scholarly journals Essential Role of Pten in Body Size Determination and Pancreatic β-Cell Homeostasis In Vivo

2006 ◽  
Vol 26 (12) ◽  
pp. 4511-4518 ◽  
Author(s):  
Kinh-Tung T. Nguyen ◽  
Panteha Tajmir ◽  
Chia Hung Lin ◽  
Nicole Liadis ◽  
Xu-Dong Zhu ◽  
...  
Keyword(s):  
Body Size ◽  
Cell Function ◽  
Regulatory Elements ◽  
Negative Regulator ◽  
Whole Body ◽  
Β Cells ◽  
Β Cell ◽  
Critical Determinant ◽  
Insulin Promoter

ABSTRACT PTEN (phosphatase with tensin homology) is a potent negative regulator of phosphoinositide 3-kinase (PI3K)/Akt signaling, an evolutionarily conserved pathway that signals downstream of growth factors, including insulin and insulin-like growth factor 1. In lower organisms, this pathway participates in fuel metabolism and body size regulation and insulin-like proteins are produced primarily by neuronal structures, whereas in mammals, the major source of insulin is the pancreatic β cells. Recently, rodent insulin transcription was also shown in the brain, particularly the hypothalamus. The specific regulatory elements of the PI3K pathway in these insulin-expressing tissues that contribute to growth and metabolism in higher organisms are unknown. Here, we report PTEN as a critical determinant of body size and glucose metabolism when targeting is driven by the rat insulin promoter in mice. The partial deletion of PTEN in the hypothalamus resulted in significant whole-body growth restriction and increased insulin sensitivity. Efficient PTEN deletion in β cells led to increased islet mass without compromise of β-cell function. Parallel enhancement in PI3K signaling was found in PTEN-deficient hypothalamus and β cells. Together, we have shown that PTEN in insulin-transcribing cells may play an integrative role in regulating growth and metabolism in vivo.

scholarly journals CK2 acts as a potent negative regulator of receptor-mediated insulin release in vitro and in vivo

2015 ◽  
Vol 112 (49) ◽  
pp. E6818-E6824 ◽  
Author(s):  
Mario Rossi ◽  
Inigo Ruiz de Azua ◽  
Luiz F. Barella ◽  
Wataru Sakamoto ◽  
Lu Zhu ◽  
...  
Keyword(s):  
Insulin Release ◽  
Cell Activity ◽  
Negative Regulator ◽  
Whole Body ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Release In Vitro

G protein-coupled receptors (GPCRs) regulate virtually all physiological functions including the release of insulin from pancreatic β-cells. β-Cell M3 muscarinic receptors (M3Rs) are known to play an essential role in facilitating insulin release and maintaining proper whole-body glucose homeostasis. As is the case with other GPCRs, M3R activity is regulated by phosphorylation by various kinases, including GPCR kinases and casein kinase 2 (CK2). At present, it remains unknown which of these various kinases are physiologically relevant for the regulation of β-cell activity. In the present study, we demonstrate that inhibition of CK2 in pancreatic β-cells, knockdown of CK2α expression, or genetic deletion of CK2α in β-cells of mutant mice selectively augmented M3R-stimulated insulin release in vitro and in vivo. In vitro studies showed that this effect was associated with an M3R-mediated increase in intracellular calcium levels. Treatment of mouse pancreatic islets with CX4945, a highly selective CK2 inhibitor, greatly reduced agonist-induced phosphorylation of β-cell M3Rs, indicative of CK2-mediated M3R phosphorylation. We also showed that inhibition of CK2 greatly enhanced M3R-stimulated insulin secretion in human islets. Finally, CX4945 treatment protected mice against diet-induced hyperglycemia and glucose intolerance in an M3R-dependent fashion. Our data demonstrate, for the first time to our knowledge, the physiological relevance of CK2 phosphorylation of a GPCR and suggest the novel concept that kinases acting on β-cell GPCRs may represent novel therapeutic targets.

scholarly journals β-Cell-specific ablation of sirtuin 4 does not affect nutrient-stimulated insulin secretion in mice

