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TALK-1 reduces delta-cell endoplasmic reticulum and cytoplasmic calcium levels limiting somatostatin secretion.
Vierra NC, Dickerson MT, Jordan KL, Dadi PK, Katdare KA, Altman MK, Milian SC, Jacobson DA
(2018) Mol Metab 9: 84-97
MeSH Terms: Animals, Calcium Signaling, Cells, Cultured, Cytoplasm, Endoplasmic Reticulum, Glucagon, Humans, Male, Mice, Mice, Inbred C57BL, Potassium Channels, Tandem Pore Domain, Somatostatin, Somatostatin-Secreting Cells
Show Abstract · Added February 7, 2018
OBJECTIVE - Single-cell RNA sequencing studies have revealed that the type-2 diabetes associated two-pore domain K (K2P) channel TALK-1 is abundantly expressed in somatostatin-secreting δ-cells. However, a physiological role for TALK-1 in δ-cells remains unknown. We previously determined that in β-cells, K flux through endoplasmic reticulum (ER)-localized TALK-1 channels enhances ER Ca leak, modulating Ca handling and insulin secretion. As glucose amplification of islet somatostatin release relies on Ca-induced Ca release (CICR) from the δ-cell ER, we investigated whether TALK-1 modulates δ-cell Ca handling and somatostatin secretion.
METHODS - To define the functions of islet δ-cell TALK-1 channels, we generated control and TALK-1 channel-deficient (TALK-1 KO) mice expressing fluorescent reporters specifically in δ- and α-cells to facilitate cell type identification. Using immunofluorescence, patch clamp electrophysiology, Ca imaging, and hormone secretion assays, we assessed how TALK-1 channel activity impacts δ- and α-cell function.
RESULTS - TALK-1 channels are expressed in both mouse and human δ-cells, where they modulate glucose-stimulated changes in cytosolic Ca and somatostatin secretion. Measurement of cytosolic Ca levels in response to membrane potential depolarization revealed enhanced CICR in TALK-1 KO δ-cells that could be abolished by depleting ER Ca with sarco/endoplasmic reticulum Ca ATPase (SERCA) inhibitors. Consistent with elevated somatostatin inhibitory tone, we observed significantly reduced glucagon secretion and α-cell Ca oscillations in TALK-1 KO islets, and found that blockade of α-cell somatostatin signaling with a somatostatin receptor 2 (SSTR2) antagonist restored glucagon secretion in TALK-1 KO islets.
CONCLUSIONS - These data indicate that TALK-1 reduces δ-cell cytosolic Ca elevations and somatostatin release by limiting δ-cell CICR, modulating the intraislet paracrine signaling mechanisms that control glucagon secretion.
Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.
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1 Members
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13 MeSH Terms
Safety and Efficacy of 68Ga-DOTATATE PET/CT for Diagnosis, Staging, and Treatment Management of Neuroendocrine Tumors.
Deppen SA, Liu E, Blume JD, Clanton J, Shi C, Jones-Jackson LB, Lakhani V, Baum RP, Berlin J, Smith GT, Graham M, Sandler MP, Delbeke D, Walker RC
(2016) J Nucl Med 57: 708-14
MeSH Terms: Female, Humans, Indium Radioisotopes, Intestinal Neoplasms, Lung Neoplasms, Male, Middle Aged, Neoplasm Staging, Neuroendocrine Tumors, Observer Variation, Organometallic Compounds, Pancreatic Neoplasms, Positron Emission Tomography Computed Tomography, Safety, Somatostatin, Stomach Neoplasms
Show Abstract · Added May 7, 2016
UNLABELLED - Our purpose was to evaluate the safety and efficacy of (68)Ga-DOTATATE PET/CT compared with (111)In-pentetreotide imaging for diagnosis, staging, and restaging of pulmonary and gastroenteropancreatic neuroendocrine tumors.
METHODS - (68)Ga-DOTATATE PET/CT and (111)In-pentetreotide scans were obtained for 78 of 97 consecutively enrolled patients with known or suspected pulmonary or gastroenteropancreatic neuroendocrine tumors. Safety and toxicity were measured by comparing vital signs, serum chemistry values, or acquisition-related medical complications before and after (68)Ga-DOTATATE injection. Added value was determined by changes in treatment plan when (68)Ga-DOTATATE PET/CT results were added to all prior imaging, including (111)In-pentetreotide. Interobserver reproducibility of (68)Ga-DOTATATE PET/CT scan interpretation was measured between blinded and nonblinded interpreters.
