Other search tools

About this data

The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.

If you have any questions or comments, please contact us.

Results: 1 to 10 of 31

Publication Record

Connections

Pancreatic islet-autonomous insulin and smoothened-mediated signalling modulate identity changes of glucagon α-cells.
Cigliola V, Ghila L, Thorel F, van Gurp L, Baronnier D, Oropeza D, Gupta S, Miyatsuka T, Kaneto H, Magnuson MA, Osipovich AB, Sander M, Wright CEV, Thomas MK, Furuyama K, Chera S, Herrera PL
(2018) Nat Cell Biol 20: 1267-1277
MeSH Terms: Animals, Cell Differentiation, Cell Plasticity, Cell Proliferation, Female, Glucagon-Secreting Cells, Insulin, Insulin-Secreting Cells, Islets of Langerhans, Male, Mice, Inbred C57BL, Mice, Knockout, Mice, SCID, Mice, Transgenic, Signal Transduction, Smoothened Receptor
Show Abstract · Added November 6, 2018
The mechanisms that restrict regeneration and maintain cell identity following injury are poorly characterized in higher vertebrates. Following β-cell loss, 1-2% of the glucagon-producing α-cells spontaneously engage in insulin production in mice. Here we explore the mechanisms inhibiting α-cell plasticity. We show that adaptive α-cell identity changes are constrained by intra-islet insulin- and Smoothened-mediated signalling, among others. The combination of β-cell loss or insulin-signalling inhibition, with Smoothened inactivation in α- or δ-cells, stimulates insulin production in more α-cells. These findings suggest that the removal of constitutive 'brake signals' is crucial to neutralize the refractoriness to adaptive cell-fate changes. It appears that the maintenance of cell identity is an active process mediated by repressive signals, which are released by neighbouring cells and curb an intrinsic trend of differentiated cells to change.
2 Communities
2 Members
1 Resources
16 MeSH Terms
α Cell Function and Gene Expression Are Compromised in Type 1 Diabetes.
Brissova M, Haliyur R, Saunders D, Shrestha S, Dai C, Blodgett DM, Bottino R, Campbell-Thompson M, Aramandla R, Poffenberger G, Lindner J, Pan FC, von Herrath MG, Greiner DL, Shultz LD, Sanyoura M, Philipson LH, Atkinson M, Harlan DM, Levy SE, Prasad N, Stein R, Powers AC
(2018) Cell Rep 22: 2667-2676
MeSH Terms: Adolescent, Adult, Animals, Case-Control Studies, Cellular Reprogramming, Child, Diabetes Mellitus, Type 1, Female, Gene Expression Regulation, Glucagon, Glucagon-Secreting Cells, Humans, Insulin Secretion, Insulin-Secreting Cells, Male, Mice, Middle Aged, Phenotype, Tissue Donors, Transcription Factors, Young Adult
Show Abstract · Added March 8, 2018
Many patients with type 1 diabetes (T1D) have residual β cells producing small amounts of C-peptide long after disease onset but develop an inadequate glucagon response to hypoglycemia following T1D diagnosis. The features of these residual β cells and α cells in the islet endocrine compartment are largely unknown, due to the difficulty of comprehensive investigation. By studying the T1D pancreas and isolated islets, we show that remnant β cells appeared to maintain several aspects of regulated insulin secretion. However, the function of T1D α cells was markedly reduced, and these cells had alterations in transcription factors constituting α and β cell identity. In the native pancreas and after placing the T1D islets into a non-autoimmune, normoglycemic in vivo environment, there was no evidence of α-to-β cell conversion. These results suggest an explanation for the disordered T1D counterregulatory glucagon response to hypoglycemia.
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
0 Communities
3 Members
0 Resources
21 MeSH Terms
Loss of mTORC1 signaling alters pancreatic α cell mass and impairs glucagon secretion.