2020 ◽  
Vol 319 (4) ◽  
pp. E805-E813
Author(s):  
Frank K. Huynh ◽  
Brett S. Peterson ◽  
Kristin A. Anderson ◽  
Zhihong Lin ◽  
Aeowynn J. Coakley ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Cell Function ◽  
Whole Body ◽  
Β Cells ◽  
Β Cell ◽  
Direct Role ◽  
Normal Glucose

Sirtuins are a family of proteins that regulate biological processes such as cellular stress and aging by removing posttranslational modifications (PTMs). We recently identified several novel PTMs that can be removed by sirtuin 4 (SIRT4), which is found in mitochondria. We showed that mice with a global loss of SIRT4 [SIRT4-knockout (KO) mice] developed an increase in glucose- and leucine-stimulated insulin secretion, and this was followed by accelerated age-induced glucose intolerance and insulin resistance. Because whole body SIRT4-KO mice had alterations to nutrient-stimulated insulin secretion, we hypothesized that SIRT4 plays a direct role in regulating pancreatic β-cell function. Thus, we tested whether β-cell-specific ablation of SIRT4 would recapitulate the elevated insulin secretion seen in mice with a global loss of SIRT4. Tamoxifen-inducible β-cell-specific SIRT4-KO mice were generated, and their glucose tolerance and glucose- and leucine-stimulated insulin secretion were measured over time. These mice exhibited normal glucose- and leucine-stimulated insulin secretion and maintained normal glucose tolerance even as they aged. Furthermore, 832/13 β-cells with a CRISPR/Cas9n-mediated loss of SIRT4 did not show any alterations in nutrient-stimulated insulin secretion. Despite the fact that whole body SIRT4-KO mice demonstrated an age-induced increase in glucose- and leucine-stimulated insulin secretion, our current data indicate that the loss of SIRT4 specifically in pancreatic β-cells, both in vivo and in vitro, does not have a significant impact on nutrient-stimulated insulin secretion. These data suggest that SIRT4 controls nutrient-stimulated insulin secretion during aging by acting on tissues external to the β-cell, which warrants further study.

scholarly journals Follow-up of GK rats during prediabetes highlights increased insulin action and fat deposition despite low insulin secretion

2008 ◽  
Vol 294 (1) ◽  
pp. E168-E175 ◽  
Author(s):  
Jamileh Movassat ◽  
Danièle Bailbé ◽  
Cécile Lubrano-Berthelier ◽  
Françoise Picarel-Blanchot ◽  
Eric Bertin ◽  
...  
Keyword(s):  
Body Composition ◽  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Cell Function ◽  
Cell Mass ◽  
The Body ◽  
Whole Body ◽  
Β Cell ◽  
Gk Rats

The adult Goto-Kakizaki (GK) rat is characterized by impaired glucose-induced insulin secretion in vivo and in vitro, decreased β-cell mass, decreased insulin sensitivity in the liver, and moderate insulin resistance in muscles and adipose tissue. GK rats do not exhibit basal hyperglycemia during the first 3 wk after birth and therefore could be considered prediabetic during this period. Our aim was to identify the initial pathophysiological changes occurring during the prediabetes period in this model of type 2 diabetes (T2DM). To address this, we investigated β-cell function, insulin sensitivity, and body composition in normoglycemic prediabetic GK rats. Our results revealed that the in vivo secretory response of GK β-cells to glucose is markedly reduced and the whole body insulin sensitivity is increased in the prediabetic GK rats in vivo. Moreover, the body composition of suckling GK rats is altered compared with age-matched Wistar rats, with an increase of the number of adipocytes before weaning despite a decreased body weight and lean mass in the GK rats. None of these changes appeared to be due to the postnatal nutritional environment of GK pups as demonstrated by cross-fostering GK pups with nondiabetic Wistar dams. In conclusion, in the GK model of T2DM, β-cell dysfunction associated with increased insulin sensitivity and the alteration of body composition are proximal events that might contribute to the establishment of overt diabetes in adult GK rats.

scholarly journals A Pdx-1-Regulated Soluble Factor Activates Rat and Human Islet Cell Proliferation

