Role of iduronate-2-sulfatase in glucose-stimulated insulin secretion by activation of exocytosis

2009 ◽  
Vol 297 (3) ◽  
pp. E793-E801 ◽  
Author(s):  
S. Piquer ◽  
S. Casas ◽  
I. Quesada ◽  
A. Nadal ◽  
M. Julià ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Dermatan Sulfate ◽  
Mrna Levels ◽  
Transfected Cells ◽  
Kinase Substrate ◽  
Kinase C ◽  
Insulin Mrna ◽  
Glucose Stimulated Insulin Secretion ◽  
Insulin Secretory Response

Iduronate-2-sulfatase (IDS) is a lysosomal enzyme expressed in pancreatic islets responsible for the degradation of proteoglycans such as perlecan and dermatan sulfate. Previous findings of our group demonstrated the involvement of IDS in the normal pathway of lysosomal degradation of secretory peptides, suggesting a role of this enzyme in β-cell secretory functionality. The present study was undertaken to characterize the effect of IDS overexpression on insulin release. INS1E cells were transiently transfected with a construct encoding human IDS (hIDS). hIDS overexpression was associated with a gain of function detected by a reduction in heparan sulfate content. hIDS potentiated the glucose-stimulated insulin secretory response compared with controls (61%) with no changes in insulin mRNA levels or insulin peptide content. Results on quantification of the exocytotic process showed a significant increase in hIDS-transfected cells compared with controls. Furthermore, ultramorphological analysis demonstrated an increase in the number of granules in the immediate vicinity of the plasma membrane in hIDS-transfected cells and a decrease in total vesicles per square micrometer. hIDS overexpression induced phosphorylation of protein kinase C (PKC) α and its newly myristoylated alanine-rich C kinase substrate, MARCKS. We conclude that IDS has a role in glucose-stimulated insulin secretion via a mechanism that involves the activation of exocytosis through phosphorylation of PKCα and MARCKS.

scholarly journals mTORC1 and mTORC2 regulate insulin secretion through Akt in INS-1 cells

2012 ◽  
Vol 216 (1) ◽  
pp. 21-29 ◽  
Author(s):  
Olivier Le Bacquer ◽  
Gurvan Queniat ◽  
Valery Gmyr ◽  
Julie Kerr-Conte ◽  
Bruno Lefebvre ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Cell Function ◽  
Antagonistic Effect ◽  
Dominant Negative ◽  
Insulin Content ◽  
Insulin Biosynthesis ◽  
Direct Role ◽  
Β Cell Function ◽  
Glucose Stimulated Insulin Secretion

Regulated associated protein of mTOR (Raptor) and rapamycin-insensitive companion of mTOR (rictor) are two proteins that delineate two different mTOR complexes, mTORC1 and mTORC2 respectively. Recent studies demonstrated the role of rictor in the development and function of β-cells. mTORC1 has long been known to impact β-cell function and development. However, most of the studies evaluating its role used either drug treatment (i.e. rapamycin) or modification of expression of proteins known to modulate its activity, and the direct role of raptor in insulin secretion is unclear. In this study, using siRNA, we investigated the role of raptor and rictor in insulin secretion and production in INS-1 cells and the possible cross talk between their respective complexes, mTORC1 and mTORC2. Reduced expression of raptor is associated with increased glucose-stimulated insulin secretion and intracellular insulin content. Downregulation of rictor expression leads to impaired insulin secretion without affecting insulin content and is able to correct the increased insulin secretion mediated by raptor siRNA. Using dominant-negative or constitutively active forms of Akt, we demonstrate that the effect of both raptor and rictor is mediated through alteration of Akt signaling. Our finding shed new light on the mechanism of control of insulin secretion and production by the mTOR, and they provide evidence for antagonistic effect of raptor and rictor on insulin secretion in response to glucose by modulating the activity of Akt, whereas only raptor is able to control insulin biosynthesis.