Bozadjieva N, Blandino-Rosano M, Chase J, Dai XQ, Cummings K, Gimeno J, Dean D, Powers AC, Gittes GK, Rüegg MA, Hall MN, MacDonald PE, Bernal-Mizrachi E
(2017) J Clin Invest 127: 4379-4393
MeSH Terms: Animals, Glucagon, Glucagon-Secreting Cells, Hepatocyte Nuclear Factor 3-beta, Mechanistic Target of Rapamycin Complex 1, Mice, Mice, Knockout, Regulatory-Associated Protein of mTOR, Signal Transduction
Show Abstract · Added September 21, 2018
Glucagon plays a major role in the regulation of glucose homeostasis during fed and fasting states. However, the mechanisms responsible for the regulation of pancreatic α cell mass and function are not completely understood. In the current study, we identified mTOR complex 1 (mTORC1) as a major regulator of α cell mass and glucagon secretion. Using mice with tissue-specific deletion of the mTORC1 regulator Raptor in α cells (αRaptorKO), we showed that mTORC1 signaling is dispensable for α cell development, but essential for α cell maturation during the transition from a milk-based diet to a chow-based diet after weaning. Moreover, inhibition of mTORC1 signaling in αRaptorKO mice and in WT animals exposed to chronic rapamycin administration decreased glucagon content and glucagon secretion. In αRaptorKO mice, impaired glucagon secretion occurred in response to different secretagogues and was mediated by alterations in KATP channel subunit expression and activity. Additionally, our data identify the mTORC1/FoxA2 axis as a link between mTORC1 and transcriptional regulation of key genes responsible for α cell function. Thus, our results reveal a potential function of mTORC1 in nutrient-dependent regulation of glucagon secretion and identify a role for mTORC1 in controlling α cell-mass maintenance.
0 Communities
1 Members
0 Resources
9 MeSH Terms
Gcg knockin mice as a tool for genetic manipulation in pancreatic alpha cells.
Shiota C, Prasadan K, Guo P, Fusco J, Xiao X, Gittes GK
(2017) Diabetologia 60: 2399-2408
MeSH Terms: Animals, Female, Glucagon, Glucagon-Like Peptide 1, Glucagon-Secreting Cells, Immunohistochemistry, Male, Mice, Mice, Transgenic, Proglucagon, Tamoxifen
Show Abstract · Added August 13, 2019
AIMS/HYPOTHESIS - The Cre/loxP system, which enables tissue-specific manipulation of genes, is widely used in mice for diabetes research. Our aim was to develop a new Cre-driver mouse line for the specific and efficient manipulation of genes in pancreatic alpha cells.
METHODS - A Gcg knockin mouse, which expresses a tamoxifen-inducible form of Cre from the endogenous preproglucagon (Gcg) gene locus, was generated by homologous recombination. The new Gcg mouse line was crossed to the Rosa26 (R26 ) Cre reporter mouse line in order to evaluate the tissue specificity, efficiency and tamoxifen dependency of Gcg -mediated recombination. Cell types of pancreatic islets were identified using immunohistochemistry. Biochemical and physiological data, including blood glucose levels, plasma glucagon and glucagon-like peptide (GLP)-1 levels, and pancreatic glucagon content, were collected and used to assess the overall effect of Gcg gene targeting on Gcg heterozygous mice.
RESULTS - Tamoxifen-treated Gcg ;R26 mice displayed Cre reporter activity, i.e. expression of tdTomato red fluorescent protein (RFP) in all known cells that produce proglucagon-derived peptides. In the adult pancreas, RFP was detected in 94-97% of alpha cells, whereas it was detected in a negligible (~ 0.2%) proportion of beta cells. While more than 98% of cells labelled with tamoxifen-induced RFP were glucagon-positive cells, 14-25% of pancreatic polypeptide (PP)-positive cells were also positive for RFP, indicating the presence of glucagon/PP bihormonal cell population. Tamoxifen-independent expression of RFP occurred in approximately 6% of alpha cells. In contrast to alpha cells and GLP-1-producing neurons, in which RFP expression persisted for at least 5 months after tamoxifen administration (presumably due to rare neogenesis in these cell types in adulthood), nearly half of RFP-positive intestinal L cells were replaced with RFP-negative L cells over the first 2 weeks after tamoxifen administration. Heterozygous Gcg mice showed reduced Gcg mRNA levels in islets, but maintained normal levels of pancreatic and plasma glucagon. The mice did not exhibit any detectable baseline physiological abnormalities, at least in young adulthood.
