Characterization of Zinc Influx Transporters (ZIPs) in Pancreatic β Cells

Liu, Ying; Batchuluun, Battsetseg; Ho, Lee Kwang; Zhu, Dan; Prentice, Kacey J.; Bhattacharjee, Ananya; Zhang, Ming; Pourasgari, Farzaneh; Hardy, Alexandre B.; Taylor, KM; Gaisano, Herbert Y.; Dai, Feihan F.; Wheeler, Michael B.

doi:10.1074/jbc.m115.640524

Cited by 61 publications

(33 citation statements)

References 79 publications

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“…Secreted insulin was measured by radioimmunoassay (Linco Research, St. Louis, MO). Static GSIS on INS-1 cells was assessed using a homogenous time-resolved fluorescence insulin assay kit (Cisbio, Bedford, MA) on a PHERAstar plate reader (BMG Labtech, Ortenberg, Germany) (26). Levels of secreted insulin from islets and INS-1 were normalized to total insulin content.…”

Section: Methodsmentioning

confidence: 99%

Synaptotagmin-7 Functions to Replenish Insulin Granules for Exocytosis in Human Islet β-Cells

et al. 2016

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Synaptotagmin (Syt)-7, a major component of the exocytotic machinery in neurons, is also the major Syt in rodent pancreatic β-cells shown to mediate glucose-stimulated insulin secretion (GSIS). However, Syt-7’s precise exocytotic actions in β-cells remain unknown. We show that Syt-7 is abundant in human β-cells. Adenovirus–short hairpin RNA knockdown (KD) of Syt-7 in human islets reduced first- and second-phase GSIS attributed to the reduction of exocytosis of predocked and newcomer insulin secretory granules (SGs). Glucose stimulation expectedly induced Syt-7 association in a Ca2+-dependent manner with syntaxin-3 and syntaxin-1A soluble N-ethylmaleimide–sensitive factor attachment protein receptor (SNARE) complexes known to mediate exocytosis of newcomer and predocked SGs, respectively. However, Syt-7-KD did not disrupt SNARE complex assembly. Instead, electron microscopy analysis showed that Syt-7-KD reduced the recruitment of SGs to the plasma membrane after glucose-stimulated depletion, which could not be rescued by glucagon-like peptide 1 pretreatment. To assess the possibility that this new action of Syt-7 on SG recruitment may involve calmodulin (CaM), pretreatment of islets with CaM blocker calmidazolium showed effects very similar to those of Syt-7-KD. Syt-7 therefore plays a novel more dominant function in the replenishment of releasable SG pools in human β-cells than its previously purported role in exocytotic fusion per se.

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Section: Methodsmentioning

confidence: 99%

Synaptotagmin-7 Functions to Replenish Insulin Granules for Exocytosis in Human Islet β-Cells

et al. 2016

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“…The recent emergence of functional genomics and (epi)genome editing using the CRISPR/Cas9 platform offers a new and exciting opportunity to experimentally dissect these regulatory circuits that control islet cell identity and function and whose disruption by genetic variants and/or environmental risk factors may contribute to T2D pathogenesis. Many studies utilize islet-derived cell lines such as MIN6 16 – 18 , INS-1(832/13) 19 – 21 , beta-TC-6 22 – 26 , alpha TC1 27 – 31 and, most recently, human EndoC-ßH1-3 32 – 34 to gain insights into the molecular processes governing islet cell identity and function. Genomic characterization of these cell lines is essential to guide such studies and to interpret their findings.…”

Section: Introductionmentioning

confidence: 99%

Alpha TC1 and Beta-TC-6 genomic profiling uncovers both shared and distinct transcriptional regulatory features with their primary islet counterparts

Lawlor

Youn

Kursawe

et al. 2017

Sci Rep

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Alpha TC1 (αTC1) and Beta-TC-6 (βTC6) mouse islet cell lines are cellular models of islet (dys)function and type 2 diabetes (T2D). However, genomic characteristics of these cells, and their similarities to primary islet alpha and beta cells, are undefined. Here, we report the epigenomic (ATAC-seq) and transcriptomic (RNA-seq) landscapes of αTC1 and βTC6 cells. Each cell type exhibits hallmarks of its primary islet cell counterpart including cell-specific expression of beta (e.g., Pdx1) and alpha (e.g., Arx) cell transcription factors (TFs), and enrichment of binding motifs for these TFs in αTC1/βTC6 cis-regulatory elements. αTC1/βTC6 transcriptomes overlap significantly with the transcriptomes of primary mouse/human alpha and beta cells. Our data further indicate that ATAC-seq detects cell-specific regulatory elements for cell types comprising ≥ 20% of a mixed cell population. We identified αTC1/βTC6 cis-regulatory elements orthologous to those containing type 2 diabetes (T2D)-associated SNPs in human islets for 33 loci, suggesting these cells’ utility to dissect T2D molecular genetics in these regions. Together, these maps provide important insights into the conserved regulatory architecture between αTC1/βTC6 and primary islet cells that can be leveraged in functional (epi)genomic approaches to dissect the genetic and molecular factors controlling islet cell identity and function.

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“…Chronic hyperglycemia causes increased urinary loss of zinc and decreased zinc levels in the body [ 18 ]. The decreased zinc level adversely affects the ability of the β -cells in the synthesis and storage of insulin [ 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Spectral Characterization, and Biochemical Evaluation of Antidiabetic Properties of a New Zinc-Diosmin Complex Studied in High Fat Diet Fed-Low Dose Streptozotocin Induced Experimental Type 2 Diabetes in Rats

Gopalakrishnan

Pillai²,

Subramanian

2015

Biochemistry Research International

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In view of the established antidiabetic properties of zinc, the present study was aimed at evaluating the hypoglycemic properties of a new zinc-diosmin complex in high fat diet fed-low dose streptozotocin induced experimental type 2 diabetes in rats. Zinc-diosmin complex was synthesized and characterized by various spectral studies. The complexation between zinc ions and diosmin was further evidenced by pH-potentiometric titrations and Job's plot. Diabetic rats were orally treated with zinc-diosmin complex at a concentration of 20 mg/kg b.w./rat/day for 30 days. At the end of the experimental period, the rats were subjected to oral glucose tolerance test. In addition, HOMA-IR and various biochemical parameters related to glucose homeostasis were analyzed. Treatment with zinc-diosmin complex significantly improved the glucose homeostasis in diabetic rats. Treatment with zinc-diosmin complex significantly improved insulin sensitivity, at least in part, through enhancing protein metabolism and alteration in the levels of muscle and liver glycogen. The assay of clinical marker enzymes revealed the nontoxic nature of the complex. Determination of renal tissue markers such as blood urea and serum creatinine indicates the renoprotective nature of the complex. These findings suggest that zinc-diosmin complex is nontoxic and has complimentary potential to develop as an antihyperglycemic agent for the treatment of diabetes mellitus.

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Characterization of Zinc Influx Transporters (ZIPs) in Pancreatic β Cells

Cited by 61 publications

References 79 publications

Synaptotagmin-7 Functions to Replenish Insulin Granules for Exocytosis in Human Islet β-Cells

Synaptotagmin-7 Functions to Replenish Insulin Granules for Exocytosis in Human Islet β-Cells

Alpha TC1 and Beta-TC-6 genomic profiling uncovers both shared and distinct transcriptional regulatory features with their primary islet counterparts

Synthesis, Spectral Characterization, and Biochemical Evaluation of Antidiabetic Properties of a New Zinc-Diosmin Complex Studied in High Fat Diet Fed-Low Dose Streptozotocin Induced Experimental Type 2 Diabetes in Rats

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