PGC-1α is associated with C2C12 Myoblast differentiation

2014 ◽  
Vol 9 (11) ◽  
pp. 1030-1036 ◽  
Author(s):  
Yaqiu Lin ◽  
Yanying Zhao ◽  
Ruiwen Li ◽  
Jiaqi Gong ◽  
Yucai Zheng ◽  
...  
Keyword(s):  
Mrna Level ◽  
Biological Significance ◽  
C2c12 Cells ◽  
Myoblast Differentiation ◽  
C2c12 Myoblast ◽  
Mrna Levels ◽  
Transfected Cells ◽  
Myosin Heavy Chain Isoform ◽  
Important Mediator

AbstractPGC-1α has been implicated as an important mediator of functional capacity of skeletal muscle. However, the role of PGC-1α in myoblast differentiation remains unexplored. In the present study, we observed a significant up-regulation of PGC-1α expression during the differentiation of murine C2C12 myoblast. To understand the biological significance of PGC-1α up-regulation in myoblast differentiation, C2C12 cells were transfected with murine PGC-1α cDNA and siRNA targeting PGC-1α, respectively. PGC-1α over-expressing clones fused to form typical myotubes with higher mRNA level of myosin heavy chain isoform I (MyHCI) and lower MyHCIIX. No obvious differentiation was observed in PGC-1α-targeted siRNA-transfected cells with marked decrement of mRNA levels of MyHCI and MyHCIIX. Furthermore, PGC-1α increased the expression of MyoD and MyoG in C2C12 cells, which controlled the commitment of precursor cells to myotubes. These results indicate that PGC-1α is associated with myoblast differentiation and elevates MyoD and MyoG expression levels in C2C12 cells.

α1-Adrenoceptor subtype activation increases proto-oncogene mRNA levels. Role of protein kinase C

1998 ◽  
Vol 342 (2-3) ◽  
pp. 311-317 ◽  
Author(s):  
J.Adolfo Garcı́a-Sáinz ◽  
Rocı́o Alcántara-Hernández ◽  
José Vázquez-Prado
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Mrna Levels ◽  
Kinase C

scholarly journals Subthreshold α2-Adrenergic Activation Counteracts Glucagon-Like Peptide-1 Potentiation of Glucose-Stimulated Insulin Secretion

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Minglin Pan ◽  
Guang Yang ◽  
Xiuli Cui ◽  
Shao-Nian Yang
Keyword(s):  
Insulin Secretion ◽  
Insulin Release ◽  
Adrenergic Agonist ◽  
Signaling Systems ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Glucose Stimulated Insulin Secretion ◽  
Insulin Secretory Response ◽  
Adrenergic Activation ◽  
Gi Proteins

The pancreatic β cell harbors α2-adrenergic and glucagon-like peptide-1 (GLP-1) receptors on its plasma membrane to sense the corresponding ligands adrenaline/noradrenaline and GLP-1 to govern glucose-stimulated insulin secretion. However, it is not known whether these two signaling systems interact to gain the adequate and timely control of insulin release in response to glucose. The present work shows that the α2-adrenergic agonist clonidine concentration-dependently depresses glucose-stimulated insulin secretion from INS-1 cells. On the contrary, GLP-1 concentration-dependently potentiates insulin secretory response to glucose. Importantly, the present work reveals that subthreshold α2-adrenergic activation with clonidine counteracts GLP-1 potentiation of glucose-induced insulin secretion. This counteractory process relies on pertussis toxin- (PTX-) sensitive Gi proteins since it no longer occurs following PTX-mediated inactivation of Gi proteins. The counteraction of GLP-1 potentiation of glucose-stimulated insulin secretion by subthreshold α2-adrenergic activation is likely to serve as a molecular mechanism for the delicate regulation of insulin release.

scholarly journals Bimodal role of conventional protein kinase C in insulin secretion from rat pancreatic β cells

