Measuring the Pancreatic β Cell Mass in Vivo with Exendin SPECT during Hyperglycemia and Severe Insulitis

2019 ◽  
Vol 16 (9) ◽  
pp. 4024-4030 ◽  
Author(s):  
Lieke Joosten ◽  
Maarten Brom ◽  
Hanneke Peeters ◽  
Desirée Bos ◽  
Eddy Himpe ◽  
...  
Keyword(s):  
Cell Mass ◽  
Pancreatic Β Cell ◽  
Β Cell

scholarly journals Role of AKT/mTORC1 pathway in pancreatic β-cell proliferation

2012 ◽  
pp. 235-243 ◽  
Author(s):  
Norman Balcazar Morales ◽  
Cecilia Aguilar de Plata
Keyword(s):  
Cell Cycle ◽  
Growth Factors ◽  
Cell Cycle Progression ◽  
Cell Mass ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Cycle Progression ◽  
Mtorc1 Signaling

Growth factors, insulin signaling and nutrients are important regulators of β-cell mass and function. The events linking these signals to regulation of β-cell mass are not completely understood. Recent findings indicate that mTOR pathway integrates signals from growth factors and nutrients with transcription, translation, cell size, cytoskeleton remodeling and mitochondrial metabolism. mTOR is a part of two distinct complexes; mTORC1 and mTORC2. The mammalian TORC1 is sensitive to rapamycin and contains Raptor, deptor, PRAS40 and the G protein β-subunit-like protein (GβL). mTORC1 activates key regulators of protein translation; ribosomal S6 kinase (S6K) and eukaryote initiation factor 4E-binding protein 1. This review summarizes current findings about the role of AKT/mTORC1 signaling in regulation of pancreatic β cell mass and proliferation. mTORC1 is a major regulator of β-cell cycle progression by modulation of cyclins D2, D3 and cdk4/cyclin D activity. These studies uncovered key novel pathways controlling cell cycle progression in β-cells in vivo. This information can be used to develop alternative approaches to expand β-cell mass in vivo and in vitro without the risk of oncogenic transformation. The acquisition of such knowledge is critical for the design of improved therapeutic strategies for the treatment and cure of diabetes as well as to understand the effects of mTOR inhibitors in β-cell function.

scholarly journals Role of Insulin-Like Growth Factor-Binding Protein 5 (IGFBP5) in Organismal and Pancreatic β-Cell Growth

2009 ◽  
Vol 94 (12) ◽  
pp. 5183-5183
Author(s):  
Catherine E. Gleason ◽  
Yun Ning ◽  
Tara P. Cominski ◽  
Rana Gupta ◽  
Klaus H. Kaestner ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Cell Size ◽  
Cell Mass ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Igf Binding Proteins ◽  
Cellular Processes ◽  
Igf I ◽  
Protein Kinase Akt

Abstract A family of IGF-binding proteins (IGFBP) exerts biological actions both dependent on and independent of IGF-I. A major effector of the insulin/IGF-I signaling pathway, the serine/threonine protein kinase Akt, mediates cellular processes such as glucose uptake, protein synthesis, cell survival, and growth. IGF-I is required for normal organismal growth, and in the pancreatic β-cell, the insulin/IGF-I signaling pathway is critical for normal and adaptive maintenance of β-cell mass. Expression of myrAkt1, an activated form of Akt, in the endocrine pancreas drives β-cell expansion through dramatic increases in both islet and β-cell size and number. Herein we present a comparative expression profiling of myrAkt1 transgenic islets that demonstrates the increased abundance of transcripts encoding proteins associated with growth, suppression of apoptosis, RNA processing, and metabolism. Although IGFBP5 is identified as a gene induced by Akt1 activation in the β-cell, Igfbp5 expression is not necessary for myrAkt1 to augment β-cell size or mass in vivo. However, in the absence of Igfbp5, mice demonstrate an increase in size and mild glucose intolerance. This is accentuated during diet-induced obesity, when Igfbp5-deficient mice have increased adiposity compared with wild-type mice on the same diet. These studies reveal a novel role for Igfbp5 in the control of growth and metabolism.

scholarly journals Role of Insulin-Like Growth Factor-Binding Protein 5 (IGFBP5) in Organismal and Pancreatic β-Cell Growth

2009 ◽  
Vol 30 (7) ◽  
pp. 930-930
Author(s):  
Catherine E. Gleason ◽  
Yun Ning ◽  
Tara P. Cominski ◽  
Rana Gupta ◽  
Klaus H. Kaestner ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Cell Size ◽  
Cell Mass ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Igf Binding Proteins ◽  
Cellular Processes ◽  
Igf I ◽  
Protein Kinase Akt

