Pathways in Beta-Cell Stimulus-Secretion Coupling as Targets for Therapeutic Insulin Secretagogues

Henquin, Jean‐Claude

doi:10.2337/diabetes.53.suppl_3.s48

Cited by 115 publications

(88 citation statements)

References 133 publications

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“…Several pathways signal the exocytosis of insulin (Henquin 2004). Glucose acts as the triggering molecule when it is taken up into the cell through the glucose transporter 2 (GLUT2).…”

Section: Gpcrs Expressed In Isletsmentioning

confidence: 99%

G-protein-coupled receptors and islet function—Implications for treatment of type 2 diabetes

Winzell

Åhrén

2007

Pharmacology & Therapeutics

161

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Islet function is regulated by a number of different signals. A main signal is generated by glucose, which stimulates insulin secretion and inhibits glucagon secretion. The glucose effects are modulated by many factors, including hormones, neurotransmitters and nutrients. Several of these factors signal through guanine nucleotide-binding protein (G-protein) coupled receptors (GPCRs). Examples of islet GPCRs are GPR40 and GPR119, which are GPCRs with fatty acids as ligands, the receptors for the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), the receptors for the islet hormones glucagon and somatostatin, the receptors for the classical neurotransmittors

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“…Several pathways signal the exocytosis of insulin (Henquin 2004). Glucose acts as the triggering molecule when it is taken up into the cell through the glucose transporter 2 (GLUT2).…”

Section: Gpcrs Expressed In Isletsmentioning

confidence: 99%

G-protein-coupled receptors and islet function—Implications for treatment of type 2 diabetes

Winzell

Åhrén

2007

Pharmacology & Therapeutics

161

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“…In addition [Ca 2ϩ ] i could also allow for cross-talk between the apical channels and basolateral K ϩ channels (e.g., see Sand et al, 2004), which we also showed may play a regulatory role in modulating the exocytic response. As well, K ϩ channels are known to modulate Ca 2ϩ responses in cells (Henquin, 2004). The identity of the NSCC is unknown; however, members of the TRP family of proteins such as polycystin 1/2 may be candidates, as polycystin 1 is expressed in the uroepithelium (IbraghimovBeskrovnaya et al, 1997).…”

Section: Regulation Of Umbrella Cell Apical Membrane Traffic By Ion Cmentioning

confidence: 99%

“…Kir6.1 and Kir6.2 are subunits of ATP-sensitive potassium channels (K ATP channels). K ATP has important roles in bladder function and can regulate membrane traffic in other cell types (Bonev and Nelson, 1993;Gopalakrishnan et al, 1999;Henquin, 2004). To further establish that K ATP was expressed in the uroepithelium and to determine its localization in umbrella cells, Western blots and immunofluorescence were performed using antibodies against Kir6.1.…”

Section: Basolateral K ؉ Channels Modulate Stretch-induced Responses mentioning

confidence: 99%

Distinct Apical and Basolateral Membrane Requirements for Stretch-induced Membrane Traffic at the Apical Surface of Bladder Umbrella Cells

Khandelwal²,

Apodaca

2009

MBoC

127

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Epithelial cells respond to mechanical stimuli by increasing exocytosis, endocytosis, and ion transport, but how these processes are initiated and coordinated and the mechanotransduction pathways involved are not well understood. We observed that in response to a dynamic mechanical environment, increased apical membrane tension, but not pressure, stimulated apical membrane exocytosis and ion transport in bladder umbrella cells. The exocytic response was independent of temperature but required the cytoskeleton and the activity of a nonselective cation channel and the epithelial sodium channel. The subsequent increase in basolateral membrane tension had the opposite effect and triggered the compensatory endocytosis of added apical membrane, which was modulated by opening of basolateral K ؉ channels. Our results indicate that during the dynamic processes of bladder filling and voiding apical membrane dynamics depend on sequential and coordinated mechanotransduction events at both membrane domains of the umbrella cell.

