Epidermal growth factor and insulin inhibit cell death in pancreatic beta cells by activation of PI3-kinase/AKT signaling pathway under oxidative stress

Maeda, Hiromichi; Rajesh, Katare Gopalrao; Suzuki, Ryo; Sasaguri, Shiro

doi:10.1016/j.transproceed.2004.04.018

Cited by 27 publications

(22 citation statements)

References 7 publications

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“…Sustained administration of EGF after testicular torsion improves bilateral testicular injury (Uguralp et al 2004). Moreover, emerging evidences demonstrated that EGF signaling is able to decrease ROS production, which has been suggested to play an important role during IR pathogenesis, in the intestine, pancreas, and renal tissue (Maeda et al 2004, Hussein Ael et al 2011. In this context, it was not surprising that testicular IR stress elicited significant increase in EGF activity (Fig.…”

Section: Role Of Egf In Testicular Ischemia-reperfusion Injurymentioning

confidence: 88%

Endogenous EGF maintains Sertoli germ cell anchoring junction integrity and is required for early recovery from acute testicular ischemia/reperfusion injury

Zhang

Zeng

et al. 2013

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Administration of exogenous epidermal growth factor (EGF) improves testicular injury after acute ischemia-reperfusion (IR) stress, but the molecular basis is poorly understood. The role of endogenous EGF in testicular recovery and the underlying intracellular signaling pathways involved were herein investigated. In mice, testicular IR injury significantly enhanced the expression level of endogenous Egf at the very beginning of reperfusion. Expression of EGF receptor (Egfr (ErbB1)) was accordingly upregulated 3 h after reperfusion. Deprivation of majority of circulated EGF by sialoadenectomy aggravated testicular detriment (especially in pachytene spermatocytes), enhanced germ cell apoptosis, and thereafter resulted in impaired meiotic differentiation after IR insult. Mechanistically, endogenous EGF signaling appeared to be indispensable for the proper maintenance of Sertoli germ cells anchoring junction dynamics during the early testicular recovery. We also provided the in vitro evidences in a well-established rat Sertoli germ cell co-cultures model that the pro-survival effect of endogenous EGF on germ cells in response to testicular IR insult is mediated, at least in part, via the phosphatidylinositol 3-kinase/pAkt pathway. Collectively, our results suggest that the augment of endogenous EGF during the early testicular recovery may act on top of an endocrinous cascade orchestrating the intimate interactions between Sertoli cells and germ cells and may operate as indispensable defensive mechanism in response to testicular IR stress. Future studies in this field would shed light on this complicated pathogenesis.

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Section: Role Of Egf In Testicular Ischemia-reperfusion Injurymentioning

confidence: 88%

Endogenous EGF maintains Sertoli germ cell anchoring junction integrity and is required for early recovery from acute testicular ischemia/reperfusion injury

Zhang

Zeng

et al. 2013

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“…In addition to the exocrine duct epithelium and centroacinar region, we also observed increased phospho-Akt immunoreactivity in islet ␤-cells of ZF rats. In ␤-cells, Akt has been proposed to function in mediating proliferation (10,22,24,45), size (10,11), and survival (11,12,21,23,24). Enhanced ␤-cell proliferation in ZF rats was limited to a restricted time (31 days of age) that preceded the onset of the largest ␤-cell mass increase (ϳ3.8-fold at 35 days of age).…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, using a rapid fixation and processing method for pancreas cryosections (19), we can reproducibly detect phosphoAkt and other labile phospho-intermediates in ␤-cell in situ. Since Akt is an established survival factor for many cells types including ␤-cells (12,21,23,24), we next examined the expression patterns of the genes encoding two related ␤-cell proteins that function in the mitochondrial regulation of apoptosis, BAD, and Bcl-2, a proapoptotic factor and a survival factor, respectively. BAD activity is inhibited upon phosphorylation and is an established target of Akt/PKB (41).…”