2004 ◽  
Vol 561 (1) ◽  
pp. 133-147 ◽  
Author(s):  
Hui Zhang ◽  
Masahiro Nagasawa ◽  
Satoko Yamada ◽  
Hideo Mogami ◽  
Yuko Suzuki ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Insulin Secretion ◽  
Protein Kinase ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Kinase C

The role of protein kinase C-δ in PTH stimulation of IGF-binding protein-5 mRNA in UMR-106–01 cells

2002 ◽  
Vol 282 (3) ◽  
pp. E534-E541 ◽  
Author(s):  
Mary S. Erclik ◽  
Jane Mitchell
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Binding Protein ◽  
Specific Inhibitor ◽  
Dominant Negative Mutant ◽  
Nuclear Fraction ◽  
Mrna Levels ◽  
Kinase C ◽  
Umr 106

We have investigated the role of protein kinase C (PKC) signal transduction pathways in parathyroid hormone (PTH) regulation of insulin-like growth factor-binding protein-5 (IGFBP-5) gene expression in the rat osteoblast-like cell line UMR-106–01. Involvement of the PKC pathway was determined by the findings that bisindolylmaleimide I inhibited 40% of the PTH effect, and 1 μM bovine PTH-(3–34) stimulated a 10-fold induction of IGFBP-5 mRNA. PTH-(1–34) and PTH-(3–34) (100 nM) both stimulated PKC-δ translocation from the membrane to the nuclear fraction. Rottlerin, a PKC-δ-specific inhibitor, and a dominant negative mutant of PKC-δ were both able to significantly inhibit PTH-(1–34) and PTH-(3–34) induction of IGFBP-5 mRNA, suggesting a stimulatory role for PKC-δ in the effects of PTH. Phorbol 12-myristate 13-acetate (PMA) stimulated PKC-α translocation from the cytosol to the membrane and inhibited ∼50% of the PTH-(1–34), forskolin, and 8-bromoadenosine 3′,5′-cyclic monophosphate-stimulated IGFBP-5 mRNA levels, suggesting that PKC-α negatively regulates protein kinase A (PKA)-mediated induction of IGFBP-5 mRNA. These results suggest that the induction of IGFBP-5 by PTH is both PKA and PKC dependent and PKC-δ is the primary mediator of the effects of PTH via the PKC pathway.

scholarly journals Metabolic cycling in control of glucose-stimulated insulin secretion

2008 ◽  
Vol 295 (6) ◽  
pp. E1287-E1297 ◽  
Author(s):  
Mette V. Jensen ◽  
Jamie W. Joseph ◽  
Sarah M. Ronnebaum ◽  
Shawn C. Burgess ◽  
A. Dean Sherry ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Β Cells ◽  
Pyruvate Metabolism ◽  
Coupling Factors ◽  
Stimulus Secretion Coupling ◽  
Channel Dependent ◽  
Glucose Stimulated Insulin Secretion ◽  
Dependent Mechanism

Glucose-stimulated insulin secretion (GSIS) is central to normal control of metabolic fuel homeostasis, and its impairment is a key element of β-cell failure in type 2 diabetes. Glucose exerts its effects on insulin secretion via its metabolism in β-cells to generate stimulus/secretion coupling factors, including a rise in the ATP/ADP ratio, which serves to suppress ATP-sensitive K+ (KATP) channels and activate voltage-gated Ca2+ channels, leading to stimulation of insulin granule exocytosis. Whereas this KATP channel-dependent mechanism of GSIS has been broadly accepted for more than 30 years, it has become increasingly apparent that it does not fully describe the effects of glucose on insulin secretion. More recent studies have demonstrated an important role for cyclic pathways of pyruvate metabolism in control of insulin secretion. Three cycles occur in islet β-cells: the pyruvate/malate, pyruvate/citrate, and pyruvate/isocitrate cycles. This review discusses recent work on the role of each of these pathways in control of insulin secretion and builds a case for the particular relevance of byproducts of the pyruvate/isocitrate cycle, NADPH and α-ketoglutarate, in control of GSIS.

