Pancreatic β-cell growth and survival – a role in obesity-linked type 2 diabetes?

Lingohr, Melissa K.; Buettner, Roland; Rhodes, Christopher J.

doi:10.1016/s1471-4914(02)02377-8

Cited by 163 publications

(150 citation statements)

References 113 publications

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“…The results suggested that at least three signaling pathways, MAPK/ERK, PI3K/AKT, and cAMP/PKA are involved in the action of GHRH agonists upon their binding to GHRH receptors on INS-1 cells. GH and various growth factors stimulate proliferation and survival of β cells; these well-characterized growth factors include IGF1 and glucagon-like peptide (GLP-1) (8,11,(28)(29)(30). It has been reported that the binding of GH to GH-receptor triggers downstream signal transduction through the JAK2-STAT5a/b pathway, which leads to increase β-cell proliferation and survival (30,31).…”

Section: Discussionmentioning

confidence: 99%

Beneficial effects of growth hormone-releasing hormone agonists on rat INS-1 cells and on streptozotocin-induced NOD/SCID mice

Zhang

Cui

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Agonists of growth hormone-releasing hormone (GHRH) have been previously reported to promote growth, function, and engraftment of islet cells following transplantation. Here we evaluated recently synthesized GHRH agonists on the proliferation and biological functions of rat pancreatic β-cell line (INS-1) and islets. In vitro treatment of INS-1 cells with GHRH agonists increased cell proliferation, the expression of cellular insulin, insulin-like growth factor-1 (IGF1), and GHRH receptor, and also stimulated insulin secretion in response to glucose challenge. Exposure of INS-1 cells to GHRH agonists, MR-356 and MR-409, induced activation of ERK and AKT pathways. Agonist MR-409 also significantly increased the levels of cellular cAMP and the phosphorylation of cAMP response element binding protein (CREB) in INS-1 cells. Treatment of rat islets with agonist, MR-409 significantly increased cell proliferation, islet size, and the expression of insulin. In vivo daily s.c. administration of 10 μg MR-409 for 3 wk dramatically reduced the severity of streptozotocin (STZ)-induced diabetes in nonobese diabetic severe combined immunodeficiency (NOD/SCID) mice. The maximal therapeutic benefits with respect to the efficiency of engraftment, ability to reach normoglycemia, gain in body weight, response to high glucose challenge, and induction of higher levels of serum insulin and IGF1 were observed when diabetic mice were transplanted with rat islets preconditioned with GHRH agonist, MR-409, and received additional treatment with MR-409 posttransplantation. This study provides an improved approach to the therapeutic use of GHRH agonists in the treatment of diabetes mellitus.GHRH agonists | diabetes | INS-1 | signaling pathways | transplantation

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Section: Discussionmentioning

confidence: 99%

Beneficial effects of growth hormone-releasing hormone agonists on rat INS-1 cells and on streptozotocin-induced NOD/SCID mice

Zhang

Cui

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Because ␤-cells replicate during the postnatal period (17), it is possible that these proliferating cells are ␤-cells and that PGE 2 signaling inhibits this ␤-cell proliferation. The number of ␤-cells in the normal adult islets is regulated by a balance between proliferation and apoptosis (19). It has been estimated that it takes three months for the renewal of 50% of the pancreatic ␤-cells (20) and nine months for the renewal of 98% (21).…”

Section: Discussionmentioning

confidence: 99%

Destruction of Pancreatic β-Cells by Transgenic Induction of Prostaglandin E2 in the Islets