2016 ◽  
Vol 36 (23) ◽  
pp. 2918-2930 ◽  
Author(s):  
Heather L. Hayes ◽  
Lu Zhang ◽  
Thomas C. Becker ◽  
Jonathan M. Haldeman ◽  
Samuel B. Stephens ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Islet Cell ◽  
Transforming Growth Factor ◽  
Cell Function ◽  
Transforming Growth Factor Β ◽  
Human Islet ◽  
Soluble Factor ◽  
Β Cells ◽  
Β Cell ◽  
Insulin Promoter

The homeodomain transcription factor Pdx-1 has important roles in pancreas and islet development as well as in β-cell function and survival. We previously reported that Pdx-1 overexpression stimulates islet cell proliferation, but the mechanism remains unclear. Here, we demonstrate that overexpression of Pdx-1 triggers proliferation largely by a non-cell-autonomous mechanism mediated by soluble factors. Consistent with this idea, overexpression of Pdx-1 under the control of a β-cell-specific promoter (rat insulin promoter [RIP]) stimulates proliferation of both α and β cells, and overexpression of Pdx-1 in islets separated by a Transwell membrane from islets lacking Pdx-1 overexpression activates proliferation in the untreated islets. Microarray and gene ontology (GO) analysis identified inhibin beta-B (Inhbb), an activin subunit and member of the transforming growth factor β (TGF-β) superfamily, as a Pdx-1-responsive gene. Overexpression of Inhbb or addition of activin B stimulates rat islet cell and β-cell proliferation, and the activin receptors RIIA and RIIB are required for the full proliferative effects of Pdx-1 in rat islets. In human islets, Inhbb overexpression stimulates total islet cell proliferation and potentiates Pdx-1-stimulated proliferation of total islet cells and β cells. In sum, this study identifies a mechanism by which Pdx-1 induces a soluble factor that is sufficient to stimulate both rat and human islet cell proliferation.

scholarly journals Perilipin2 down-regulation in β cells impairs insulin secretion under nutritional stress and damages mitochondria

2020 ◽  
Author(s):  
Akansha Mishra ◽  
Siming Liu ◽  
Joseph Promes ◽  
Mikako Harata ◽  
William Sivitz ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Cell Function ◽  
Islet Cells ◽  
Cell Metabolism ◽  
Nutritional Stress ◽  
Β Cells ◽  
Β Cell ◽  
Down Regulation

Perilipin 2 (PLIN2) is the lipid droplet (LD) protein in β cells that increases under nutritional stress. Down-regulation of PLIN2 is often sufficient to reduce LD accumulation. To determine whether PLIN2 positively or negatively affects β cell function under nutritional stress, PLIN2 was down-regulated in mouse β cells, INS1 cells, and human islet cells. β cell specific deletion of PLIN2 in mice on a high fat diet reduced glucose-stimulated insulin secretion (GSIS) in vivo and in vitro. Down-regulation of PLIN2 in INS1 cells blunted GSIS after 24 h incubation with 0.2 mM palmitic acids. Down-regulation of PLIN2 in human pseudoislets cultured at 5.6 mM glucose impaired both phases of GSIS, indicating that PLIN2 is critical for GSIS. Down-regulation of PLIN2 decreased specific OXPHOS proteins in all three models and reduced oxygen consumption rates in INS1 cells and mouse islets. Moreover, we found that PLIN2 deficient INS1 cells increased the distribution of a fluorescent oleic acid analog to mitochondria and showed signs of mitochondrial stress as indicated by susceptibility to fragmentation and alterations of acyl-carnitines and glucose metabolites. Collectively, PLIN2 in β cells have an important role in preserving insulin secretion, β cell metabolism and mitochondrial function under nutritional stress.

