjects were divided into tertiles based on FSTL3 levels, women with the lowest levels demonstrated a marked increase in risk for developing GDM in univariate (odds ratio 11.2 [95% CI 3.6–35.3]) and multivariate (14.0 [4.1–47.9]) analyses. There was a significant negative correlation between first-trimester FSTL3 levels and ∼28-week nonfasting glucose levels (r = −0.30, P < 0.001).CONCLUSIONSFirst-trimester FSTL3 levels are associated with glucose intolerance and GDM later in pregnancy.

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Section: Discussionsupporting

confidence: 61%

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confidence: 94%

First-Trimester Follistatin-Like-3 Levels in Pregnancies Complicated by Subsequent Gestational Diabetes Mellitus

et al. 2009

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“…More recently, it was found that activin expression is increased in ductal tissues and co-localized with the cytokeratin maker for ductal cells after reduction of β-cell mass with streptozotocin or partial pancreatectomy (Zhang et al 2002). Activin was also found to increase proliferation of rat ductal cells in vitro , as well as to induce their differentiation into insulin producing cells expressing PDX-1, Ngn-3, and other genetic markers of β-cells (Park et al 2007). Glucose-stimulated insulin secretion was also enhanced in these cells, and when transplanted, were able to reverse streptozotocin-induced diabetes in rats (Park et al 2007).…”

Section: B Advances In Biological Actions Of Activin In Adults and Ementioning

confidence: 99%

The biology of activin: recent advances in structure, regulation and function

Xia

Schneyer²

2009

Journal of Endocrinology

209

149

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Activin was discovered in the 1980s as a gonadal protein that stimulated FSH release from pituitary gonadotropes and was thought of as a reproductive hormone. In the ensuing decades, many additional activities of activin were described and it was found to be produced in a wide variety of cell types at nearly all stages of development. Its signaling and actions are regulated intracellularly and by extracellular antagonists. Over the past 5 years, a number of important advances have been made that clarify our understanding of the structural basis for signaling and regulation, as well as the biological roles of activin in stem cells, embryonic development and in adults. These include the crystallization of activin in complex with the activin type II receptor ActRIIB, or with the binding proteins follistatin and follistatin-like 3, as well as identification of activin's roles in gonadal sex development, follicle development, luteolysis, b-cell proliferation and function in the islet, stem cell pluripotency and differentiation into different cell types and in immune cells. These advances are reviewed to provide perspective for future studies.

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“…Interestingly, this expression is upregulated in models of pancreatic regeneration after injury although the proliferative index of activin or activin receptor-positive cells was not elevated. Moreover, follistatin is expressed in expanding ductal epithelium and localized to proliferating cells, suggesting that inhibition of activin action by local follistatin might lead to increased proliferation during this particular stage [35,36]. Perhaps the increased activin expression and presumably action contributes to differentiation of ductal epithelium into endocrine cells that has been observed after injury [37].…”

Section: Activin/tgfβ Subfamily Signaling In Regulation Of β-Cell Andmentioning

confidence: 99%

Emerging roles for the TGFβ family in pancreatic β-cell homeostasis

Brown

Schneyer

2010

Trends in Endocrinology & Metabolism

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Loss of functional β-cells is a primary mechanism of type 2 diabetes creating an acute need for understanding how β-cell number and function are regulated in adults under normal physiological conditions. Recent studies suggest a role for TGFβ family ligands in regulating β-cell function and glucose homeostasis. These ligands might influence β-cell proliferation and/or incorporation of new β-cells from progenitors in adults. Soluble antagonists of these ligands also appear to have important roles in regulating ligand activity to maintain homeostasis. These studies suggest that the coordinated activity of several TGFβ ligands might have important regulatory actions in adult β-cells and raise the possibility of developing new therapies for diabetes based on using agonists or antagonists of these ligands. TGFβ family, β-cells and diabetesThe recent obesity epidemic in the US and other developed countries has contributed to an increased incidence of insulin resistance and diabetes, resulting in a more urgent search for novel therapeutic approaches. Loss of β-cell number and/or function results in reduced ability to control blood glucose concentrations, hyperglycemia, and diabetes -a process often exacerbated by peripheral insulin resistance that requires ever increasing insulin output from remaining β-cells. Indeed, recent GWAS studies have identified a number of genetic polymorphisms associated with increased diabetes risk, the majority of which implicate genes important for proper β-cell function. [1][2][3]. The critical nature of functional β-cells to glucose control has focused research on finding new sources for β-cells for transplantation or on factors that can lead to enhanced β-cell function and/or mass. Recent studies suggest that several members of the TGFβ family of growth factors might fill this role under normal physiological conditions and thus, might also be exploited to develop new therapies for diabetes. Although these growth factors are most widely known for their critical roles in development and tissue specification [4], more recent evidence suggests they also mediate numerous actions in adults involving homeostatic control of normal physiological processes, as well as roles in pathology, such as cancer [5]. Although potential actions of some TGFβ family members in glucose regulation were suggested more than 20 years ago, a specific role for a subset of these ligands has been only recently described, including regulation of glucose homeostasis in peripheral tissues and modulation of β-cell function (Table 1).In this review, we examine data from both in vitro and in vivo approaches supporting a role for TGFβ family ligands in glucose homeostasis in adults. These actions of TGFβ family © 2010 Elsevier Ltd. All rights reserved.Corresponding Author: Schneyer, A. (alan.schneyer@bhs.org). This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting,...

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Effects of Activin A on Pancreatic Ductal Cells in Streptozotocin-Induced Diabetic Rats

Abstract: The pancreatic ductal cells could be efficiently differentiated into insulin secreting cells by activin A treatment in vitro and normalize hyperglycemia in vivo.

Cited by 18 publications

References 20 publications

First-Trimester Follistatin-Like-3 Levels in Pregnancies Complicated by Subsequent Gestational Diabetes Mellitus

First-Trimester Follistatin-Like-3 Levels in Pregnancies Complicated by Subsequent Gestational Diabetes Mellitus

The biology of activin: recent advances in structure, regulation and function

Emerging roles for the TGFβ family in pancreatic β-cell homeostasis

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