RESULTS - (68)Ga-DOTATATE PET/CT and (111)In-pentetreotide scans were significantly different in impact on treatment (P < 0.001). (68)Ga-DOTATATE PET/CT combined with CT or liver MRI changed care in 28 of 78 (36%) patients. Interobserver agreement between blinded and nonblinded interpreters was high. No participant had a trial-related event requiring treatment. Mild, transient events were tachycardia in 1, alanine transaminase elevation in 1, and hyperglycemia in 2 participants. No clinically significant arrhythmias occurred. (68)Ga-DOTATATE PET/CT correctly identified 3 patients for peptide-receptor radiotherapy incorrectly classified by (111)In-pentetreotide.
CONCLUSION - (68)Ga-DOTATATE PET/CT was equivalent or superior to (111)In-pentetreotide imaging in all 78 patients. No adverse events requiring treatment were observed. (68)Ga-DOTATATE PET/CT changed treatment in 36% of participants. Given the lack of significant toxicity, lower radiation exposure, and improved accuracy compared with (111)In-pentetreotide, (68)Ga-DOTATATE imaging should be used instead of (111)In-pentetreotide imaging where available.
© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
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1 Members
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16 MeSH Terms
Inactivating the permanent neonatal diabetes gene Mnx1 switches insulin-producing β-cells to a δ-like fate and reveals a facultative proliferative capacity in aged β-cells.
Pan FC, Brissova M, Powers AC, Pfaff S, Wright CV
(2015) Development 142: 3637-48
MeSH Terms: Animals, Cell Transdifferentiation, Cellular Senescence, Diabetes Mellitus, Eye Proteins, Homeodomain Proteins, Humans, Hyperplasia, Insulin-Secreting Cells, Mice, PAX6 Transcription Factor, Paired Box Transcription Factors, Repressor Proteins, Somatostatin-Secreting Cells, Transcription Factors
Show Abstract · Added December 28, 2015
Homozygous Mnx1 mutation causes permanent neonatal diabetes in humans, but via unknown mechanisms. Our systematic and longitudinal analysis of Mnx1 function during murine pancreas organogenesis and into the adult uncovered novel stage-specific roles for Mnx1 in endocrine lineage allocation and β-cell fate maintenance. Inactivation in the endocrine-progenitor stage shows that Mnx1 promotes β-cell while suppressing δ-cell differentiation programs, and is crucial for postnatal β-cell fate maintenance. Inactivating Mnx1 in embryonic β-cells (Mnx1(Δbeta)) caused β-to-δ-like cell transdifferentiation, which was delayed until postnatal stages. In the latter context, β-cells escaping Mnx1 inactivation unexpectedly upregulated Mnx1 expression and underwent an age-independent persistent proliferation. Escaper β-cells restored, but then eventually surpassed, the normal pancreatic β-cell mass, leading to islet hyperplasia in aged mice. In vitro analysis of islets isolated from Mnx1(Δbeta) mice showed higher insulin secretory activity and greater insulin mRNA content than in wild-type islets. Mnx1(Δbeta) mice also showed a much faster return to euglycemia after β-cell ablation, suggesting that the new β-cells derived from the escaper population are functional. Our findings identify Mnx1 as an important factor in β-cell differentiation and proliferation, with the potential for targeting to increase the number of endogenous β-cells for diabetes therapy.
© 2015. Published by The Company of Biologists Ltd.
0 Communities
3 Members
0 Resources
15 MeSH Terms
Insulin Delivery Into the Peripheral Circulation: A Key Contributor to Hypoglycemia in Type 1 Diabetes.
Gregory JM, Kraft G, Scott MF, Neal DW, Farmer B, Smith MS, Hastings JR, Allen EJ, Donahue EP, Rivera N, Winnick JJ, Edgerton DS, Nishimura E, Fledelius C, Brand CL, Cherrington AD
(2015) Diabetes 64: 3439-51
MeSH Terms: Administration, Intravenous, Animals, Blood Glucose, Diabetes Mellitus, Type 1, Dogs, Glucagon, Glucose, Humans, Hypoglycemia, Insulin, Male, Portal Vein, Somatostatin
Show Abstract · Added July 15, 2015
Hypoglycemia limits optimal glycemic control in type 1 diabetes mellitus (T1DM), making novel strategies to mitigate it desirable. We hypothesized that portal (Po) vein insulin delivery would lessen hypoglycemia. In the conscious dog, insulin was infused into the hepatic Po vein or a peripheral (Pe) vein at a rate four times of basal. In protocol 1, a full counterregulatory response was allowed, whereas in protocol 2, glucagon was fixed at basal, mimicking the diminished α-cell response to hypoglycemia seen in T1DM. In protocol 1, glucose fell faster with Pe insulin than with Po insulin, reaching 56 ± 3 vs. 70 ± 6 mg/dL (P = 0.04) at 60 min. The change in area under the curve (ΔAUC) for glucagon was similar between Pe and Po, but the peak occurred earlier in Pe. The ΔAUC for epinephrine was greater with Pe than with Po (67 ± 17 vs. 36 ± 14 ng/mL/180 min). In protocol 2, glucose also fell more rapidly than in protocol 1 and fell faster in Pe than in Po, reaching 41 ± 3 vs. 67 ± 2 mg/dL (P < 0.01) by 60 min. Without a rise in glucagon, the epinephrine responses were much larger (ΔAUC of 204 ± 22 for Pe vs. 96 ± 29 ng/mL/180 min for Po). In summary, Pe insulin delivery exacerbates hypoglycemia, particularly in the presence of a diminished glucagon response. Po vein insulin delivery, or strategies that mimic it (i.e., liver-preferential insulin analogs), should therefore lessen hypoglycemia.
