scholarly journals Secrets of insulin and IGF-1 regulation of insulin secretion revealed

2004 ◽  
Vol 377 (1) ◽  
pp. e1-e2 ◽  
Author(s):  
Peter R. SHEPHERD
Keyword(s):  
Insulin Secretion ◽  
Growth Factor ◽  
Insulin Release ◽  
Small Interfering Rna ◽  
Insulin Receptors ◽  
Insulin Like Growth Factor ◽  
Β Cells ◽  
Ongoing Controversy ◽  
Knock Down ◽  
Interfering Rna

There has been ongoing controversy over the respective roles of insulin-like growth factor-1 receptors and insulin receptors in controlling insulin release from β-cells of the pancreas. An acute knock-down experiment exploiting small interfering RNA approaches provides a resolution: both are required.

scholarly journals Facilitative Glucose Transporter 9 Expression Affects Glucose Sensing in Pancreatic β-Cells

Endocrinology ◽  
2009 ◽  
Vol 150 (12) ◽  
pp. 5302-5310 ◽  
Author(s):  
Sarah A. Evans ◽  
Manuel Doblado ◽  
Maggie M. Chi ◽  
John A. Corbett ◽  
Kelle H. Moley
Keyword(s):  
Plasma Membrane ◽  
Insulin Secretion ◽  
Small Interfering Rna ◽  
Glucose Sensing ◽  
Low Density ◽  
Β Cells ◽  
Microsome Fraction ◽  
Glucose Stimulated Insulin Secretion ◽  
Rna Knockdown ◽  
Interfering Rna

Abstract Facilitative glucose transporters (GLUTs) including GLUT9, accelerate the facilitative diffusion of glucose across the plasma membrane. Studies in GLUT2-deficient mice suggested the existence of another GLUT in the mammalian β-cell responsible for glucose sensing. The objective of this study was to determine the expression and function of GLUT9 in murine and human β-cells. mRNA and protein expression levels were determined for both isoforms of GLUT9 in murine and human isolated islets as well as insulinoma cell lines (MIN6). Immunohistochemistry and subcellular localization were performed to localize the protein within the cell. Small interfering RNA knockdown of GLUT9 was used to determine the effect of this transporter, in the presence of GLUT2, on cell metabolism and insulin secretion in MIN6 and INS cells. In this report we demonstrate that GLUT9a and GLUT9b are expressed in pancreatic islets and that this expression localizes to insulin-containing β-cells. Subcellular localization studies indicate that mGLUT9b is found associated with the plasma membrane as well as in the high-density microsome fraction and low-density microsome fraction, whereas mGLUT9a appears to be located only in the high-density microsome and low-density microsome under basal conditions. Functionally GLUT9 appears to participate in the regulation of glucose-stimulated insulin secretion in addition to GLUT2. small interfering RNA knockdown of GLUT9 results in reduced cellular ATP levels that correlate with reductions in glucose-stimulated insulin secretion in MIN6 and INS cells. These studies confirm the expression of GLUT9a and GLUT9b in murine and human β-cells and suggest that GLUT9 may participate in glucose-sensing in β-cells.

Oleic acid interacts with GPR40 to induce Ca2+ signaling in rat islet β-cells: mediation by PLC and L-type Ca2+ channel and link to insulin release

2005 ◽  
Vol 289 (4) ◽  
pp. E670-E677 ◽  
Author(s):  
Ken Fujiwara ◽  
Fumihiko Maekawa ◽  
Toshihiko Yada
Keyword(s):  
Insulin Secretion ◽  
Oleic Acid ◽  
Insulin Release ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Insulinoma Cell ◽  
Transduction Mechanisms ◽  
Glucose Stimulated Insulin Secretion ◽  
Interfering Rna ◽  
G Protein Coupled

It has long been thought that long-chain free fatty acids (FFAs) stimulate insulin secretion via mechanisms involving their metabolism in pancreatic β-cells. Recently, it was reported that FFAs function as endogenous ligands for GPR40, a G protein-coupled receptor, to amplify glucose-stimulated insulin secretion in an insulinoma cell line and rat islets. However, signal transduction mechanisms for GPR40 in β-cells are little known. The present study was aimed at elucidating GPR40-linked Ca2+ signaling mechanisms in rat pancreatic β-cells. We employed oleic acid (OA), an FFA that has a high affinity for the rat GPR40, and examined its effect on cytosolic Ca2+ concentration ([Ca2+]i) in single β-cells by fura 2 fluorescence imaging. OA at 1–10 μM concentration-dependently increased [Ca2+]i in the presence of 5.6, 8.3, and 11.2 mM, but not 2.8 mM, glucose. OA-induced [Ca2+]i increases at 11.2 mM glucose were inhibited in β-cells transfected with small interfering RNA targeted to rat GPR40 mRNA. OA-induced [Ca2+]i increases were also inhibited by phospholipase C (PLC) inhibitors, U73122 and neomycin, Ca2+-free conditions, and an L-type Ca2+ channel blocker, nitrendipine. Furthermore, OA increased insulin release from isolated islets at 8.3 mM glucose, and it was markedly attenuated by PLC and L-type Ca2+ channel inhibitors. These results demonstrate that OA interacts with GPR40 to increase [Ca2+]i via PLC- and L-type Ca2+ channel-mediated pathway in rat islet β-cells, which may be link to insulin release.

