Transgenic Mouse Overexpressing Syntaxin-1A as a Diabetes Model

Lam, Patrick; Leung, Yuk‐Man; Sheu, Laura; Ellis, James; Tsushima, Robert G.; Osborne, Lucy R.; Gaisano, Herbert Y.

doi:10.2337/diabetes.54.9.2744

Cited by 49 publications

(46 citation statements)

References 37 publications

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“…Reduced insulin release has been commonly linked to defective exocytosis. Stxbp1 positively regulates insulin secretion, and it has been reported to be reduced in the islets of both T2D patients and GK rats (Zhang et al 2002, Lam et al 2005, Andersson et al 2012. Our results indicated that the expression levels of miR-218 and miR-322 were raised in mouse islets exposed to high levels of glucose for a long period (72 h), which is followed by the sharp decrease in expression of Stxbp1 and the blocking of insulin secretion.…”

Section: Figuresupporting

confidence: 50%

Characterization of miR-218/322-Stxbp1 pathway in the process of insulin secretion

You

Wan

et al. 2014

Journal of Molecular Endocrinology

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MicroRNAs (miRNAs) have been implicated in a variety of physiological processes, however, the function of miRNAs in insulin secretion and type 2 diabetes is still unclear. Stxbp1 plays an essential role in exocytosis, and is crucial for insulin secretion. In this study, we focused on the molecular mechanism of Stxbp1 in insulin secretion by identifying its upstream regulators: miR-218 and miR-322. The expression of Stxbp1 was significantly increased in isolated mouse islets exposed to high levels of glucose within 1 h; while two of its predicted upstream miRNAs were found to be downregulated. Further study found that miR-218 and miR-322 directly interact with Stxbp1 by targeting the 3 0 UTR of its mRNA. MIN6 cells overexpressing the two miRNAs showed a sharp decline in insulin secretion and a decreased sensitivity to glucose; while the inhibition of the two miRNAs promoted insulin secretion. However, islets treated with prolonged high levels of glucose, which is known as glucolipotoxicity, displayed relatively high expression of miR-218 and miR-322, and a reduced level of expression of Stxbp1 accompanied by the blocking of insulin secretion. In summary, this study identified a pathway consisting of miR-218/322 and Stxbp1 in insulin secretion, contributing to a network of b-cell function involving miRNA.

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Section: Figuresupporting

confidence: 50%

Characterization of miR-218/322-Stxbp1 pathway in the process of insulin secretion

You

Wan

et al. 2014

Journal of Molecular Endocrinology

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“…Our previous report on syntaxin-1A-overexpressing mice showed that a moderate increase of ϳ30% of islet syntaxin-1A levels was sufficient to cause hyperglycemia from reduction in ␤-cell insulin exocytosis and inhibition of L-type Ca 2ϩ current density (49). However, there was no effect on K ATP or Kv2.1 channels, suggesting that these distinct components of the insulin secretory process exhibit differing sensitivity to syntaxin-1A modulation.…”

Section: Discussionmentioning

confidence: 85%

The Actions of a Novel Potent Islet β-Cell–Specific ATP-Sensitive K+ Channel Opener Can Be Modulated by Syntaxin-1A Acting on Sulfonylurea Receptor 1

Kang

Elias

et al. 2007

Diabetes

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Islet ␤-cell-specific ATP-sensitive K ؉ (K ATP ) channel openers thiadiazine dioxides induce islet rest to improve insulin secretion, but their molecular basis of action remains unclear. We reported that syntaxin-1A binds nucleotide binding folds of sulfonylurea receptor 1 (SUR1) in ␤-cells to inhibit K ATP channels. As a strategy to elucidate the molecular mechanism of action of these K ATP channel openers, we explored the possibility that 6-chloro-3-(1-methylcyclobutyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (NNC55-0462) might influence syntaxin-1A-SUR1 interactions or vice versa. Whole-cell and inside-out patch-clamp electrophysiology was used to examine the effects of glutathione S-transferase (GST)-syntaxin-1A dialysis or green fluorescence protein/syntaxin-1A cotransfection on NNC55-0462 actions. In vitro pull-down binding studies were used to examine NNC55-0462 influence on syntaxin-1A-SUR1 interactions. Dialysis of GST-syntaxin-1A into the cell cytoplasm reduced both potency and efficacy of extracellularly perfused NNC55-0462 in a HEK cell line stably expressing Kir6.2/SUR1 (BA8 cells) and in rat islet ␤-cells. Moreover, inside-out membrane patches excised from BA8 cells showed that both GST-syntaxin-1A and its H3 domain inhibited K ATP channels previously activated by NNC55-0462. This action on K ATP channels is isoform-specific to syntaxin-1A because syntaxin-2 was without effect. Furthermore, the parent compound diazoxide showed similar sensitivity to GST-syntaxin-1A inhibition. NNC55-0462, however, did not influence syntaxin-1A-SUR1 binding interaction. Our results demonstrated that syntaxin-1A interactions with SUR1 at its cytoplasmic domains can modulate the actions of the K ATP channel openers NNC55-0462 and diazoxide on K ATP channels. The reduced levels of islet syntaxin-1A in diabetes would thus be expected to exert a positive influence on the therapeutic effects of this class of K ATP channel openers. Diabetes

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“…Both Stx1a knock out -and Stx1a transgenic mice display a reduced insulin release and an impaired glucose homeostasis, possibly via an aberrant regulation of pancreatic b-cell ion channels. The genetic alteration of STX1A levels might also contribute to impaired glucose metabolism, which occurs with increased incidence in adults with WBS [23,163,164]. In cognitive functional test, Stx1a knock out mice demonstrated an increased conditioned fear memory lacking any other difference in appearance compared with control littermate [165].…”

Section: The Single Copy Gene Part Of the Wbs Regionmentioning

confidence: 99%

The genomic basis of the Williams – Beuren syndrome

Schubert

2008

Cell. Mol. Life Sci.

214

161

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. The Williams-Beuren syndrome is a genomic disorder (prevalence: 1/7,500 to 1/20,000), caused by a hemizygous contiguous gene deletion on chromosome 7q11.23. Typical symptoms comprise supravalvular aortic stenosis, mental retardation, overfriendliness and visuospatial impairment. The common deletion sizes range of 1.5–1.8 mega base pairs (Mb), encompassing app. 28 genes. For a few genes, a genotype-phenotype correlation has been established. The best-explored gene within this region is the elastin gene; its haploinsufficiency causes arterial stenosis. The region of the Williams-Beuren syndrome consists of a single copy gene region (~1.2 Mb) flanked by repetitive sequences – Low Copy Repeats (LCR). The deletions arise as a consequence of misalignment of these repetitive sequences during meiosis and a following unequal crossing over due to high similarity of LCRs. This review presents an overview of the Williams-Beuren syndrome region considering the genomic assembly, chromosomal rearrangements and their mechanisms (i.e. deletions, duplications, inversions) and evolutionary and historical aspects.

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Transgenic Mouse Overexpressing Syntaxin-1A as a Diabetes Model

Cited by 49 publications

References 37 publications

Characterization of miR-218/322-Stxbp1 pathway in the process of insulin secretion

Characterization of miR-218/322-Stxbp1 pathway in the process of insulin secretion

The Actions of a Novel Potent Islet β-Cell–Specific ATP-Sensitive K+ Channel Opener Can Be Modulated by Syntaxin-1A Acting on Sulfonylurea Receptor 1

The genomic basis of the Williams – Beuren syndrome

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