CONCLUSIONS/INTERPRETATION - The newly developed Gcg knockin mouse shows faithful expression of CreER in pancreatic alpha cells, intestinal L cells and GLP-1-producing neurons. This mouse line will be particularly useful for manipulating genes in alpha cells, due to highly specific and efficient CreER-mediated recombination in this cell type in the pancreas.
0 Communities
0 Members
0 Resources
MeSH Terms
Glucagon antagonism in islet cell proliferation.
Dean ED, Unger RH, Holland WL
(2017) Proc Natl Acad Sci U S A 114: 3006-3008
MeSH Terms: Cell Proliferation, Glucagon, Glucagon-Secreting Cells, Humans, Insulin, Islets of Langerhans
Added September 21, 2018
0 Communities
1 Members
0 Resources
MeSH Terms
Combined Deletion of Slc30a7 and Slc30a8 Unmasks a Critical Role for ZnT8 in Glucose-Stimulated Insulin Secretion.
Syring KE, Boortz KA, Oeser JK, Ustione A, Platt KA, Shadoan MK, McGuinness OP, Piston DW, Powell DR, O'Brien RM
(2016) Endocrinology 157: 4534-4541
MeSH Terms: Animals, Body Weight, Cation Transport Proteins, Female, Glucagon-Secreting Cells, Glucose, Glucose Intolerance, Insulin, Insulin Secretion, Insulin-Secreting Cells, Islets of Langerhans, Male, Mice, Mice, Knockout, Sex Factors, Zinc Transporter 8
Show Abstract · Added March 14, 2018
Polymorphisms in the SLC30A8 gene, which encodes the ZnT8 zinc transporter, are associated with altered susceptibility to type 2 diabetes (T2D), and SLC30A8 haploinsufficiency is protective against the development of T2D in obese humans. SLC30A8 is predominantly expressed in pancreatic islet β-cells, but surprisingly, multiple knockout mouse studies have shown little effect of Slc30a8 deletion on glucose tolerance or glucose-stimulated insulin secretion (GSIS). Multiple other Slc30a isoforms are expressed at low levels in pancreatic islets. We hypothesized that functional compensation by the Slc30a7 isoform, which encodes ZnT7, limits the impact of Slc30a8 deletion on islet function. We therefore analyzed the effect of Slc30a7 deletion alone or in combination with Slc30a8 on in vivo glucose metabolism and GSIS in isolated islets. Deletion of Slc30a7 alone had complex effects in vivo, impairing glucose tolerance and reducing the glucose-stimulated increase in plasma insulin levels, hepatic glycogen levels, and pancreatic insulin content. Slc30a7 deletion also affected islet morphology and increased the ratio of islet α- to β-cells. However, deletion of Slc30a7 alone had no effect on GSIS in isolated islets, whereas combined deletion of Slc30a7 and Slc30a8 abolished GSIS. These data demonstrate that the function of ZnT8 in islets can be unmasked by removal of ZnT7 and imply that ZnT8 may affect T2D susceptibility through actions in other tissues where it is expressed at low levels rather than through effects on pancreatic islet function.
0 Communities
1 Members
0 Resources
16 MeSH Terms
Glucagon receptor inactivation leads to α-cell hyperplasia in zebrafish.