Increased expression of GAD65 and GABA in pancreatic β-cells impairs first-phase insulin secretion

2000 ◽  
Vol 279 (3) ◽  
pp. E684-E694 ◽  
Author(s):  
Yuguang Shi ◽  
Jamil Kanaani ◽  
Virginie Menard-Rose ◽  
Yan Hui Ma ◽  
Pi-Yun Chang ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Cell Function ◽  
Normal Glucose Tolerance ◽  
Negative Regulator ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Pancreas Perfusion ◽  
First Phase Insulin Secretion

The functional role of glutamate decarboxylase (GAD) and its product GABA in pancreatic islets has remained elusive. Mouse β-cells express the larger isoform GAD67, whereas human islets express only the smaller isoform GAD65. We have generated two lines of transgenic mice expressing human GAD65 in pancreatic β-cells (RIP7-hGAD65, Lines 1 and 2) to study the effect that GABA generated by this isoform has on islet cell function. The ascending order of hGAD65 expression and/or activity in β-cells was Line 1 heterozygotes < Line 2 heterozygotes < Line 1 homozygotes. Line 1 heterozygotes have normal glucose tolerance, whereas Line 1 homozygotes and Line 2 heterozygotes exhibit impaired glucose tolerance and inhibition of insulin secretion in vivo in response to glucose. In addition, fasting levels of blood glucose are elevated and insulin is decreased in Line 1 homozygotes. Pancreas perfusion experiments suggest that GABA generated by GAD65 may function as a negative regulator of first-phase insulin secretion in response to glucose by affecting a step proximal to or at the KATP +channel.

scholarly journals Downregulation of lncRNA TUG1 Affects Apoptosis and Insulin Secretion in Mouse Pancreatic β Cells

2015 ◽  
Vol 35 (5) ◽  
pp. 1892-1904 ◽  
Author(s):  
Dan-dan Yin ◽  
Er-bao Zhang ◽  
Liang-hui You ◽  
Ning Wang ◽  
Lin-tao Wang ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Cell Function ◽  
Annexin V ◽  
Pancreatic Tissue ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Lncrna Tug1

Background: Increasing evidence indicates that long noncoding RNAs (IncRNAs) perform specific biological functions in diverse processes. Recent studies have reported that IncRNAs may be involved in β cell function. The aim of this study was to characterize the role of IncRNA TUG1 in mouse pancreatic β cell functioning both in vitro and in vivo. Methods: qRT-PCR analyses were performed to detect the expression of lncRNA TUG1 in different tissues. RNAi, MTT, TUNEL and Annexin V-FITC assays and western blot, GSIS, ELISA and immunochemistry analyses were performed to detect the effect of lncRNA TUG1 on cell apoptosis and insulin secretion in vitro and in vivo. Results: lncRNA TUG1 was highly expressed in pancreatic tissue compared with other organ tissues, and expression was dynamically regulated by glucose in Nit-1 cells. Knockdown of lncRNA TUG1 expression resulted in an increased apoptosis ratio and decreased insulin secretion in β cells both in vitro and in vivo . Immunochemistry analyses suggested decreased relative islet area after treatment with lncRNA TUG1 siRNA. Conclusion: Downregulation of lncRNA TUG1 expression affected apoptosis and insulin secretion in pancreatic β cells in vitro and in vivo. lncRNA TUG1 may represent a factor that regulates the function of pancreatic β cells.

scholarly journals Beta-cell specific insulin resistance promotes glucose-stimulated insulin hypersecretion

2020 ◽  
Author(s):  
Søs Skovsø ◽  
Evgeniy Panzhinskiy ◽  
Jelena Kolic ◽  
Derek A. Dionne ◽  
Xiao-Qing Dai ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Tolerance ◽  
Cell Mass ◽  
Whole Body ◽  
Calcium Oscillation ◽  
Male Mice ◽  
Β Cells ◽  
Β Cell ◽  
Specific Insulin

