scholarly journals Expression of thyrotropin-releasing hormone receptor in immortalized beta-cell lines and rat pancreas

2004 ◽  
Vol 181 (3) ◽  
pp. 401-412 ◽  
Author(s):  
LG Luo ◽  
N Yano
Keyword(s):  
Beta Cell ◽  
Beta Cells ◽  
Cell Lines ◽  
Pancreatic Beta Cells ◽  
Egf Receptor ◽  
Thyrotropin Releasing Hormone ◽  
Receptor Expression ◽  
Receptor Type ◽  
Trh Receptor

Thyrotropin-releasing hormone (TRH), a hypothalamic tripeptide, is expressed in pancreatic islets at peak levels during the late gestation and early neonate period. TRH increases insulin production in cultured beta-cells, suggesting that it might play a role in regulating pancreatic beta-cell function. However, there is limited information on TRH receptor expression in the pancreas. The aim of the present study was to explore the distribution of the TRH receptor in the pancreas and its function in pancreatic beta-cells. TRH receptor type 1 (TRHR1) gene expression was detected by RT-PCR and verified by Northern blotting and immunoblotting in the beta-cell lines, INS-1 and betaTC-6, and the rat pancreatic organ. The absence of TRH receptor type 2 expression in the tissue and cells indicated the tissue specificity of TRH receptor expression in the pancreas. The TRHR1 signals (detected by in situ hybridization) were distributed not only in islets but also in the surrounding areas of the pancreatic ductal and vasal epithelia. The apparent dissociation constant value for the affinity of [(3)H]3-methyl-histidine TRH (MeTRH) is 4.19 in INS-1 and 3.09 nM in betaTC-6. In addition, TRH induced epidermal growth factor (EGF) receptor phosphorylation with a half-maximum concentration of approximately 50 nM, whereas the high affinity analogue of TRH, MeTRH, was 1 nM. This suggested that the affinity of TRH ligands for the TRH receptor influences the activation of EGF receptor phosphorylation in betaTC-6 cells. Our observations suggested that the biological role of TRH in pancreatic beta-cells is via the activation of TRHR1. Further research is required to identify the role of TRHR1 in the pancreas aside from the islets.

Regulation of alpha 2-adrenergic receptor expression and signaling in pancreatic beta-cells

1995 ◽  
Vol 269 (1) ◽  
pp. E162-E171 ◽  
Author(s):  
D. Hamamdzic ◽  
E. Duzic ◽  
J. D. Sherlock ◽  
S. M. Lanier
Keyword(s):  
Beta Cell ◽  
Beta Cells ◽  
Cell Lines ◽  
Pancreatic Beta Cells ◽  
Pancreatic Beta Cell ◽  
Receptor Activation ◽  
Tissue Response ◽  
Receptor Expression ◽  
Receptor Density ◽  
Binding Studies

Activation of alpha 2-adrenergic receptors (alpha 2-AR) in pancreatic beta-cells inhibits insulin secretion in response to various stimuli, and acute or long-term regulation of alpha 2-AR receptor-mediated effects may influence the tissue response to glucose dishomeostasis. As an initial approach to this issue, we determined the effect of various metabolic and hormonal treatments on alpha 2-AR expression and coupling in the pancreatic beta-cell lines HIT-T15 and RIN-5AH. Radioligand binding studies ([3H]RX-821002) and RNA blot analysis indicate that both pancreatic beta-cell lines express the alpha 2A/D-AR subtype [for HIT-T15 the maximum binding (Bmax) = 113 +/- 28; for RIN-5AH Bmax = 93 +/- 18 fmol/mg of cellular protein]. Treatment of HIT-T15 or RIN-5AH cells with glucocorticoids [dexamethasone, hydrocortisone, or prednisolone (1 microM)] increased alpha 2-AR mRNA level and receptor protein density three- to fivefold. The glucocorticoid-induced increase in receptor density in HIT-T15 cells was associated with 1) an increase in the amount of receptors coupled to G protein as determined by analysis of high-affinity 5'-guanylyl imidodiphosphate-sensitive binding of [3H]UK-14304, a selective alpha 2-AR agonist, and 2) a greater inhibition of forskolin-induced elevation of cellular adenosine 3',5'-cyclic monophosphate after receptor activation. Receptor density in HIT-T15 cells was not altered by different growth conditions, insulin (1 microM), phorbol 12-myristate 13-acetate (1 microM), or the sex steroids testosterone and progesterone (1 microM). These data indicate that glucocorticoids upregulate alpha 2-AR expression and signaling in pancreatic beta-cells. Such regulation may operate in a cell-specific manner, allowing discrete modulation of tissue responses to glucose dishomeostasis.

scholarly journals Multi-Organ Crosstalk with Endocrine Pancreas: A Focus on How Gut Microbiota Shapes Pancreatic Beta-Cells