Oshima

Taketo

Oshima

2006

Journal of Biological Chemistry

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Type 2 diabetes mellitus is characterized by insulin resistance of peripheral tissues and dysfunction of pancreatic ␤-cells. Furthermore, the number of pancreatic ␤-cells decreases as a secondary effect of advanced type 2 diabetes, although the molecular mechanism has not been elucidated. Recently, it has been shown that hyperglycemic conditions induce the expression of cyclooxygenase-2 in pancreatic islets and increase the downstream product prostaglandin E 2 (PGE 2 ). To investigate whether high glucose-induced PGE 2 has an adverse effect on pancreatic ␤-cells, we generated transgenic mice (RIP-C2mE) that express cyclooxygenase-2 and microsomal prostaglandin E synthase-1 in their ␤-cells using the rat insulin-2 gene promoter (RIP). The homozygous RIP-C2mE (Tg/Tg) mice showed severe hyperglycemia from six weeks of age. Although the heterozygous RIP-C2mE (Tg/؊) mice showed normal blood glucose levels throughout their lifetime, this level increased significantly compared with that of wild-type mice when glucose was loaded. The relative number of ␤-cells to the total islet cell number was reduced to 54 and 14% in the RIP-C2mE (Tg/؊) and (Tg/Tg) mice, respectively, whereas that in the wild-type mice was 84%. Importantly, the proliferation rate in the islets of the RIP-C2mE (Tg/Tg) mice at four weeks of age decreased significantly in comparison to that in the wild-type mice. Because ␤-cells replicate not only during the postnatal period but also in the adult pancreas at a basal level, it is possible that increased PGE 2 signaling thus contributes to the reduction of the pancreatic ␤-cell mass through inhibition of proliferation, thereby aggravating diabetes further.Type 2 diabetes mellitus is characterized by the insensitivity of the peripheral tissues to insulin and the reduced function of the pancreatic ␤-cells. It has been suggested that chronic hyperglycemia impairs ␤-cell function as a secondary adverse effect of diabetes (1). Furthermore, the ␤-cell mass in pancreatic islets is reduced significantly in type 2 diabetes patients (2-4). In type 1 diabetes, a complexed autoimmune disease, an inflammatory cytokine interleukin-1␤ (IL-1␤) 2 is an important mediator in the impaired function and destruction of pancreatic ␤-cells (5). For example, the treatment of isolated islets with IL-1 inhibits insulin secretion, and this is followed by islet destruction (6). Moreover, adenoviral transduction of the IL-1 receptor antagonist protein into the islets protects against the IL-1␤-induced dysfunction (7). On the other hand, the long term exposure of islets to high glucose conditions has been shown to result in the induction of IL-1␤, followed by ␤-cell apoptosis (8). This high glucose-induced ␤-cell destruction is prevented by treating the islets with an IL-1 receptor antagonist. Accordingly, it is possible that IL-1␤ plays a pivotal role in type 2 diabetes as well.Recently, it has been reported that high glucose conditions induce the expression of cyclooxygenase-2 (COX-2) in pancreatic islets with an increase of the downs...

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“…66 Extensive research is directed to understand what unique properties b cells have to confer glucose responsive insulin production and secretion. The hallmark of pancreas dysfunction in noninsulin-dependent diabetes mellitus is diminished glucose-responsive insulin secretion, which is regulated by signals derived from mitochondrial metabolism.…”

Section: Pancreatic B Cell Function and Survivalmentioning

confidence: 99%

From acute ER stress to physiological roles of the Unfolded Protein Response

2006

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When protein folding in the endoplasmic reticulum (ER) is disrupted by alterations in homeostasis in the ER lumen, eucaryotic cells activate a series of signal transduction cascades that are collectively termed the unfolded protein response (UPR). Here we summarize our current understanding of how the UPR functions upon acute and severe stress. We discuss the mechanism of UPR receptor activation, UPR signal transduction to translational and transcriptional responses, UPR termination, and UPR signals that activate upon irreversible damage. Further, we review recent studies that have revealed that UPR provides a wide spectrum of physiological roles. Each individual UPR subpathway provides a unique and specialized role in diverse developmental and metabolic processes. This is especially observed for professional secretory cells, such as plasma cells, pancreatic b cells, hepatocytes, and osteoblasts, where high-level secretory protein synthesis requires a highly evolved mechanism to properly fold, process, and secrete proteins. There is a growing body of data that suggest that different subpathways of the UPR are required throughout the entire life of eucaryotic organisms, from regulation of differentiation to induction of apoptosis.

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Pancreatic β-cell growth and survival – a role in obesity-linked type 2 diabetes?

Cited by 163 publications

References 113 publications

Beneficial effects of growth hormone-releasing hormone agonists on rat INS-1 cells and on streptozotocin-induced NOD/SCID mice

Beneficial effects of growth hormone-releasing hormone agonists on rat INS-1 cells and on streptozotocin-induced NOD/SCID mice

Destruction of Pancreatic β-Cells by Transgenic Induction of Prostaglandin E2 in the Islets

From acute ER stress to physiological roles of the Unfolded Protein Response

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