scholarly journals Aldosterone Stimulates Elastogenesis in Cardiac Fibroblasts via Mineralocorticoid Receptor-independent Action Involving the Consecutive Activation of Gα13, c-Src, the Insulin-like Growth Factor-I Receptor, and Phosphatidylinositol 3-Kinase/Akt

2009 ◽  
Vol 284 (24) ◽  
pp. 16633-16647 ◽  
Author(s):  
Severa Bunda ◽  
Yanting Wang ◽  
Thomas F. Mitts ◽  
Peter Liu ◽  
Sara Arab ◽  
...  
Keyword(s):  
Growth Factor ◽  
Signaling Pathway ◽  
Mineralocorticoid Receptor ◽  
Small Interfering Rna ◽  
Cardiac Fibroblasts ◽  
Insulin Like Growth Factor ◽  
Phosphatidylinositol 3 Kinase ◽  
Factor I ◽  
Growth Factor I ◽  
Interfering Rna

We previously demonstrated that aldosterone, which stimulates collagen production through the mineralocorticoid receptor (MR)-dependent pathway, also induces elastogenesis via a parallel MR-independent mechanism involving insulin-like growth factor-I receptor (IGF-IR) signaling. The present study provides a more detailed explanation of this signaling pathway. Our data demonstrate that small interfering RNA-driven elimination of MR in cardiac fibroblasts does not inhibit aldosterone-induced IGF-IR phosphorylation and subsequent increase in elastin production. These results exclude the involvement of the MR in aldosterone-induced increases in elastin production. Results of further experiments aimed at identifying the upstream signaling component(s) that might be activated by aldosterone also eliminate the putative involvement of pertussis toxin-sensitive Gαi proteins, which have previously been shown to be responsible for some MR-independent effects of aldosterone. Instead, we found that small interfering RNA-dependent elimination of another heterotrimeric G protein, Gα13, eliminates aldosterone-induced elastogenesis. We further demonstrate that aldosterone first engages Gα13 and then promotes its transient interaction with c-Src, which constitutes a prerequisite step for aldosterone-dependent activation of the IGF-IR and propagation of consecutive downstream elastogenic signaling involving phosphatidylinositol 3-kinase/Akt. In summary, the data we present reveal new details of an MR-independent cellular signaling pathway through which aldosterone stimulates elastogenesis in human cardiac fibroblasts.

scholarly journals Sterol Regulatory Element-Binding Protein 1 Mediates Liver X Receptor-β-Induced Increases in Insulin Secretion and Insulin Messenger Ribonucleic Acid Levels

Endocrinology ◽  
2006 ◽  
Vol 147 (8) ◽  
pp. 3898-3905 ◽  
Author(s):  
Heike Zitzer ◽  
Wolf Wente ◽  
Martin B. Brenner ◽  
Sabine Sewing ◽  
Karsten Buschard ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Small Interfering Rna ◽  
Binding Protein ◽  
Regulatory Element ◽  
Insulin Content ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Element Binding Protein ◽  
Sterol Regulatory Element ◽  
Interfering Rna