© 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
5 Members
2 Resources
13 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
Somatostatin and insulin mediate glucose-inhibited glucagon secretion in the pancreatic α-cell by lowering cAMP.
Elliott AD, Ustione A, Piston DW
(2015) Am J Physiol Endocrinol Metab 308: E130-43
MeSH Terms: Animals, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Flow Cytometry, Glucagon, Glucagon-Secreting Cells, Glucose, Humans, Insulin, Islets of Langerhans, Male, Mice, Mice, Inbred C57BL, Microscopy, Confocal, Signal Transduction, Somatostatin
Show Abstract · Added January 20, 2015
The dysregulation of glucose-inhibited glucagon secretion from the pancreatic islet α-cell is a critical component of diabetes pathology and metabolic disease. We show a previously uncharacterized [Ca(2+)]i-independent mechanism of glucagon suppression in human and murine pancreatic islets whereby cAMP and PKA signaling are decreased. This decrease is driven by the combination of somatostatin, which inhibits adenylyl cyclase production of cAMP via the Gαi subunit of the SSTR2, and insulin, which acts via its receptor to activate phosphodiesterase 3B and degrade cytosolic cAMP. Our data indicate that both somatostatin and insulin signaling are required to suppress cAMP/PKA and glucagon secretion from both human and murine α-cells, and the combination of these two signaling mechanisms is sufficient to reduce glucagon secretion from isolated α-cells as well as islets. Thus, we conclude that somatostatin and insulin together are critical paracrine mediators of glucose-inhibited glucagon secretion and function by lowering cAMP/PKA signaling with increasing glucose.
Copyright © 2015 the American Physiological Society.
0 Communities
2 Members
0 Resources
16 MeSH Terms
Diabetes recovery by age-dependent conversion of pancreatic δ-cells into insulin producers.
Chera S, Baronnier D, Ghila L, Cigliola V, Jensen JN, Gu G, Furuyama K, Thorel F, Gribble FM, Reimann F, Herrera PL
(2014) Nature 514: 503-7
MeSH Terms: Aging, Animals, Cell Dedifferentiation, Cell Proliferation, Cell Transdifferentiation, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 1, Forkhead Box Protein O1, Forkhead Transcription Factors, Glucagon-Secreting Cells, Humans, Insulin, Insulin Secretion, Insulin-Secreting Cells, Mice, Regeneration, Sexual Maturation, Somatostatin, Somatostatin-Secreting Cells
Show Abstract · Added October 15, 2015
Total or near-total loss of insulin-producing β-cells occurs in type 1 diabetes. Restoration of insulin production in type 1 diabetes is thus a major medical challenge. We previously observed in mice in which β-cells are completely ablated that the pancreas reconstitutes new insulin-producing cells in the absence of autoimmunity. The process involves the contribution of islet non-β-cells; specifically, glucagon-producing α-cells begin producing insulin by a process of reprogramming (transdifferentiation) without proliferation. Here we show the influence of age on β-cell reconstitution from heterologous islet cells after near-total β-cell loss in mice. We found that senescence does not alter α-cell plasticity: α-cells can reprogram to produce insulin from puberty through to adulthood, and also in aged individuals, even a long time after β-cell loss. In contrast, before puberty there is no detectable α-cell conversion, although β-cell reconstitution after injury is more efficient, always leading to diabetes recovery. This process occurs through a newly discovered mechanism: the spontaneous en masse reprogramming of somatostatin-producing δ-cells. The juveniles display 'somatostatin-to-insulin' δ-cell conversion, involving dedifferentiation, proliferation and re-expression of islet developmental regulators. This juvenile adaptability relies, at least in part, upon the combined action of FoxO1 and downstream effectors. Restoration of insulin producing-cells from non-β-cell origins is thus enabled throughout life via δ- or α-cell spontaneous reprogramming. A landscape with multiple intra-islet cell interconversion events is emerging, offering new perspectives for therapy.
0 Communities
1 Members
0 Resources
19 MeSH Terms
Loss of Fbw7 reprograms adult pancreatic ductal cells into α, δ, and β cells.