Li M, Dean ED, Zhao L, Nicholson WE, Powers AC, Chen W
(2015) J Endocrinol 227: 93-103
MeSH Terms: Animals, Animals, Genetically Modified, Cell Proliferation, Cloning, Molecular, Embryo, Nonmammalian, Gene Expression Regulation, Developmental, Gene Silencing, Glucagon-Secreting Cells, Hyperplasia, Receptors, Glucagon, Zebrafish
Show Abstract · Added February 6, 2016
Glucagon antagonism is a potential treatment for diabetes. One potential side effect is α-cell hyperplasia, which has been noted in several approaches to antagonize glucagon action. To investigate the molecular mechanism of the α-cell hyperplasia and to identify the responsible factor, we created a zebrafish model in which glucagon receptor (gcgr) signaling has been interrupted. The genetically and chemically tractable zebrafish, which provides a robust discovery platform, has two gcgr genes (gcgra and gcgrb) in its genome. Sequence, phylogenetic, and synteny analyses suggest that these are co-orthologs of the human GCGR. Similar to its mammalian counterparts, gcgra and gcgrb are mainly expressed in the liver. We inactivated the zebrafish gcgra and gcgrb using transcription activator-like effector nuclease (TALEN) first individually and then both genes, and assessed the number of α-cells using an α-cell reporter line, Tg(gcga:GFP). Compared to WT fish at 7 days postfertilization, there were more α-cells in gcgra-/-, gcgrb-/-, and gcgra-/-;gcgrb-/- fish and there was an increased rate of α-cell proliferation in the gcgra-/-;gcgrb-/- fish. Glucagon levels were higher but free glucose levels were lower in gcgra-/-, gcgrb-/-, and gcgra-/-;gcgrb-/- fish, similar to Gcgr-/- mice. These results indicate that the compensatory α-cell hyperplasia in response to interruption of glucagon signaling is conserved in zebrafish. The robust α-cell hyperplasia in gcgra-/-;gcgrb-/- larvae provides a platform to screen for chemical and genetic suppressors, and ultimately to identify the stimulus of α-cell hyperplasia and its signaling mechanism.
© 2015 Society for Endocrinology.
0 Communities
3 Members
0 Resources
11 MeSH Terms
EphA4 Receptor Forward Signaling Inhibits Glucagon Secretion From α-Cells.
Hutchens T, Piston DW
(2015) Diabetes 64: 3839-51
MeSH Terms: Animals, Glucagon, Glucagon-Secreting Cells, Humans, Insulin, Islets of Langerhans, Mice, Mice, Transgenic, Receptor, EphA4, Signal Transduction
Show Abstract · Added February 4, 2016
The loss of inhibition of glucagon secretion exacerbates hyperglycemia in type 1 and 2 diabetes. However, the molecular mechanisms that regulate glucagon secretion in unaffected and diabetic states remain relatively unexplained. We present evidence supporting a new model of juxtacrine-mediated regulation of glucagon secretion where neighboring islet cells negatively regulate glucagon secretion through tonic stimulation of α-cell EphA receptors. Primarily through EphA4 receptors, this stimulation correlates with maintenance of a dense F-actin network. In islets, additional stimulation and inhibition of endogenous EphA forward signaling result in inhibition and enhancement, respectively, of glucagon secretion, accompanied by an increase and decrease, respectively, in α-cell F-actin density. Sorted α-cells lack endogenous stimulation of EphA forward signaling from neighboring cells, resulting in enhanced basal glucagon secretion as compared with islets and the elimination of glucose inhibition of glucagon secretion. Restoration of EphA forward signaling in sorted α-cells recapitulates both normal basal glucagon secretion and glucose inhibition of glucagon secretion. Additionally, α-cell-specific EphA4(-/-) mice exhibit abnormal glucagon dynamics, and EphA4(-/-) α-cells contain less dense F-actin networks than EphA4(+/+) α-cells. This juxtacrine-mediated model provides insight into the functional and dysfunctional regulation of glucagon secretion and opens up new therapeutic strategies for the clinical management of diabetes.
© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
0 Communities
1 Members
0 Resources
10 MeSH Terms
Novel Observations From Next-Generation RNA Sequencing of Highly Purified Human Adult and Fetal Islet Cell Subsets.