Abstract A family of IGF-binding proteins (IGFBP) exerts biological actions both dependent on and independent of IGF-I. A major effector of the insulin/IGF-I signaling pathway, the serine/threonine protein kinase Akt, mediates cellular processes such as glucose uptake, protein synthesis, cell survival, and growth. IGF-I is required for normal organismal growth, and in the pancreatic β-cell, the insulin/IGF-I signaling pathway is critical for normal and adaptive maintenance of β-cell mass. Expression of myrAkt1, an activated form of Akt, in the endocrine pancreas drives β-cell expansion through dramatic increases in both islet and β-cell size and number. Herein we present a comparative expression profiling of myrAkt1 transgenic islets that demonstrates the increased abundance of transcripts encoding proteins associated with growth, suppression of apoptosis, RNA processing, and metabolism. Although IGFBP5 is identified as a gene induced by Akt1 activation in the β-cell, Igfbp5 expression is not necessary for myrAkt1 to augment β-cell size or mass in vivo. However, in the absence of Igfbp5, mice demonstrate an increase in size and mild glucose intolerance. This is accentuated during diet-induced obesity, when Igfbp5-deficient mice have increased adiposity compared with wild-type mice on the same diet. These studies reveal a novel role for Igfbp5 in the control of growth and metabolism.

scholarly journals A Role for β-Cell-Expressed G Protein-Coupled Receptor 119 in Glycemic Control by Enhancing Glucose-Dependent Insulin Release

Endocrinology ◽  
2007 ◽  
Vol 148 (6) ◽  
pp. 2601-2609 ◽  
Author(s):  
Zhi-Liang Chu ◽  
Robert M. Jones ◽  
Hongmei He ◽  
Chris Carroll ◽  
Veronica Gutierrez ◽  
...  
Keyword(s):  
Insulin Release ◽  
Cell Mass ◽  
Oral Glucose ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Glucagon Like Peptide 1 ◽  
Orally Active ◽  
G Protein Coupled

Pancreatic β-cell dysfunction is a hallmark event in the pathogenesis of type 2 diabetes. Injectable peptide agonists of the glucagon-like peptide 1 (GLP-1) receptor have shown significant promise as antidiabetic agents by virtue of their ability to amplify glucose-dependent insulin release and preserve pancreatic β-cell mass. These effects are mediated via stimulation of cAMP through β-cell GLP-1 receptors. We report that the Gαs-coupled receptor GPR119 is largely restricted to insulin-producing β-cells of pancreatic islets. Additionally, we show here that GPR119 functions as a glucose-dependent insulinotropic receptor. Unlike receptors for GLP-1 and other peptides that mediate enhanced glucose-dependent insulin release, GPR119 was suitable for the development of potent, orally active, small-molecule agonists. The GPR119-specific agonist AR231453 significantly increased cAMP accumulation and insulin release in both HIT-T15 cells and rodent islets. In both cases, loss of GPR119 rendered AR231453 inactive. AR231453 also enhanced glucose-dependent insulin release in vivo and improved oral glucose tolerance in wild-type mice but not in GPR119-deficient mice. Diabetic KK/Ay mice were also highly responsive to AR231453. Orally active GPR119 agonists may offer significant promise as novel antihyperglycemic agents acting in a glucose-dependent fashion.

scholarly journals LKB1 deletion with the RIP2.Cre transgene modifies pancreatic β-cell morphology and enhances insulin secretion in vivo

2010 ◽  
Vol 298 (6) ◽  
pp. E1261-E1273 ◽  
Author(s):  
Gao Sun ◽  
Andrei I. Tarasov ◽  
James A. McGinty ◽  
Paul M. French ◽  
Angela McDonald ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Protein Kinase ◽  
Cell Function ◽  
Cell Mass ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Insulin Secretion In Vivo ◽  
Insulin Promoter ◽  
Ribosomal S6 Kinase

The tumor suppressor liver kinase B1 (LKB1), also called STK11, is a protein kinase mutated in Peutz-Jeghers syndrome. LKB1 phosphorylates AMP-activated protein kinase (AMPK) and several related protein kinases. Whereas deletion of both catalytic isoforms of AMPK from the pancreatic β-cell and hypothalamic neurons using the rat insulin promoter (RIP2). Cre transgene (βAMPKdKO) diminishes insulin secretion in vivo, deletion of LKB1 in the β-cell with an inducible Pdx-1.CreER transgene enhances insulin secretion in mice. To determine whether the differences between these models reflect genuinely distinct roles for the two kinases in the β-cell or simply differences in the timing and site(s) of deletion, we have therefore created mice deleted for LKB1 with the RIP2.Cre transgene. In marked contrast to βAMPKdKO mice, βLKB1KO mice showed diminished food intake and weight gain, enhanced insulin secretion, unchanged insulin sensitivity, and improved glucose tolerance. In line with the phenotype of Pdx1- CreER mice, total β-cell mass and the size of individual islets and β-cells were increased and islet architecture was markedly altered in βLKB1KO islets. Signaling by mammalian target of rapamycin (mTOR) to eIF4-binding protein-1 and ribosomal S6 kinase was also enhanced. In contrast to Pdx1- CreER-mediated deletion, the expression of Glut2, glucose-induced changes in membrane potential and intracellular Ca2+ were sharply reduced in βLKB1KO mouse islets and the stimulation of insulin secretion was modestly inhibited. We conclude that LKB1 and AMPK play distinct roles in the control of insulin secretion and that the timing of LKB1 deletion, and/or its loss from extrapancreatic sites, influences the final impact on β-cell function.

