scholarly journals Transgenic mice overexpressing PACAP in pancreatic β-cells: acute and chronic effects on insulin and glucose homeostasis

2004 ◽  
Vol 123 (4) ◽  
pp. 261-266
Author(s):  
Shuhei TOMIMOTO ◽  
Hitoshi HASHIMOTO ◽  
Norihito SHINTANI ◽  
Akemichi BABA
Keyword(s):  
Transgenic Mice ◽  
Glucose Homeostasis ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Chronic Effects ◽  
Acute And Chronic Effects

scholarly journals Critical Role of Egr Transcription Factors in Regulating Insulin Biosynthesis, Blood Glucose Homeostasis, and Islet Size

Endocrinology ◽  
2012 ◽  
Vol 153 (7) ◽  
pp. 3040-3053 ◽  
Author(s):  
Isabelle Müller ◽  
Oliver G. Rössler ◽  
Christine Wittig ◽  
Michael D. Menger ◽  
Gerald Thiel
Keyword(s):  
Transcription Factors ◽  
Glucose Tolerance ◽  
Transgenic Mice ◽  
Glucose Homeostasis ◽  
Insulin Biosynthesis ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Islet Size

Expression of early growth response protein (Egr)-1, a protein of the Egr family of zinc finger transcription factors, is stimulated in glucose-treated pancreatic β-cells and insulinoma cells. The purpose of this study was to elucidate the role of Egr transcription factors in pancreatic β-cells in vivo. To overcome the problem associated with redundancy of functions between Egr proteins, conditional transgenic mice were generated expressing a dominant-negative mutant of Egr-1 in pancreatic β-cells. The Egr-1 mutant interferes with DNA binding of all Egr proteins and thus impairs the biological functions of the entire Egr family. Expression of the Egr-1 mutant reduced expression of TGFβ and basic fibroblast growth factor, known target genes of Egr-1, whereas the expression of Egr-1, Egr-3, Ets-like gene-1 (Elk-1), and specificity protein-3 was not changed in the presence of the Egr-1 mutant. Expression of the homeobox protein pancreas duodenum homeobox-1, a major regulator of insulin biosynthesis, was reduced in islets expressing the Egr-1 mutant. Accordingly, insulin mRNA and protein levels were reduced by 75 or 25%, respectively, whereas expression of glucagon and somatostatin was not altered after expression of the Egr-1 mutant in β-cells. Glucose tolerance tests revealed that transgenic mice expressing the Egr-1 mutant in pancreatic β-cells displayed impaired glucose tolerance. In addition, increased caspase-3/7 activity was detected as a result of transgene expression, leading to a 20% decrease of the size of the islets. These results show that Egr proteins play an important role in controlling insulin biosynthesis, glucose homeostasis, and islet size of pancreatic β-cells in vivo.

scholarly journals Autocrine IGF2 programmes β-cell plasticity under conditions of increased metabolic demand

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ionel Sandovici ◽  
Constanze M. Hammerle ◽  
Sam Virtue ◽  
Yurena Vivas-Garcia ◽  
Adriana Izquierdo-Lahuerta ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Homeostasis ◽  
Association Studies ◽  
Susceptibility Gene ◽  
Chow Diet ◽  
Genome Wide Association Studies ◽  
Cell Plasticity ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells

AbstractWhen exposed to nutrient excess and insulin resistance, pancreatic β-cells undergo adaptive changes in order to maintain glucose homeostasis. The role that growth control genes, highly expressed in early pancreas development, might exert in programming β-cell plasticity in later life is a poorly studied area. The imprinted Igf2 (insulin-like growth factor 2) gene is highly transcribed during early life and has been identified in recent genome-wide association studies as a type 2 diabetes susceptibility gene in humans. Hence, here we investigate the long-term phenotypic metabolic consequences of conditional Igf2 deletion in pancreatic β-cells (Igf2βKO) in mice. We show that autocrine actions of IGF2 are not critical for β-cell development, or for the early post-natal wave of β-cell remodelling. Additionally, adult Igf2βKO mice maintain glucose homeostasis when fed a chow diet. However, pregnant Igf2βKO females become hyperglycemic and hyperinsulinemic, and their conceptuses exhibit hyperinsulinemia and placentomegalia. Insulin resistance induced by congenital leptin deficiency also renders Igf2βKO females more hyperglycaemic compared to leptin-deficient controls. Upon high-fat diet feeding, Igf2βKO females are less susceptible to develop insulin resistance. Based on these findings, we conclude that in female mice, autocrine actions of β-cell IGF2 during early development determine their adaptive capacity in adult life.