Biomolecules ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 104
Author(s):  
Elisa Fernández-Millán ◽  
Carlos Guillén
Keyword(s):  
Beta Cell ◽  
Beta Cells ◽  
Cell Biology ◽  
Pancreatic Beta Cells ◽  
Metabolic Diseases ◽  
Cell Function ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Short Chain Fatty Acids

Type 2 diabetes (T2D) results from impaired beta-cell function and insufficient beta-cell mass compensation in the setting of insulin resistance. Current therapeutic strategies focus their efforts on promoting the maintenance of functional beta-cell mass to ensure appropriate glycemic control. Thus, understanding how beta-cells communicate with metabolic and non-metabolic tissues provides a novel area for investigation and implicates the importance of inter-organ communication in the pathology of metabolic diseases such as T2D. In this review, we provide an overview of secreted factors from diverse organs and tissues that have been shown to impact beta-cell biology. Specifically, we discuss experimental and clinical evidence in support for a role of gut to beta-cell crosstalk, paying particular attention to bacteria-derived factors including short-chain fatty acids, lipopolysaccharide, and factors contained within extracellular vesicles that influence the function and/or the survival of beta cells under normal or diabetogenic conditions.

scholarly journals Pancreatic beta cells cultured from individual preneoplastic foci in a multistage tumorigenesis pathway: a potentially general technique for isolating physiologically representative cell lines.

1993 ◽  
Vol 13 (7) ◽  
pp. 4223-4232 ◽  
Author(s):  
F Radvanyi ◽  
S Christgau ◽  
S Baekkeskov ◽  
C Jolicoeur ◽  
D Hanahan
Keyword(s):  
Major Histocompatibility Complex ◽  
Beta Cell ◽  
Beta Cells ◽  
Cell Lines ◽  
Pancreatic Beta Cells ◽  
Type I ◽  
Major Histocompatibility ◽  
Normal Cells ◽  
Histocompatibility Complex ◽  
Preneoplastic Foci

Culturing and comparing the discrete stages of tumorigenesis provide a route to defining important components of the cancer phenotype and, in addition, present the opportunity to establish cell cultures more representative of normal cells than the ultimate malignant cancer cells. Herein we report that preneoplastic foci in one multistep tumorigenesis pathway can be cultured in vitro and show that they preserve distinctive characteristics of the normal cells from which they arose, pancreatic beta cells. In the RIP1-Tag2 line of transgenic mice, which express the simian virus 40 T antigen in insulin-producing beta cells, pancreatic islets develop into vascularized tumors in a multistage pathway. We established conditions for reproducible derivation of beta-cell lines from individual hyperplastic islets that have not yet developed into solid tumors. Most of these cell lines, designated beta HC, release insulin at physiological concentrations of glucose. In contrast to tumor-derived lines (beta TC), which are not properly regulated, the ability of the beta HC lines to respond correctly to glucose correlated with maintenance of normally depressed levels of low-Km hexokinases. Glutamic acid decarboxylase (GAD), an early autoantigen in type I diabetes, was detected in most of the beta HC lines. The relative levels of the two forms of this enzyme (GAD65 and GAD67) varied significantly between the different cell lines, suggesting independent regulation. Class I major histocompatibility complex antigens were detected on the beta HC cells, and the levels of surface major histocompatibility complex expression correlated with their capacity to serve as targets in a cytotoxic T-cell killing assay. The beta HC lines will be of value for studies of beta-cell physiology, autoantigenicity, and tumor development. This work suggests the possibility of culturing preneoplastic stages of other cancers, both to address the mechanisms of transformation and to provide a source of cells that maintain important qualities of their normal progenitors.

scholarly journals Alpk1 Sensitizes Pancreatic Beta Cells to Cytokine-Induced Apoptosis via Upregulating TNF-α Signaling Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Fei Ding ◽  
Xi Luo ◽  
Yiting Tu ◽  
Xianlan Duan ◽  
Jia Liu ◽  
...  
Keyword(s):  
Beta Cell ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Pancreatic Beta Cell ◽  
Min6 Cells ◽  
Beta Cell Failure ◽  
Tnf Α ◽  
Induced Apoptosis ◽  
Pro Inflammatory Cytokines

