Dopamine regulates pancreatic glucagon and insulin secretion via adrenergic and dopaminergic receptors

AbstractDopamine (DA) and norepinephrine (NE) are catecholamines primarily studied in the central nervous system that also act in the pancreas as peripheral regulators of metabolism. Pancreatic catecholamine signaling has also been increasingly implicated as a mechanism responsible for the metabolic disturbances produced by antipsychotic drugs (APDs). Critically, however, the mechanisms by which catecholamines modulate pancreatic hormone release are not completely understood. We show that human and mouse pancreatic α- and β-cells express the catecholamine biosynthetic and signaling machinery, and that α-cells synthesize DA de novo. This locally-produced pancreatic DA signals via both α- and β-cell adrenergic and dopaminergic receptors with different affinities to regulate glucagon and insulin release. Significantly, we show DA functions as a biased agonist at α2A-adrenergic receptors, preferentially signaling via the canonical G protein-mediated pathway. Our findings highlight the interplay between DA and NE signaling as a novel form of regulation to modulate pancreatic hormone release. Lastly, pharmacological blockade of DA D2-like receptors in human islets with APDs significantly raises insulin and glucagon release. This offers a new mechanism where APDs act directly on islet α- and β-cell targets to produce metabolic disturbances.

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PDX1LOW MAFALOW β-cells contribute to islet function and insulin release

Nature Communications ◽

10.1038/s41467-020-20632-z ◽

2021 ◽

Vol 12 (1) ◽

Cited By ~ 1

Author(s):

Daniela Nasteska ◽

Nicholas H. F. Fine ◽

Fiona B. Ashford ◽

Federica Cuozzo ◽

Katrina Viloria ◽

...

Keyword(s):

Insulin Secretion ◽

Insulin Release ◽

Metabolic Stress ◽

Human Islets ◽

Islet Function ◽

Β Cells ◽

Β Cell ◽

Ionic Fluxes ◽

Transcriptomic Level ◽

Adult Islet

AbstractTranscriptionally mature and immature β-cells co-exist within the adult islet. How such diversity contributes to insulin release remains poorly understood. Here we show that subtle differences in β-cell maturity, defined using PDX1 and MAFA expression, contribute to islet operation. Functional mapping of rodent and human islets containing proportionally more PDX1HIGH and MAFAHIGH β-cells reveals defects in metabolism, ionic fluxes and insulin secretion. At the transcriptomic level, the presence of increased numbers of PDX1HIGH and MAFAHIGH β-cells leads to dysregulation of gene pathways involved in metabolic processes. Using a chemogenetic disruption strategy, differences in PDX1 and MAFA expression are shown to depend on islet Ca2+ signaling patterns. During metabolic stress, islet function can be restored by redressing the balance between PDX1 and MAFA levels across the β-cell population. Thus, preserving heterogeneity in PDX1 and MAFA expression, and more widely in β-cell maturity, might be important for the maintenance of islet function.

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Differential activation of ER stress and apoptosis in response to chronically elevated free fatty acids in pancreatic β-cells

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00478.2007 ◽

2008 ◽

Vol 294 (3) ◽

pp. E540-E550 ◽

Cited By ~ 108

Author(s):

Elida Lai ◽

George Bikopoulos ◽

Michael B. Wheeler ◽

Maria Rozakis-Adcock ◽

Allen Volchuk

Keyword(s):