scholarly journals Pancreatic β cells control glucose homeostasis via the secretion of exosomal miR‐29 family

2021 ◽  
Vol 10 (3) ◽  
Author(s):  
Jing Li ◽  
Yujing Zhang ◽  
Yangyang Ye ◽  
Dameng Li ◽  
Yuchen Liu ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
Β Cells ◽  
Pancreatic Β Cells

Specific Deletion of CASK in Pancreatic β Cells Affects Glucose Homeostasis and Improves Insulin Sensitivity in Obese Mice by Reducing Hyperinsulinemia Running Title: β Cell CASK Deletion Reduces Hyperinsulinemia

2021 ◽  
Author(s):  
Xingjing Liu ◽  
Peng Sun ◽  
Qingzhao Yuan ◽  
Jinyang Xie ◽  
Ting Xiao ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Glucose Homeostasis ◽  
Chow Diet ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Calcium Calmodulin Dependent ◽  
Normal Chow

Calcium/calmodulin-dependent serine protein kinase (CASK) is involved in the secretion of insulin vesicles in pancreatic β-cells. The present study revealed a new <i>in vivo </i>role of CASK in glucose homeostasis during the progression of type 2 diabetes mellitus (T2DM). A Cre-loxP system was used to specifically delete the <i>Cask </i>gene in mouse β-cells (βCASKKO), and the glucose metabolism was evaluated in <a>βCASKKO</a> mice fed a normal chow diet (ND) or a high-fat diet (HFD). ND-fed mice exhibited impaired insulin secretion in response to glucose stimulation. Transmission electron microscopy showed significantly reduced numbers of insulin granules at or near the cell membrane in the islets of βCASKKO mice. By contrast, HFD-fed βCASKKO mice showed reduced blood glucose and a partial relief of hyperinsulinemia and insulin resistance when compared to HFD-fed wildtype mice. The IRS1/PI3K/AKT signaling pathway was upregulated in the adipose tissue of HFD-βCASKKO mice. These results indicated that knockout of the <i>Cask</i> gene in β cells had a diverse effect on glucose homeostasis: reduced insulin secretion in ND-fed mice, but improves insulin sensitivity in HFD-fed mice. Therefore, CASK appears to function in the insulin secretion and contributes to hyperinsulinemia and insulin resistance during the development of obesity-related T2DM.

scholarly journals Erratum. WASH Regulates Glucose Homeostasis by Facilitating Glut2 Receptor Recycling in Pancreatic β-Cells. Diabetes 2019;68:377–386

Diabetes ◽  
2020 ◽  
Vol 69 (5) ◽  
pp. 1083-1083
Author(s):  
Li Ding ◽  
Lingling Han ◽  
John Dube ◽  
Daniel D. Billadeau
Keyword(s):  
Glucose Homeostasis ◽  
Receptor Recycling ◽  
Β Cells ◽  
Pancreatic Β Cells

scholarly journals A Role for Intestinal Endocrine Cell-Expressed G Protein-Coupled Receptor 119 in Glycemic Control by Enhancing Glucagon-Like Peptide-1 and Glucose-Dependent Insulinotropic Peptide Release

Endocrinology ◽  
2008 ◽  
Vol 149 (5) ◽  
pp. 2038-2047 ◽  
Author(s):  
Zhi-Liang Chu ◽  
Chris Carroll ◽  
Jean Alfonso ◽  
Veronica Gutierrez ◽  
Hongmei He ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Glucose Homeostasis ◽  
Oral Glucose ◽  
Hormone Release ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Incretin Hormone ◽  
Glucagon Like Peptide ◽  
Insulinotropic Peptide ◽  
G Protein Coupled