Pancreatic beta cell failure is the hallmark of type 1 diabetes (T1D). Recent studies have suggested that pathogen recognizing receptors (PRRs) are involved in the survival, proliferation and function of pancreatic beta cells. So far, little is known about the role of alpha-protein kinase 1 (ALPK1), a newly identified cytosolic PRR specific for ADP-β-D-manno-heptose (ADP-heptose), in beta cell survival. In current study we aimed to fill the knowledge gap by investigating the role of Alpk1 in the apoptosis of MIN6 cells, a murine pancreatic beta cell line. We found that the expression of Alpk1 was significantly elevated in MIN6 cells exposed to pro-inflammatory cytokines, but not to streptozotocin, low-dose or high-dose glucose. Activation of Alpk1 by ADP heptose alone was insufficient to induce beta cell apoptosis. However, it significantly exacerbated cytokine-induced apoptosis in MIN6 cells. Mechanistic investigations showed that Alpk1 activation was potent to further induce the expression of tumor necrosis factor (TNF)-α and Fas after cytokine stimulation, possibly due to enhanced activation of the TIFA/TAK1/NF-κB signaling axis. Treatment of GLP-1 receptor agonist decreased the expression of TNF-α and Fas and improved the survival of beta cells exposed to pro-inflammatory cytokines and ADP heptose. In summary, our data suggest that Alpk1 sensitizes beta cells to cytokine-induced apoptosis by potentiating TNF-α signaling pathway, which may provide novel insight into beta cell failure and T1D development.

scholarly journals Imaging Beta-Cell Function in the Pancreas of Non-Human Primates Using a Zinc-Sensitive MRI Contrast Agent

2021 ◽  
Vol 12 ◽  
Author(s):  
Veronica Clavijo Jordan ◽  
Catherine D. G. Hines ◽  
Liza T. Gantert ◽  
Shubing Wang ◽  
Stacey Conarello ◽  
...  
Keyword(s):  
Beta Cell ◽  
Contrast Agent ◽  
Contrast Enhancement ◽  
Beta Cells ◽  
Beta Cell Function ◽  
Pancreatic Beta Cells ◽  
Cell Function ◽  
Mri Contrast Agent ◽  
C Peptide

Non-invasive beta cell function measurements may provide valuable information for improving diabetes diagnostics and disease management as the integrity and function of pancreatic beta cells have been found to be compromised in Type-1 and Type-2 diabetes. Currently, available diabetes assays either lack functional information or spatial identification of beta cells. In this work, we introduce a method to assess the function of beta cells in the non-human primate pancreas non-invasively with MRI using a Gd-based zinc(II) sensor as a contrast agent, Gd-CP027. Additionally, we highlight the role of zinc(II) ions in the paracrine signaling of the endocrine pancreas via serological measurements of insulin and c-peptide. Non-human primates underwent MRI exams with simultaneous blood sampling during a Graded Glucose Infusion (GGI) with Gd-CP027 or with a non-zinc(II) sensitive contrast agent, gadofosveset. Contrast enhancement of the pancreas resulting from co-release of zinc(II) ion with insulin was observed focally when using the zinc(II)-specific agent, Gd-CP027, whereas little enhancement was detected when using gadofosveset. The contrast enhancement detected by Gd-CP027 increased in parallel with an increased dose of infused glucose. Serological measurements of C-peptide and insulin indicate that Gd-CP027, a high affinity zinc(II) contrast agent, potentiates their secretion only as a function of glucose stimulation. Taken in concert, this assay offers the possibility of detecting beta cell function in vivo non-invasively with MRI and underscores the role of zinc(II) in endocrine glucose metabolism.

scholarly journals Aberrant development of pancreatic beta cells derived from human iPSCs with FOXA2 deficiency

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ahmed K. Elsayed ◽  
Ihab Younis ◽  
Gowher Ali ◽  
Khalid Hussain ◽  
Essam M. Abdelalim
Keyword(s):  
Beta Cell ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Pancreatic Beta Cell ◽  
Cell Development ◽  
Nervous System Development ◽  
Aberrant Expression ◽  
Pancreatic Development ◽  
Human Ipscs

AbstractFOXA2 has been identified as an essential factor for pancreas development and emerging evidence supports an association between FOXA2 and diabetes. Although the role of FOXA2 during pancreatic development is well-studied in animal models, its role during human islet cell development remains unclear. Here, we generated induced pluripotent stem cells (iPSCs) from a patient with FOXA2 haploinsufficiency (FOXA2+/− iPSCs) followed by beta-cell differentiation to understand the role of FOXA2 during pancreatic beta-cell development. Our results showed that FOXA2 haploinsufficiency resulted in aberrant expression of genes essential for the differentiation and proper functioning of beta cells. At pancreatic progenitor (PP2) and endocrine progenitor (EPs) stages, transcriptome analysis showed downregulation in genes associated with pancreatic development and diabetes and upregulation in genes associated with nervous system development and WNT signaling pathway. Knockout of FOXA2 in control iPSCs (FOXA2−/− iPSCs) led to severe phenotypes in EPs and beta-cell stages. The expression of NGN3 and its downstream targets at EPs as well as INSUILIN and GLUCAGON at the beta-cell stage, were almost absent in the cells derived from FOXA2−/− iPSCs. These findings indicate that FOXA2 is crucial for human pancreatic endocrine development and its defect may lead to diabetes based on FOXA2 dosage.