AbstractInsulin receptor (Insr) protein can be found at higher levels in pancreatic β-cells than in most other cell types, but the consequences of β-cell insulin resistance remain enigmatic. Ins1cre allele was used to delete Insr specifically in β-cells of both female and male mice which were compared to Ins1cre-containing littermate controls at multiple ages and on multiple diets. RNA-seq of recombined β-cells revealed significant differences in multiple pathways previously implicated in insulin secretion and cellular fate, including rewired Ras and NFκB signaling. Male, but not female, βInsrKO mice had reduced oxygen consumption rate, while action potential and calcium oscillation frequencies were increased in Insr knockout β-cells from female, but not male mice. Female βInsrKO and βInsrHET mice exhibited elevated insulin release in perifusion experiments, during hyperglycemic clamps, and following i.p. glucose challenge. Deletion of Insr did not reduce β-cell mass up to 9 months of age, nor did it impair hyperglycemia-induced proliferation. Based on our data, we adapted a mathematical model to include β-cell insulin resistance, which predicted that β-cell Insr knockout would improve glucose tolerance depending on the degree of whole-body insulin resistance. Indeed, glucose tolerance was significantly improved in female βInsrKO and βInsrHET mice when compared to controls at 9, 21 and 39 weeks. We did not observe improved glucose tolerance in adult male mice or in high fat diet-fed mice, corroborating the prediction that global insulin resistance obscures the effects of β-cell specific insulin resistance. We further validated our in vivo findings using the Ins1-CreERT transgenic line and found improved glucose tolerance 4 weeks after tamoxifen-mediated Insr deletion. Collectively, our data show that loss of β-cell Insr alone is sufficient to drive glucose-induced hyperinsulinemia, thereby improving glucose homeostasis in otherwise insulin sensitive dietary and age contexts.

scholarly journals The HDAC Inhibitor Butyrate Impairs β Cell Function and Activates the Disallowed Gene Hexokinase I

2021 ◽  
Vol 22 (24) ◽  
pp. 13330
Author(s):  
Stephanie Bridgeman ◽  
Gaewyn Ellison ◽  
Philip Newsholme ◽  
Cyril Mamotte
Keyword(s):  
Insulin Secretion ◽  
Low Dose ◽  
Cell Function ◽  
High Dose ◽  
Hdac Inhibition ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function

Histone deacetylase (HDAC) inhibitors such as butyrate have been reported to reduce diabetes risk and protect insulin-secreting pancreatic β cells in animal models. However, studies on insulin-secreting cells in vitro have found that butyrate treatment resulted in impaired or inappropriate insulin secretion. Our study explores the effects of butyrate on insulin secretion by BRIN BD-11 rat pancreatic β cells and examined effects on the expression of genes implicated in β cell function. Robust HDAC inhibition with 5 mM butyrate or trichostatin A for 24 h in β cells decreased basal insulin secretion and content, as well as insulin secretion in response to acute stimulation. Treatment with butyrate also increased expression of the disallowed gene hexokinase I, possibly explaining the impairment to insulin secretion, and of TXNIP, which may increase oxidative stress and β cell apoptosis. In contrast to robust HDAC inhibition (>70% after 24 h), low-dose and acute high-dose treatment with butyrate enhanced nutrient-stimulated insulin secretion. In conclusion, although protective effects of HDAC inhibition have been observed in vivo, potent HDAC inhibition impairs β cell function in vitro. The chronic low dose and acute high dose butyrate treatments may be more reflective of in vivo effects.

scholarly journals In vivo Imaging β-cell Function Reveals Two Waves of β-cell Maturation

2017 ◽  
Author(s):  
Jia Zhao ◽  
Weijian Zong ◽  
Yi Wu ◽  
Jiayu Shen ◽  
Dongzhou Gou ◽  
...  
Keyword(s):  
Cell Function ◽  
Light Sheet ◽  
Cell Maturation ◽  
Β Cells ◽  
Β Cell ◽  
New Strategy ◽  
Β Cell Function ◽  
Insulin Secreting Cells

AbstractThe insulin-secreting cells generated from stem cells in vitro are less glucose responsive than primary β-cells. To search for the missing ingredients that are needed for β-cell maturation, we have longitudinally monitored function of every β-cell in Tg (ins:Rcamp1.07) zebrafish embryos with a newly-invented two-photon light-sheet microscope. We have shown that β-cell maturation begins from the islet mantle and propagates to the islet core during the hatching period, coordinated by the islet vascularization. Lower concentration of glucose is optimal to initiate β-cell maturation, while increased glucose delivery to every cell through microcirculation is required for functional boosting of the β-cells. Both the initiation and the boosting of β-cell maturation demands activation of calcineurin/NFAT by glucose. Calcineurin activator combined with glucose promotes mouse neonatal β-cells cultured in vitro to mature to a functional state similar to adult β-cells, suggesting a new strategy for improving stem cell-derived β-like cell function in vitro.

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