Er Stress ◽

Cell Lines ◽

Cell Apoptosis ◽

Human Islets ◽

Pancreatic Β Cell ◽

Β Cell ◽

Min6 Cells ◽

Relative Contribution ◽

Induced Apoptosis

Chronic exposure to elevated saturated free fatty acid (FFA) levels has been shown to induce endoplasmic reticulum (ER) stress that may contribute to promoting pancreatic β-cell apoptosis. Here, we compared the effects of FFAs on apoptosis and ER stress in human islets and two pancreatic β-cell lines, rat INS-1 and mouse MIN6 cells. Isolated human islets cultured in vitro underwent apoptosis, and markers of ER stress pathways were elevated by chronic palmitate exposure. Palmitate also induced apoptosis in MIN6 and INS-1 cells, although the former were more resistant to both apoptosis and ER stress. MIN6 cells were found to express significantly higher levels of ER chaperone proteins than INS-1 cells, which likely accounts for the ER stress resistance. We attempted to determine the relative contribution that ER stress plays in palmitate-induced β-cell apoptosis. Although overexpressing GRP78 in INS-1 cells partially reduced susceptibility to thapsigargin, this failed to reduce palmitate-induced ER stress or apoptosis. In INS-1 cells, palmitate induced apoptosis at concentrations that did not result in significant ER stress. Finally, MIN6 cells depleted of GRP78 were more susceptible to tunicamycin-induced apoptosis but not to palmitate-induced apoptosis compared with control cells. These results suggest that ER stress is likely not the main mechanism involved in palmitate-induced apoptosis in β-cell lines. Human islets and MIN6 cells were found to express high levels of stearoyl-CoA desaturase-1 compared with INS-1 cells, which may account for the decreased susceptibility of these cells to the cytotoxic effects of palmitate.

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Effects of glucose and d-3-hydroxybutyrate on human pancreatic islet cell function

Clinical Science ◽

10.1042/cs0680567 ◽

1985 ◽

Vol 68 (5) ◽

pp. 567-572 ◽

Cited By ~ 6

Author(s):

C. J. Rhodes ◽

I. L. Campbell ◽

T. M. Szopa ◽

T. J. Biden ◽

P. D. Reynolds ◽

...

Keyword(s):

Insulin Release ◽

Human Tissue ◽

Islet Cell ◽

Cell Function ◽

Human Islets ◽

Β Cell ◽

Pancreatic Islet Cell ◽

Sigmoidal Curve ◽

Β Cell Function ◽

Islet Cell Function

1. β-Cell function in human islets derived from a number of kidney donors was investigated by using various types of islet preparations. 2. With fresh islets, both insulin release and biosynthesis were increased by raising glucose concentrations, although the response was a variable one. 3. In fresh islets, the effects of 5 mmol of glucose/l on release were potentiated by 10 mmol of d-3-hydroxybutyrate/l. 4. Insulin release at 20 mmol of glucose/l was inhibited by adrenaline (0.1 mmol/l), and potentiated by theophylline (10 mmol/l) in the presence of 5 mmol of glucose/l, in islets cultured for 4 days. 5. After culture for 8 days, islets still showed an increase in insulin release and biosynthesis in response to glucose. 6. Pancreas slices derived from fresh human tissue also responded to increasing concentrations of glucose with a sigmoidal curve for insulin release.

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Furin controls β cell function via mTORC1 signaling

10.1101/2020.04.09.027839 ◽

2020 ◽

Cited By ~ 1

Author(s):

Bas Brouwers ◽

Ilaria Coppola ◽

Katlijn Vints ◽

Bastian Dislich ◽

Nathalie Jouvet ◽

...

Keyword(s):

Secretory Pathway ◽

Cell Function ◽

Mammalian Target Of Rapamycin ◽

Human Islets ◽

Β Cells ◽

Β Cell ◽

Differential Proteomics ◽

Atpase Subunit ◽

Proteolytic Activation ◽

Mtorc1 Signaling

AbstractFurin is a proprotein convertase (PC) responsible for proteolytic activation of a wide array of precursor proteins within the secretory pathway. It maps to the PRC1 locus, a type 2 diabetes susceptibility locus, yet its specific role in pancreatic β cells is largely unknown. The aim of this study was to determine the role of furin in glucose homeostasis. We show that furin is highly expressed in human islets, while PCs that potentially could provide redundancy are expressed at considerably lower levels. β cell-specific furin knockout (βfurKO) mice are glucose intolerant, due to smaller islets with lower insulin content and abnormal dense core secretory granule morphology. RNA expression analysis and differential proteomics on βfurKO islets revealed activation of Activating Transcription Factor 4 (ATF4), which was mediated by mammalian target of rapamycin C1 (mTORC1). βfurKO cells show impaired cleavage of the essential V-ATPase subunit Ac45, and by blocking this pump in β cells the mTORC1 pathway is activated. Furthermore, βfurKO cells show lack of insulin receptor cleavage and impaired response to insulin. Taken together, these results suggest a model of mTORC1-ATF4 hyperactivation in β cells lacking furin, which causes β cell dysfunction.