Role of protein kinase C in the regulation of insulin secretion

1989 ◽  
Vol 17 (1) ◽  
pp. 61-63 ◽  
Author(s):  
PETER M. JONES ◽  
SIMON L. HOWELL
Keyword(s):  
Protein Kinase C ◽  
Insulin Secretion ◽  
Protein Kinase ◽  
Kinase C

scholarly journals Activation of protein kinase C partially alleviates noradrenaline inhibition of insulin secretion

1993 ◽  
Vol 289 (2) ◽  
pp. 497-501 ◽  
Author(s):  
S J Persaud ◽  
P M Jones ◽  
S L Howell
Keyword(s):  
Protein Kinase C ◽  
Insulin Secretion ◽  
Protein Kinase ◽  
Cyclic Amp ◽  
Insulin Release ◽  
Inhibitory Effect ◽  
Kinase C ◽  
Dependent Protein ◽  
Glucose Stimulated Insulin Secretion ◽  
Rat Islets Of Langerhans

The sympathetic neurotransmitter noradrenaline (NA) fully inhibited both phases of glucose-stimulated insulin secretion from rat islets of Langerhans. The secretory response to the protein kinase C (PKC) activator, 4 beta-phorbol myristate acetate (4 beta PMA), in the absence of exogenous glucose was also abolished by NA. However, at 20 mM glucose 4 beta PMA partially alleviated the inhibitory effect of NA both on insulin release and on cyclic AMP generation. Inhibition of insulin release by NA, albeit much decreased, was still observed in the presence of maximal stimulatory concentrations of both 4 beta PMA and dibutyryl cyclic AMP. The relieving effect of 4 beta PMA on the inhibition of insulin secretion by NA was not overcome by the competitive antagonist of cyclic AMP-dependent protein kinase, Rp-adenosine 3′,5′-cyclic phosphorothioate. Down-regulation of islet PKC activity by overnight exposure to 4 beta PMA did not affect the inhibitory capacity of NA. These results suggest that NA inhibits insulin release independently of interaction with PKC, but that activation of this enzyme decreases the inhibitory effect of NA at stimulatory concentrations of glucose. This protective effect of 4 beta PMA could not be attributed to a decrease in NA inhibition of cyclic AMP generation.

scholarly journals Emerging role of testosterone in pancreatic β cell function and insulin secretion

2019 ◽  
Vol 240 (3) ◽  
pp. R97-R105 ◽  
Author(s):  
Weiwei Xu ◽  
Jamie Morford ◽  
Franck Mauvais-Jarvis
Keyword(s):  
Insulin Secretion ◽  
Metabolic Regulation ◽  
Cell Function ◽  
Visceral Obesity ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function ◽  
Glucagon Like Peptide 1 ◽  
Glucose Stimulated Insulin Secretion

One of the most sexually dimorphic aspects of metabolic regulation is the bidirectional modulation of glucose homeostasis by testosterone in male and females. Severe testosterone deficiency predisposes men to type 2 diabetes (T2D), while in contrast, androgen excess predisposes women to hyperglycemia. The role of androgen deficiency and excess in promoting visceral obesity and insulin resistance in men and women respectively is well established. However, although it is established that hyperglycemia requires β cell dysfunction to develop, the role of testosterone in β cell function is less understood. This review discusses recent evidence that the androgen receptor (AR) is present in male and female β cells. In males, testosterone action on AR in β cells enhances glucose-stimulated insulin secretion by potentiating the insulinotropic action of glucagon-like peptide-1. In females, excess testosterone action via AR in β cells promotes insulin hypersecretion leading to oxidative injury, which in turn predisposes to T2D.

Sign in / Sign up

Export Citation Format

Share Document