Role of pancreatic beta-cells in the process of beta-cell death

Diabetes ◽  
2001 ◽  
Vol 50 (Supplement 1) ◽  
pp. S52-S57 ◽  
Author(s):  
D. Pipeleers ◽  
A. Hoorens ◽  
M. Marchial-Pipeleers ◽  
M. Van de Casteele ◽  
L. Bouwens ◽  
...  
Keyword(s):  
Cell Death ◽  
Beta Cell ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Beta Cell Death

Pancreatic beta cells cultured from individual preneoplastic foci in a multistage tumorigenesis pathway: a potentially general technique for isolating physiologically representative cell lines

1993 ◽  
Vol 13 (7) ◽  
pp. 4223-4232
Author(s):  
F Radvanyi ◽  
S Christgau ◽  
S Baekkeskov ◽  
C Jolicoeur ◽  
D Hanahan
Keyword(s):  
Major Histocompatibility Complex ◽  
Beta Cell ◽  
Beta Cells ◽  
Cell Lines ◽  
Pancreatic Beta Cells ◽  
Type I ◽  
Major Histocompatibility ◽  
Normal Cells ◽  
Histocompatibility Complex ◽  
Preneoplastic Foci

Culturing and comparing the discrete stages of tumorigenesis provide a route to defining important components of the cancer phenotype and, in addition, present the opportunity to establish cell cultures more representative of normal cells than the ultimate malignant cancer cells. Herein we report that preneoplastic foci in one multistep tumorigenesis pathway can be cultured in vitro and show that they preserve distinctive characteristics of the normal cells from which they arose, pancreatic beta cells. In the RIP1-Tag2 line of transgenic mice, which express the simian virus 40 T antigen in insulin-producing beta cells, pancreatic islets develop into vascularized tumors in a multistage pathway. We established conditions for reproducible derivation of beta-cell lines from individual hyperplastic islets that have not yet developed into solid tumors. Most of these cell lines, designated beta HC, release insulin at physiological concentrations of glucose. In contrast to tumor-derived lines (beta TC), which are not properly regulated, the ability of the beta HC lines to respond correctly to glucose correlated with maintenance of normally depressed levels of low-Km hexokinases. Glutamic acid decarboxylase (GAD), an early autoantigen in type I diabetes, was detected in most of the beta HC lines. The relative levels of the two forms of this enzyme (GAD65 and GAD67) varied significantly between the different cell lines, suggesting independent regulation. Class I major histocompatibility complex antigens were detected on the beta HC cells, and the levels of surface major histocompatibility complex expression correlated with their capacity to serve as targets in a cytotoxic T-cell killing assay. The beta HC lines will be of value for studies of beta-cell physiology, autoantigenicity, and tumor development. This work suggests the possibility of culturing preneoplastic stages of other cancers, both to address the mechanisms of transformation and to provide a source of cells that maintain important qualities of their normal progenitors.

scholarly journals PICK1 is essential for insulin production and the maintenance of glucose homeostasis

2018 ◽  
Vol 29 (5) ◽  
pp. 587-596 ◽  
Author(s):  
Jia Li ◽  
Zhuo Mao ◽  
Jiandong Huang ◽  
Jun Xia
Keyword(s):  
Beta Cell ◽  
Beta Cells ◽  
Knockout Mice ◽  
Pancreatic Beta Cells ◽  
Cell Function ◽  
Critical Role ◽  
Insulin Deficiency ◽  
Granule Formation ◽  
Proinsulin Processing

Protein interacting with C-kinase 1 (PICK1) is a peripheral membrane protein that controls insulin granule formation, trafficking, and maturation in INS-1E cells. However, global Pick1-knockout mice showed only a subtle diabetes-like phenotype. This raises the possibility that compensatory effects from tissues other than pancreatic beta cells may obscure the effects of insulin deficiency. To explore the role of PICK1 in pancreatic islets, we generated mice harboring a conditional Pick1 allele in a C57BL/6J background. The conditional Pick1-knockout mice exhibited impaired glucose tolerance, profound insulin deficiency, and hyperglycemia. In vitro experiments showed that the ablation of Pick1 in pancreatic beta cells selectively decreased the initial rapid release of insulin and the total insulin levels in the islets. Importantly, the specific ablation of Pick1 induced elevated proinsulin levels in the circulation and in the islets, accompanied by a reduction in the proinsulin processing enzymes prohormone convertase 1/3 (PC1/3). The deletion of Pick1 triggered the specific elimination of chromogranin B in pancreatic beta cells, which is believed to control granule formation and release. Collectively, these data demonstrate the critical role of PICK1 in secretory granule biogenesis, proinsulin processing, and beta cell function. We conclude that the beta cell–specific deletion of Pick1 in mice led to hyperglycemia and eventually to diabetes.

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