scholarly journals Pancreatic β-cell overexpression of the glucagon receptor gene results in enhanced β-cell function and mass

2009 ◽  
Vol 297 (3) ◽  
pp. E695-E707 ◽  
Author(s):  
Richard W. Gelling ◽  
Patricia M. Vuguin ◽  
Xiu Quan Du ◽  
Lingguang Cui ◽  
John Rømer ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Cell Mass ◽  
Insulin Content ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Glucagon Receptor ◽  
Pancreatic Insulin ◽  
Pancreatic Insulin Content

In addition to its primary role in regulating glucose production from the liver, glucagon has many other actions, reflected by the wide tissue distribution of the glucagon receptor (Gcgr). To investigate the role of glucagon in the regulation of insulin secretion and whole body glucose homeostasis in vivo, we generated mice overexpressing the Gcgr specifically on pancreatic β-cells (RIP-Gcgr). In vivo and in vitro insulin secretion in response to glucagon and glucose was increased 1.7- to 3.9-fold in RIP-Gcgr mice compared with controls. Consistent with the observed increase in insulin release in response to glucagon and glucose, the glucose excursion resulting from both a glucagon challenge and intraperitoneal glucose tolerance test (IPGTT) was significantly reduced in RIP-Gcgr mice compared with controls. However, RIP-Gcgr mice display similar glucose responses to an insulin challenge. β-Cell mass and pancreatic insulin content were also increased (20 and 50%, respectively) in RIP-Gcgr mice compared with controls. When fed a high-fat diet (HFD), both control and RIP-Gcgr mice developed similar degrees of obesity and insulin resistance. However, the severity of both fasting hyperglycemia and impaired glucose tolerance (IGT) were reduced in RIP-Gcgr mice compared with controls. Furthermore, the insulin response of RIP-Gcgr mice to an IPGTT was twice that of controls when fed the HFD. These data indicate that increased pancreatic β-cell expression of the Gcgr increased insulin secretion, pancreatic insulin content, β-cell mass, and, when mice were fed a HFD, partially protected against hyperglycemia and IGT.

scholarly journals Specific and Combined Effects of Insulin and Glucose on Functional Pancreatic β-Cell Mass in Vivo in Adult Rats

Endocrinology ◽  
2003 ◽  
Vol 144 (6) ◽  
pp. 2717-2727 ◽  
Author(s):  
Maryline Paris ◽  
Catherine Bernard-Kargar ◽  
Marie-France Berthault ◽  
Luc Bouwens ◽  
Alain Ktorza
Keyword(s):  
Cell Mass ◽  
Combined Effects ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Adult Rats

scholarly journals Ontology of the apelinergic system in mouse pancreas during pregnancy and relationship with β-cell mass

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Brenda Strutt ◽  
Sandra Szlapinski ◽  
Thineesha Gnaneswaran ◽  
Sarah Donegan ◽  
Jessica Hill ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Insulin Secretion ◽  
Glucose Transporter ◽  
Cell Mass ◽  
Elevated Serum ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Transporter 2 ◽  
Glucose Stimulated Insulin Secretion

AbstractThe apelin receptor (Aplnr) and its ligands, Apelin and Apela, contribute to metabolic control. The insulin resistance associated with pregnancy is accommodated by an expansion of pancreatic β-cell mass (BCM) and increased insulin secretion, involving the proliferation of insulin-expressing, glucose transporter 2-low (Ins+Glut2LO) progenitor cells. We examined changes in the apelinergic system during normal mouse pregnancy and in pregnancies complicated by glucose intolerance with reduced BCM. Expression of Aplnr, Apelin and Apela was quantified in Ins+Glut2LO cells isolated from mouse pancreata and found to be significantly higher than in mature β-cells by DNA microarray and qPCR. Apelin was localized to most β-cells by immunohistochemistry although Aplnr was predominantly associated with Ins+Glut2LO cells. Aplnr-staining cells increased three- to four-fold during pregnancy being maximal at gestational days (GD) 9–12 but were significantly reduced in glucose intolerant mice. Apelin-13 increased β-cell proliferation in isolated mouse islets and INS1E cells, but not glucose-stimulated insulin secretion. Glucose intolerant pregnant mice had significantly elevated serum Apelin levels at GD 9 associated with an increased presence of placental IL-6. Placental expression of the apelinergic axis remained unaltered, however. Results show that the apelinergic system is highly expressed in pancreatic β-cell progenitors and may contribute to β-cell proliferation in pregnancy.

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