We recently showed that activation of G protein-coupled receptor 119 (GPR119) (also termed glucose dependent insulinotropic receptor) improves glucose homeostasis via direct cAMP-mediated enhancement of glucose-dependent insulin release in pancreatic β-cells. Here we show that GPR119 also stimulates incretin hormone release and thus may regulate glucose homeostasis by this additional mechanism. GPR119 mRNA was found to be expressed at significant levels in intestinal subregions that produce glucose-dependent insulinotropic peptide and glucagon-like peptide (GLP)-1. Furthermore, in situ hybridization studies indicated that most GLP-1-producing cells coexpress GPR119 mRNA. In GLUTag cells, a well-established model of intestinal L-cell function, the potent GPR119 agonist AR231453 stimulated cAMP accumulation and GLP-1 release. When administered in mice, AR231453 increased active GLP-1 levels within 2 min after oral glucose delivery and substantially enhanced total glucose-dependent insulinotropic peptide levels. Blockade of GLP-1 receptor signaling with exendin(9–39) reduced the ability of AR231453 to improve glucose tolerance in mice. Conversely, combined administration of AR231453 and the DPP-4 inhibitor sitagliptin to wild-type mice significantly amplified both plasma GLP-1 levels and oral glucose tolerance, relative to either agent alone. In mice lacking GPR119, no such enhancement was seen. Thus, GPR119 regulates glucose tolerance by acting on intestinal endocrine cells as well as pancreatic β-cells. These data also suggest that combined stimulation of incretin hormone release and protection against incretin hormone degradation may be an effective antidiabetic strategy.

Biologically active human islet amyloid polypeptide/amylin in transgenic mice

1997 ◽  
Vol 136 (1) ◽  
pp. 107-113 ◽  
Author(s):  
Karen L van Hulst ◽  
Walter Born ◽  
Roman Muff ◽  
Cor Oosterwijk ◽  
Marinus A Blankenstein ◽  
...  
Keyword(s):  
Biological Activity ◽  
Transgenic Mice ◽  
Islet Amyloid Polypeptide ◽  
Human Islet ◽  
Cell Protein ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Islet Amyloid ◽  
Human Islet Amyloid Polypeptide ◽  
Human And Mouse

Abstract Objective: Human islet amyloid polypeptide (hIAPP), also named amylin, is a pancreatic β cell protein implicated in the pathogenesis of pancreatic islet amyloid formation and type 2 diabetes mellitus. To study the (patho)physiological roles of hIAPP, we have generated transgenic mice that overexpress hIAPP mRNA, in relation to endogenous mouse IAPP (mIAPP) mRNA, in pancreatic β cells. The biological activity of human and mouse IAPP derived from pancreatic extracts was determined. Methods: Pancreatic and plasma extracts of transgenic and control mice were analyzed by reversedphase high-performance liquid chromatography (HPLC) and radioimmunoassay, yielding a separation of hIAPP from mIAPP. Biological activity of immunoreactive human and mouse IAPP components derived from pancreatic extracts was assessed by calcitonin receptor-mediated stimulation of cyclic AMP accumulation in T47D human breast carcinoma cells. Results: The predominant immunoreactive human and mouse IAPP gene products had the retention times on HPLC analysis of the corresponding synthetic peptides. The ratio of bioactive over immunoreactive hIAPP and mIAPP was 0·93 ±0·18 and 1·19 ±0·56 respectively. In extracts of two plasma pools from 4 transgenic animals, hIAPP was 4·6- to 7-fold more abundant than mIAPP. Conclusion; This study has shown that correctly processed hIAPP produced in transgenic mouse pancreatic β cells exhibits full biological activity. The results validate these transgenic mice for the study of (patho)physiological roles of hIAPP in vivo. European Journal of Endocrinology 136 107–113

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