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“…K ATP channel-blocking drugs such as the sulfonylureas and the glinides can promote insulin secretion and are used in the treatment of diabetes type 2. Insulin secretion is also modulated and amplified by other pathways within the ␤-cell that are, in general, K ATP channel-independent (7,8). In addition, the extent of insulin secretion is also influenced by adaptive variation of the total number of ␤-cells.…”

mentioning

confidence: 99%

Resveratrol Binds to the Sulfonylurea Receptor (SUR) and Induces Apoptosis in a SUR Subtype-specific Manner

Hambrock

Franz

Hiller

et al. 2007

Journal of Biological Chemistry

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Sulfonylurea receptors (SURs) constitute the regulatory subunits of ATP-sensitive K ؉ channels (K ATP channels). SUR binds nucleotides and synthetic K ATP channel modulators, e.g. the antidiabetic sulfonylurea glibenclamide, which acts as a channel blocker. However, knowledge about naturally occurring ligands of SUR is very limited. In this study, we show that the plant phenolic compound trans-resveratrol can bind to SUR and displace binding of glibenclamide. Electrophysiological measurements revealed that resveratrol is a blocker of pancreatic SUR1/ K IR 6.2 K ATP channels. We further demonstrate that, like glibenclamide, resveratrol induces enhanced apoptosis. This was shown by analyzing different apoptotic parameters (cell detachment, nuclear condensation and fragmentation, and activities of different caspase enzymes). The observed apoptotic effect was specific to cells expressing the SUR1 isoform and was not mediated by the electrical activity of K ATP channels, as it was observed in human embryonic kidney 293 cells expressing SUR1 alone. Enhanced susceptibility to resveratrol was not observed in pancreatic ␤-cells from SUR1 knock-out mice or in cells expressing the isoform SUR2A or SUR2B or the mutant SUR1(M1289T). Resveratrol was much more potent than glibenclamide in inducing SUR1-specific apoptosis. Treatment with etoposide, a classical inducer of apoptosis, did not result in SUR isoform-specific apoptosis. In conclusion, resveratrol is a natural SUR ligand that can induce apoptosis in a SUR isoform-specific manner. Considering the tissue-specific expression patterns of SUR isoforms and the possible effects of SUR mutations on susceptibility to apoptosis, these observations could be important for diabetes and/or cancer research.Sulfonylurea receptors (SURs) 2 are members of the ATPbinding cassette protein family (subfamily C). SURs are known to be the important regulatory subunits of ATP-sensitive K ϩ channels (K ATP channels). These channels are heteromeric complexes composed of four SUR subunits that surround a central pore formed by four subunits from the K IR 6.x family. K ATP channels found in various tissues exhibit distinct physiological and pharmacological properties because of the combination of different subunit isoforms (reviewed in Ref. 1). In addition to two nucleotide-binding domains, SUR possesses binding sites for synthetic K ATP channel modulators. The binding sites for blockers and openers are different, but they are linked via complex allosteric interactions (2, 3).Because of their nucleotide sensitivity, K ATP channels couple the energy metabolism of a cell to the membrane potential. This is important in the pancreatic ␤-cell, in which closure of K ATP channels triggers insulin secretion via membrane depolarization in response to changes in blood glucose levels (4 -6). K ATP channel-blocking drugs such as the sulfonylureas and the glinides can promote insulin secretion and are used in the treatment of diabetes type 2. Insulin secretion is also modulated and amplified by other pathways...

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Pathways in Beta-Cell Stimulus-Secretion Coupling as Targets for Therapeutic Insulin Secretagogues

Cited by 115 publications

References 133 publications

G-protein-coupled receptors and islet function—Implications for treatment of type 2 diabetes

G-protein-coupled receptors and islet function—Implications for treatment of type 2 diabetes

Distinct Apical and Basolateral Membrane Requirements for Stretch-induced Membrane Traffic at the Apical Surface of Bladder Umbrella Cells

Resveratrol Binds to the Sulfonylurea Receptor (SUR) and Induces Apoptosis in a SUR Subtype-specific Manner

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