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The regulator of G-protein signaling RGS16 promotes insulin secretion and β-cell proliferation in rodent and human islets

Molecular Metabolism ◽

10.1016/j.molmet.2016.08.010 ◽

2016 ◽

Vol 5 (10) ◽

pp. 988-996 ◽

Cited By ~ 14

Author(s):

Kevin Vivot ◽

Valentine S. Moullé ◽

Bader Zarrouki ◽

Caroline Tremblay ◽

Arturo D. Mancini ◽

...

Keyword(s):

Cell Proliferation ◽

Insulin Secretion ◽

G Protein ◽

Human Islets ◽

G Protein Signaling ◽

Protein Signaling ◽

Β Cell

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Dysgenesis and dysfunction of pancreas and pituitary due to FOXA2 gene defects

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab352 ◽

2021 ◽

Author(s):

Sare Betul Kaygusuz ◽

Esra Arslan Ates ◽

Maria Lillina Vignola ◽

Burcu Volkan ◽

Bilgen Bilge Geckinli ◽

...

Keyword(s):

Transcriptional Activation ◽

Developmental Disorders ◽

De Novo ◽

Luciferase Reporter ◽

Forkhead Box ◽

First Case ◽

The Central Nervous System ◽

Gene Defects ◽

Congenital Hypopituitarism ◽

Pancreatic Hypoplasia

Abstract Context Developmental disorders of the pituitary gland leading to congenital hypopituitarism can either be isolated or associated with extra-pituitary abnormalities (syndromic hypopituitarism). A large number of syndromic hypopituitarism cases are linked to mutations in transcription factors. The Forkhead box A2 (FOXA2) is a transcription factor that plays a key role in the central nervous system, foregut and pancreatic development. Objective To characterize two patients with syndromic hypopituitarism due to FOXA2 gene defects. Results We report a novel heterozygous nonsense c.616C>T (p.Q206X) variant, which leads to a truncated protein that lacks part of the DNA-binding domain of FOXA2, resulting in impaired transcriptional activation of the GLUT2-luciferase reporter. The patient is the sixth patient described in the literature with a FOXA2 mutation, and the first patient exhibiting pancreatic hypoplasia. We also report a second patient with a novel de novo 8.53 megabase (Mb) deletion of 20p11.2 that encompasses FOXA2, who developed diabetes mellitus that responded to sulfonylurea treatment. Conclusions Our two cases broaden the molecular and clinical spectrum of FOXA2-related disease, reporting the first nonsense mutation and the first case of pancreatic dysgenesis.

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In Vivo Microdialysis of Endogenous and 13C-labeled TCA Metabolites in Rat Brain: Reversible and Persistent Effects of Mitochondrial Inhibition and Transient Cerebral Ischemia

Metabolites ◽

10.3390/metabo9100204 ◽

2019 ◽

Vol 9 (10) ◽

pp. 204 ◽

Cited By ~ 1

Author(s):

Jesper F. Havelund ◽

Kevin H. Nygaard ◽

Troels H. Nielsen ◽

Carl-Henrik Nordström ◽

Frantz R. Poulsen ◽

...

Keyword(s):

Cerebral Ischemia ◽

Mitochondrial Dysfunction ◽

Rat Brain ◽

De Novo ◽

Tricarboxylic Acid Cycle ◽

Experimental Models ◽

Transient Cerebral Ischemia ◽

Metabolic Disturbances ◽

Metabolic Marker

Cerebral micro-dialysis allows continuous sampling of extracellular metabolites, including glucose, lactate and pyruvate. Transient ischemic events cause a rapid drop in glucose and a rise in lactate levels. Following such events, the lactate/pyruvate (L/P) ratio may remain elevated for a prolonged period of time. In neurointensive care clinics, this ratio is considered a metabolic marker of ischemia and/or mitochondrial dysfunction. Here we propose a novel, sensitive microdialysis liquid chromatography-mass spectrometry (LC-MS) approach to monitor mitochondrial dysfunction in living brain using perfusion with 13C-labeled succinate and analysis of 13C-labeled tricarboxylic acid cycle (TCA) intermediates. This approach was evaluated in rat brain using malonate-perfusion (10–50 mM) and endothelin-1 (ET-1)-induced transient cerebral ischemia. In the malonate model, the expected changes upon inhibition of succinate dehydrogenase (SDH) were observed, i.e., an increase in endogenous succinate and decreases in fumaric acid and malic acid. The inhibition was further elaborated by incorporation of 13C into specific TCA intermediates from 13C-labeled succinate. In the ET-1 model, increases in non-labeled TCA metabolites (reflecting release of intracellular compounds) and decreases in 13C-labeled TCA metabolites (reflecting inhibition of de novo synthesis) were observed. The analysis of 13C incorporation provides further layers of information to identify metabolic disturbances in experimental models and neuro-intensive care patients.