Sancho R, Gruber R, Gu G, Behrens A
(2014) Cell Stem Cell 15: 139-53
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Differentiation, Cell Line, Tumor, Cell Lineage, F-Box Proteins, F-Box-WD Repeat-Containing Protein 7, Gene Deletion, Gene Expression Profiling, Gene Expression Regulation, Developmental, Glucagon-Secreting Cells, Glucose, HEK293 Cells, Humans, Insulin, Insulin Secretion, Insulin-Secreting Cells, Mice, Multipotent Stem Cells, Nerve Tissue Proteins, Pancreatic Ducts, Proteasome Endopeptidase Complex, Regeneration, Somatostatin-Secreting Cells, Ubiquitin-Protein Ligases, Ubiquitination
Show Abstract · Added January 23, 2015
The adult pancreas is capable of limited regeneration after injury but has no defined stem cell population. The cell types and molecular signals that govern the production of new pancreatic tissue are not well understood. Here, we show that inactivation of the SCF-type E3 ubiquitin ligase substrate recognition component Fbw7 induces pancreatic ductal cells to reprogram into α, δ, and β cells. Loss of Fbw7 stabilized the transcription factor Ngn3, a key regulator of endocrine cell differentiation. The induced β cells resemble islet β cells in morphology and histology, express genes essential for β cell function, and release insulin after glucose challenge. Thus, loss of Fbw7 appears to reawaken an endocrine developmental differentiation program in adult pancreatic ductal cells. Our study highlights the plasticity of seemingly differentiated adult cells, identifies Fbw7 as a master regulator of cell fate decisions in the pancreas, and reveals adult pancreatic duct cells as a latent multipotent cell type.
Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
1 Communities
1 Members
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26 MeSH Terms
Cell lineage distribution atlas of the human stomach reveals heterogeneous gland populations in the gastric antrum.
Choi E, Roland JT, Barlow BJ, O'Neal R, Rich AE, Nam KT, Shi C, Goldenring JR
(2014) Gut 63: 1711-20
MeSH Terms: Cell Lineage, Enteroendocrine Cells, Gastric Mucosa, Gastrins, Ghrelin, Humans, Immunohistochemistry, Parietal Cells, Gastric, Pyloric Antrum, Somatostatin, Stomach
Show Abstract · Added March 10, 2014
OBJECTIVE - The glands of the stomach body and antral mucosa contain a complex compendium of cell lineages. In lower mammals, the distribution of oxyntic glands and antral glands define the anatomical regions within the stomach. We examined in detail the distribution of the full range of cell lineages within the human stomach.
DESIGN - We determined the distribution of gastric gland cell lineages with specific immunocytochemical markers in entire stomach specimens from three non-obese organ donors.
RESULTS - The anatomical body and antrum of the human stomach were defined by the presence of ghrelin and gastrin cells, respectively. Concentrations of somatostatin cells were observed in the proximal stomach. Parietal cells were seen in all glands of the body of the stomach as well as in over 50% of antral glands. MIST1 expressing chief cells were predominantly observed in the body although individual glands of the antrum also showed MIST1 expressing chief cells. While classically described antral glands were observed with gastrin cells and deep antral mucous cells without any parietal cells, we also observed a substantial population of mixed type glands containing both parietal cells and G cells throughout the antrum.
CONCLUSIONS - Enteroendocrine cells show distinct patterns of localisation in the human stomach. The existence of antral glands with mixed cell lineages indicates that human antral glands may be functionally chimeric with glands assembled from multiple distinct stem cell populations.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
1 Communities
3 Members
0 Resources
11 MeSH Terms
Targeted multiplex imaging mass spectrometry in transmission geometry for subcellular spatial resolution.
Thiery-Lavenant G, Zavalin AI, Caprioli RM
(2013) J Am Soc Mass Spectrom 24: 609-14
MeSH Terms: Histocytochemistry, Humans, Insulin, Islets of Langerhans, Molecular Imaging, Somatostatin, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Subcellular Fractions, Synaptophysin
Show Abstract · Added March 7, 2014
Targeted multiplex imaging mass spectrometry utilizes several different antigen-specific primary antibodies, each directly labeled with a unique photocleavable mass tag, to detect multiple antigens in a single tissue section. Each photocleavable mass tag bound to an antibody has a unique molecular weight and can be readily ionized by laser desorption ionization mass spectrometry. This article describes a mass spectrometry method that allows imaging of targeted single cells within tissue using transmission geometry laser desorption ionization mass spectrometry. Transmission geometry focuses the laser beam on the back side of the tissue placed on a glass slide, providing a 2 μm diameter laser spot irradiating the biological specimen. This matrix-free method enables simultaneous localization at the sub-cellular level of multiple antigens using specific tagged antibodies. We have used this technology to visualize the co-expression of synaptophysin and two major hormones peptides, insulin and somatostatin, in duplex assays in beta and delta cells contained in a human pancreatic islet.
1 Communities
1 Members
0 Resources
9 MeSH Terms