Section: Fig 3 ␤-Cell Growth Characteristics In Young Zucker Ratsmentioning

confidence: 99%

Mechanisms of Compensatory β-Cell Growth in Insulin-Resistant Rats

et al. 2005

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The physiological mechanisms underlying the compensatory growth of ␤-cell mass in insulin-resistant states are poorly understood. Using the insulin-resistant Zucker fatty (fa/fa) (ZF) rat and the corresponding Zucker lean control (ZLC) rat, we investigated the factors contributing to the age-/obesity-related enhancement of ␤-cell mass. A 3.8-fold ␤-cell mass increase was observed in ZF rats as early as 5 weeks of age, an age that precedes severe insulin resistance by several weeks. Closer investigation showed that ZF rat pups were not born with heightened ␤-cell mass but developed a modest increase over ZLC rats by 20 days that preceded weight gain or hyperinsulinemia that first developed at 24 days of age. In these ZF pups, an augmented survival potential of ␤-cells of ZF pups was observed by enhanced activated (phospho-) Akt, phospho-BAD, and Bcl-2 immunoreactivity in the postweaning period. However, increased ␤-cell proliferation in the ZF rats was only detected at 31 days of age, a period preceding massive ␤-cell growth. During this phase, we also detected an increase in the numbers of small ␤-cell clusters among ducts and acini, increased duct pancreatic/duodenal homeobox-1 (PDX-1) immunoreactivity, and an increase in islet number in the ZF rats suggesting duct-and acini-mediated heightened ␤-cell neogenesis. Interestingly, in young ZF rats, specific cells associated with ducts, acini, and islets exhibited an increased frequency of PDX-1 ؉ /phospho-Akt ؉ staining, indicating a potential role for Akt in ␤-cell differentiation. Thus, several adaptive mechanisms account for the compensatory growth of ␤-cells in ZF rats, a combination of enhanced survival and neogenesis with a transient rise in proliferation before 5 weeks of age, with Akt serving as a potential mediator in these processes. Diabetes 54: 2294 -2304, 2005 T he pancreatic islet ␤-cell regulates cellular fuel metabolism and glucose homeostasis through its secretion of insulin. Numerous studies in rodents and humans have shown a tremendous capacity for ␤-cell expansion in response to physiological and pathophysiological changes in tissue insulin requirements, i.e., insulin resistance (1-3). Over the last several years, much has been learned about the molecular regulation of ␤-cell development from mice with targeted genetic mutations of transcription factors and cell signaling intermediates. These studies have identified a key role for the insulin/IGF-1 signaling pathway in the adaptive response to insulin resistance, particularly the intermediates insulin receptor substrate-2 (IRS-2) (4 -9), Akt/protein kinase B (PKB) (10 -13), and the forkhead transcription factor Foxo1 (14) as putative regulators of the gene encoding pancreatic-duodenal homeobox-1 (PDX-1) (15). Although the details are not known about how the ␤-cell mass is regulated in response to progressive insulin resistance, a recent study implicates PDX-1 with a key role (16). Although the relative contribution of hyperplasia of existing ␤-cells versus new cell development (neogenesis) from...

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“…As a consequence of PTEN loss, AKT serine/threonine kinase and its downstream effectors are hyperactivated (48,51). AKT is critical for ␤-cell survival both in vitro and in transplantation models (1,10,12,33,34,46,54). Recent studies using genetic approaches have further demonstrated that a constitutively activated form of AKT enhances not only cell survival, but also cell proliferation and cell size, thereby increasing overall ␤-cell mass (3, 52).…”

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confidence: 99%

Selective Deletion of Pten in Pancreatic β Cells Leads to Increased Islet Mass and Resistance to STZ-Induced Diabetes

Stiles¹,

Kuralwalla-Martinez

Guo³

et al. 2006

Molecular and Cellular Biology

122

136

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Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a lipid phosphatase. PTEN inhibits the action of phosphatidylinositol-3-kinase and reduces the levels of phosphatidylinositol triphosphate, a crucial second messenger for cell proliferation and survival, as well as insulin signaling. In this study, we deleted Pten specifically in the insulin producing ␤ cells during murine pancreatic development. Pten deletion leads to increased cell proliferation and decreased cell death, without significant alteration of ␤-cell differentiation. Consequently, the mutant pancreas generates more and larger islets, with a significant increase in total ␤-cell mass. PTEN loss also protects animals from developing streptozotocin-induced diabetes. Our data demonstrate that PTEN loss in ␤ cells is not tumorigenic but beneficial. This suggests that modulating the PTEN-controlled signaling pathway is a potential approach for ␤-cell protection and regeneration therapies.␤ cells are produced through neogenesis from precursor cells and/or replication of mature and differentiated ␤ cells. During embryonic development, both neogenesis and replication contribute to the growth of the pancreas. The proliferation rate of ␤ cells in the adult pancreas, however, is relatively low. The adult pancreas undergoes slow turnover, with only approximately 0.5% mitotic activity, primarily by replication of differentiated cells (16). Nutrient and growth factors, such as high glucose concentrations, insulin-like growth factor 1 (IGF-1), and growth hormone, can induce ␤-cell replication (6, 39). Adult ␤-cell proliferation has been observed among pregnant and obese individuals for whom the demand for insulin is increased (40). During ␤-cell or pancreatic injuries, mitotic activity of ␤ cells is also increased (4,6,7,20,22,40). It has been suggested that after injury, ␤-cell regeneration may be the result of progenitor cell proliferation and differentiation (5). However, recent findings by Dor et al. suggest that in murine islets, proliferation of preexisting ␤ cells is the major mechanism for regeneration under both physiological and injury conditions (15). Together, these findings suggest that ␤ cells in pancreatic islets have a significant potential for replication. However, little is known about the factors regulating ␤-cell mass during neogenesis and adult pancreas turnover.Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is an indispensable regulator for cell growth and survival (48, 51). PTEN functions as a lipid phosphatase to dephosphorylate phosphatidylinositol triphosphate, the product of phosphatidylinositol-3-kinase (PI3K) (35, 56). By antagonizing PI3K function, PTEN inhibits the signals of insulin, IGF-1, and platelet-derived growth factor, the major mitogenic and survival factors of ␤ cells (13). As a consequence of PTEN loss, AKT serine/threonine kinase and its downstream effectors are hyperactivated (48,51). AKT is critical for ␤-cell survival both in vitro and in transplantation models (1,10,12,33,34,46,54). Re...

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Epidermal growth factor and insulin inhibit cell death in pancreatic beta cells by activation of PI3-kinase/AKT signaling pathway under oxidative stress

Cited by 27 publications

References 7 publications

Endogenous EGF maintains Sertoli germ cell anchoring junction integrity and is required for early recovery from acute testicular ischemia/reperfusion injury

Endogenous EGF maintains Sertoli germ cell anchoring junction integrity and is required for early recovery from acute testicular ischemia/reperfusion injury

Mechanisms of Compensatory β-Cell Growth in Insulin-Resistant Rats

Selective Deletion of Pten in Pancreatic β Cells Leads to Increased Islet Mass and Resistance to STZ-Induced Diabetes

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