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Enhancer of Zeste Homolog 2 (EZH2) Mediates Glucolipotoxicity-Induced Apoptosis in β-Cells

International Journal of Molecular Sciences ◽

10.3390/ijms21218016 ◽

2020 ◽

Vol 21 (21) ◽

pp. 8016

Author(s):

Tina Dahlby ◽

Christian Simon ◽

Marie Balslev Backe ◽

Mattias Salling Dahllöf ◽

Edward Holson ◽

...

Keyword(s):

Er Stress ◽

Molecular Mechanisms ◽

Selective Inhibition ◽

Human Islets ◽

Β Cells ◽

Β Cell ◽

Enhancer Of Zeste ◽

Cell Gene Expression ◽

Nfκb Pathway ◽

Induced Apoptosis

Selective inhibition of histone deacetylase 3 (HDAC3) prevents glucolipotoxicity-induced β-cell dysfunction and apoptosis by alleviation of proapoptotic endoplasmic reticulum (ER) stress-signaling, but the precise molecular mechanisms of alleviation are unexplored. By unbiased microarray analysis of the β-cell gene expression profile of insulin-producing cells exposed to glucolipotoxicity in the presence or absence of a selective HDAC3 inhibitor, we identified Enhancer of zeste homolog 2 (EZH2) as the sole target candidate. β-Cells were protected against glucolipotoxicity-induced ER stress and apoptosis by EZH2 attenuation. Small molecule inhibitors of EZH2 histone methyltransferase activity rescued human islets from glucolipotoxicity-induced apoptosis. Moreover, EZH2 knockdown cells were protected against glucolipotoxicity-induced downregulation of the protective non-canonical Nuclear factor of kappa light polypeptide gene enhancer in B-cells (NFκB) pathway. We conclude that EZH2 deficiency protects from glucolipotoxicity-induced ER stress, apoptosis and downregulation of the non-canonical NFκB pathway, but not from insulin secretory dysfunction. The mechanism likely involves transcriptional regulation via EZH2 functioning as a methyltransferase and/or as a methylation-dependent transcription factor.

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Regulatory Mechanisms of Somatostatin Expression

International Journal of Molecular Sciences ◽

10.3390/ijms21114170 ◽

2020 ◽

Vol 21 (11) ◽

pp. 4170 ◽

Cited By ~ 1

Author(s):

Emmanuel Ampofo ◽

Lisa Nalbach ◽

Michael D. Menger ◽

Matthias W. Laschke

Keyword(s):

Hormone Secretion ◽

Growth Hormone Secretion ◽

Peptide Hormone ◽

Regulatory Mechanisms ◽

Insulin Synthesis ◽

The Central Nervous System ◽

Health And Disease ◽

Glucagon And Insulin ◽

Somatostatin Expression

Somatostatin is a peptide hormone, which most commonly is produced by endocrine cells and the central nervous system. In mammals, somatostatin originates from pre-prosomatostatin and is processed to a shorter form, i.e., somatostatin-14, and a longer form, i.e., somatostatin-28. The two peptides repress growth hormone secretion and are involved in the regulation of glucagon and insulin synthesis in the pancreas. In recent years, the processing and secretion of somatostatin have been studied intensively. However, little attention has been paid to the regulatory mechanisms that control its expression. This review provides an up-to-date overview of these mechanisms. In particular, it focuses on the role of enhancers and silencers within the promoter region as well as on the binding of modulatory transcription factors to these elements. Moreover, it addresses extracellular factors, which trigger key signaling pathways, leading to an enhanced somatostatin expression in health and disease.

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