Liver X receptors (LXRα and LXRβ) regulate glucose and lipid metabolism. Pancreatic β-cells and INS-1E insulinoma cells express only the LXRβ isoform. Activation of LXRβ with the synthetic agonist T0901317 increased glucose-induced insulin secretion and insulin content, whereas deletion of the receptor in LXRβ knockout mice severely blunted insulin secretion. Analysis of gene expression in LXR agonist-treated INS-1E cells and islets from LXRβ-deficient mice revealed that LXRβ positively regulated expression of ATP-binding cassette transporter A1 (ABCA1), sterol regulatory element-binding protein 1 (SREBP-1), insulin, PDX-1, glucokinase, and glucose transporter 2 (Glut2). Down-regulation of SREBP-1 expression with the specific small interfering RNA blocked basal and LXRβ-induced expression of pancreatic duodenal homeobox 1 (PDX-1), insulin, and Glut2 genes. SREBP-1 small interfering RNA also prevented an increase in insulin secretion and insulin content induced by T0901317. Moreover, 5-(tetradecyloxy)-2-furoic acid, an inhibitor of the SREBP-1 target gene acetyl-coenzyme A carboxylase, blocked T0901317-induced stimulation of insulin secretion. In conclusion, activation of LXRβ in pancreatic β-cells increases insulin secretion and insulin mRNA expression via SREBP-1-regulated pathway. These data support the role of LXRβ, SREBP-1, and cataplerosis/anaplerosis pathways in the control of insulin secretion in pancreatic β-cells.

scholarly journals Distinct roles for insulin and insulin-like growth factor-1 receptors in pancreatic beta-cell glucose sensing revealed by RNA silencing

2004 ◽  
Vol 377 (1) ◽  
pp. 149-158 ◽  
Author(s):  
Gabriela da SILVA XAVIER ◽  
Qingwen QIAN ◽  
Peter J. CULLEN ◽  
Guy A. RUTTER
Keyword(s):  
Gene Expression ◽  
Insulin Secretion ◽  
Growth Factor ◽  
Rna Silencing ◽  
Pancreatic Beta Cell ◽  
Regulation Of Gene Expression ◽  
Glucose Sensing ◽  
Insulin Like Growth Factor ◽  
Β Cells ◽  
Elevated Glucose

The importance of the insulin receptor (IR) and the insulin-like growth factor-1 receptor (IGF-1R) for glucose-regulated insulin secretion and gene expression in pancreatic islet β-cells is at present unresolved. Here, we have used small interfering RNAs (siRNAs) to silence the expression of each receptor selectively in clonal MIN6 β-cells. Reduction of IR levels by >90% completely inhibited glucose (30 mM compared with 3 mM)-induced insulin secretion, but had no effect on depolarization-stimulated secretion. IR depletion also blocked the accumulation of preproinsulin (PPI), pancreatic duodenum homoeobox-1 (PDX-1) and glucokinase (GK) mRNAs at elevated glucose concentrations, as assessed by quantitative real-time PCR analysis (TaqMan®). Similarly, depletion of IGF-1R inhibited glucose-induced insulin secretion but, in contrast with the effects of IR silencing, had little impact on the regulation of gene expression by glucose. Moreover, loss of IGF-1R, but not IR, markedly inhibited glucose-stimulated increases in cytosolic and mitochondrial ATP, suggesting a role for IGF-1R in the maintenance of oxidative metabolism and in the generation of mitochondrial coupling factors. RNA silencing thus represents a useful tool for the efficient and selective inactivation of receptor tyrosine kinases in isolated β-cells. By inhibiting glucose-stimulated insulin secretion through the inactivation of IGF-1R, this approach also demonstrates the existence of insulin-independent mechanisms whereby elevated glucose concentrations regulate PPI, PDX-1 and GK gene expression in β-cells.

scholarly journals PDX1LOW MAFALOW β-cells contribute to islet function and insulin release

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Daniela Nasteska ◽  
Nicholas H. F. Fine ◽  
Fiona B. Ashford ◽  
Federica Cuozzo ◽  
Katrina Viloria ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Release ◽  
Metabolic Stress ◽  
Human Islets ◽  
Islet Function ◽  
Β Cells ◽  
Β Cell ◽  
Ionic Fluxes ◽  
Transcriptomic Level ◽  
Adult Islet

AbstractTranscriptionally mature and immature β-cells co-exist within the adult islet. How such diversity contributes to insulin release remains poorly understood. Here we show that subtle differences in β-cell maturity, defined using PDX1 and MAFA expression, contribute to islet operation. Functional mapping of rodent and human islets containing proportionally more PDX1HIGH and MAFAHIGH β-cells reveals defects in metabolism, ionic fluxes and insulin secretion. At the transcriptomic level, the presence of increased numbers of PDX1HIGH and MAFAHIGH β-cells leads to dysregulation of gene pathways involved in metabolic processes. Using a chemogenetic disruption strategy, differences in PDX1 and MAFA expression are shown to depend on islet Ca2+ signaling patterns. During metabolic stress, islet function can be restored by redressing the balance between PDX1 and MAFA levels across the β-cell population. Thus, preserving heterogeneity in PDX1 and MAFA expression, and more widely in β-cell maturity, might be important for the maintenance of islet function.

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