Blodgett DM, Nowosielska A, Afik S, Pechhold S, Cura AJ, Kennedy NJ, Kim S, Kucukural A, Davis RJ, Kent SC, Greiner DL, Garber MG, Harlan DM, diIorio P
(2015) Diabetes 64: 3172-81
MeSH Terms: Adolescent, Adult, Child, Preschool, Female, Fetus, Gene Expression Profiling, Gene Expression Regulation, Developmental, Glucagon-Secreting Cells, Humans, Insulin-Secreting Cells, Islets of Langerhans, Male, Middle Aged, Pregnancy, Pregnancy Trimester, Second, RNA, Sequence Analysis, RNA, Somatostatin-Secreting Cells, Young Adult
Show Abstract · Added October 12, 2016
Understanding distinct gene expression patterns of normal adult and developing fetal human pancreatic α- and β-cells is crucial for developing stem cell therapies, islet regeneration strategies, and therapies designed to increase β-cell function in patients with diabetes (type 1 or 2). Toward that end, we have developed methods to highly purify α-, β-, and δ-cells from human fetal and adult pancreata by intracellular staining for the cell-specific hormone content, sorting the subpopulations by flow cytometry, and, using next-generation RNA sequencing, we report the detailed transcriptomes of fetal and adult α- and β-cells. We observed that human islet composition was not influenced by age, sex, or BMI, and transcripts for inflammatory gene products were noted in fetal β-cells. In addition, within highly purified adult glucagon-expressing α-cells, we observed surprisingly high insulin mRNA expression, but not insulin protein expression. This transcriptome analysis from highly purified islet α- and β-cell subsets from fetal and adult pancreata offers clear implications for strategies that seek to increase insulin expression in type 1 and type 2 diabetes.
© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
0 Communities
1 Members
0 Resources
19 MeSH Terms
TASK-1 Potassium Channels Limit Pancreatic α-Cell Calcium Influx and Glucagon Secretion.
Dadi PK, Luo B, Vierra NC, Jacobson DA
(2015) Mol Endocrinol 29: 777-87
MeSH Terms: Animals, Calcium Signaling, Cells, Cultured, Female, Gene Expression, Glucagon, Glucagon-Secreting Cells, Glucose, Humans, Male, Membrane Potential, Mitochondrial, Mice, Inbred C57BL, Mice, Transgenic, Nerve Tissue Proteins, Potassium Channels, Tandem Pore Domain
Show Abstract · Added April 28, 2015
Glucose regulation of pancreatic α-cell Ca(2+) entry through voltage-dependent Ca(2+) channels is essential for normal glucagon secretion and becomes defective during the pathogenesis of diabetes mellitus. The 2-pore domain K(+) channel, TWIK-related acid-sensitive K(+) channel 1 (TASK-1), is an important modulator of membrane voltage and Ca(2+) entry. However, its role in α-cells has not been determined. Therefore, we addressed how TASK-1 channels regulate α-cell electrical activity, Ca(2+) entry, and glucagon secretion. We find that TASK-1 channels expressed in human and rodent α-cells are blocked by the TASK-1 channel inhibitor A1899. Alpha-cell 2-pore domain K(+) currents were also significantly reduced after ablation of mouse α-cell TASK-1 channels. Inhibition of TASK-1 channels with A1899 caused plasma membrane potential depolarization in both human and mouse α-cells, which resulted in increased electrical excitability. Moreover, ablation of α-cell TASK-1 channels increased α-cell electrical excitability under elevated glucose (11 mM) conditions compared with control α-cells. This resulted in significantly elevated α-cell Ca(2+) influx when TASK-1 channels were inhibited in the presence of high glucose (14 mM). However, there was an insignificant change in α-cell Ca(2+) influx after TASK-1 inhibition in low glucose (1 mM). Glucagon secretion from mouse and human islets was also elevated specifically in high (11 mM) glucose after acute TASK-1 inhibition. Interestingly, mice deficient for α-cell TASK-1 showed improvements in both glucose inhibition of glucagon secretion and glucose tolerance, which resulted from the chronic loss of α-cell TASK-1 currents. Therefore, these data suggest an important role for TASK-1 channels in limiting α-cell excitability and glucagon secretion during glucose stimulation.
0 Communities
2 Members
0 Resources
15 MeSH Terms