Regulation of pancreatic β-cell function and mass dynamics by prostaglandin signaling

Carboneau, Lindsey; Breyer, Richard M.; Gannon, Maureen

doi:10.1007/s12079-017-0377-7

Cited by 31 publications

(35 citation statements)

References 94 publications

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“…The presence of inflammatory receptors like PGTER4 may couple localized pancreatic or more global responses to islet output of insulin. Systemic delivery of high levels of PGE2 appear to lower insulin secretion 39,40 , but the selective effects on  cell proliferation or survival versus direct effects on insulin secretion are not fully separated. The broader context of activating PGE2 levels in pancreatic islets may cause a variety of effects.…”

Section: Discussionmentioning

confidence: 99%

Discovery of ciliary G protein-coupled receptors regulating pancreatic islet insulin and glucagon secretion

Hilgendorf

Bevacqua

et al. 2020

Preprint

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Multiple G protein coupled receptors (GPCRs) are expressed in pancreatic islet cells but the majority have unknown functions. We observe specific GPCRs localized to primary cilia, a prominent signaling organelle, in pancreatic α- and β-cells. Loss of cilia disrupts β-cell endocrine function, but the molecular drivers are unknown. Using functional expression, we identified multiple GPCRs localized to cilia in mouse and human islet α- and β-cells, including FFAR4, PTGER4, DRD5, ADRB2, KISS1R, and P2RY14. Free fatty acid receptor 4 (FFAR4) and prostaglandin E receptor 4 (PTGER4) agonists stimulate ciliary cAMP signaling and promote glucagon and insulin secretion by α- and β-cell lines, and by mouse and human islets. Transport of GPCRs to primary cilia requires TULP3, whose knockdown in primary human and mouse islets depleted ciliary FFAR4 and PTGER4, and impaired regulated glucagon or insulin secretion, without affecting ciliary structure. Our findings provide index evidence that regulated hormone secretion by islet α- and β-cells is regulated by ciliary GPCRs providing new targets for diabetes.

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Section: Discussionmentioning

confidence: 99%

Discovery of ciliary G protein-coupled receptors regulating pancreatic islet insulin and glucagon secretion

Hilgendorf

Bevacqua

et al. 2020

Preprint

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“…COX 1 and 2), which catalyze the intermediate conversion of PGH2 to PGE2. Elevated islet expression of specific PGE2 synthetic enzymes and/or islet PGE2 excretion has been observed in islets from T2D animals and humans (2,5,6,8,9,20,37). Yet, in this study, PGE2 production was not enhanced in HGOB islets above the levels observed in either lean or NGOB.…”

Section: Discussionmentioning

confidence: 99%

EP3 signaling is decoupled from regulation of glucose-stimulated insulin secretion in β-cells compensating for obesity and insulin resistance

Schaid

Harrington

Kelly

et al. 2020

Preprint

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Of the β-cell signaling pathways altered by non-diabetic obesity and insulin resistance, some are adaptive while others actively contribute to β-cell failure and demise. Cytoplasmic calcium (Ca2+) and cyclic AMP (cAMP), which control the timing and amplitude of insulin secretion, are two important signaling intermediates that can be controlled by stimulatory and inhibitory G protein-coupled receptors. Previous work has shown the importance of the cAMP-inhibitory EP3 receptor in the beta-cell dysfunction of type 2 diabetes. To examine alterations in β-cell cAMP during diabetes progression we utilized a β-cell specific cAMP biosensor in tandem with islet Ca2+ recordings and insulin secretion assays. Three groups of C57BL/6J mice were used as a model of the progression from metabolic health to type 2 diabetes: wildtype, normoglycemic LeptinOb, and hyperglycemic LeptinOb. Here, we report robust increases in β-cell cAMP and insulin secretion responses in normoglycemic Leptinob mice as compared to wild-type: an effect that was lost in islets from hyperglycemic Leptinob mice, despite elevated Ca2+ duty cycle. Yet, the correlation of EP3 expression and activity to reduce cAMP levels and Ca2+ duty cycle with reduced insulin secretion only held true in hyperglycemic LeptinOb mice. Our results suggest alterations in beta-cell EP3 signaling may be both adaptive and maladaptive and define β-cell EP3 signaling as much more nuanced than previously understood.

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“…ПЗ має дві частини: екзокринну, що продукує широкий спектр травних ферментів, і ендокринну, яка формує 1-3 % маси залози і є джерелом панкреатичних гормонів [22,27]. Ендокринна і екзокринна частини ПЗ розвиваються з одного ембрі-онального джерела [3,10] і тісно пов'язані анатомічно, однак при цьому часто ці дві частини вивчаються окремо один від одного [2,5,14,17,27].…”

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“…Протягом 4 місяців у щурів усіх груп було зроблено аналіз змін маси тіла. 4-місячних тварин декапітували, збирали ПЗ для гістологічного та імуногістохімічного дослідження [5,18].…”

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“…Для оцінки наявності та вираженості запальних змін на тлі експериментального ожиріння було здійснено імуногістохімічне дослідження з оцінкою кількості і розподілу CD68 позитивних клітин [7]. Крім того, оцінювали експресію таких відомих маркерів запалення, як NF-kB і циклооксигеназа 2 (СОХ2), а також експресію TNF-альфа імуногістохімічно за стандартним протоколом [5,15]. Підрахували відсоток імунопозитивних клітин в різних компартментах ПЗ.…”

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Morphogenesis of pancreas under the conditions of glutamate-induced obesity: mechanisms of correction effect of melanin

et al. 2018

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The aim of work was to study the morphogenesis of pancreas in rats with glutamate-induced obesity and to evaluate the effects of melanin under these conditions. We included 45 newborn Wistarmale rats, divided into 3 groups of 15 animals each.1 group – newborns rats of intact group were administered with saline subcutaneously (s.c.) in the volume of 8 µl/g at 2–10th postnatal days. 2group – newborns rats of MSG-group received a solution of MSG (4,0 mg/g of body weight) s.c. at 2–10th postnatal days. 3 group – rats received aqueous solution of melanin in dose 1 mg/kg at volume 2,5 ml/kg per os (p.o.). Melanin was obtained from yeast-like fungi Nadsoniellanigra X1 strain from Ukrainian Antarctic station. Melanin administration was started at the age of 4 weeks just after wean and continued for 3 months intermittently alternating two- week course of introduction with two-week course of break. Within 4 months after birth, rats had a normal diet. Pancreas tissue was fixed in 10 % formalin, dehydrated and imbedded in paraffin wax. Paraffin sections of 5μm were cut and stained with hematoxylin and eosin. As low-grade inflammation is one of the leading mechanisms of pancreas lesion in obesity, the proinflammatory activation of pancreas cells was analyzed by immunohistochemical assessment of CD68 cells, NF-kB and TNF-α expression. The injection of glutamate sodium causes the development of obesity with an increase in the amount of visceral fat, an increase in the number of proinflammatory macrophages in it and an increase in the expression of NF-kB and TNFα. In the pancreas, there is a hyperplasia of the insular apparatus, associated with macrophage infiltration and an increase in the expression of COX-2. The introduction of melanin prevented the morphogenesis of the pancreas in animals from glutamate-induced obesity, leveling the activation of proinflammatory signaling paths.

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Regulation of pancreatic β-cell function and mass dynamics by prostaglandin signaling

Cited by 31 publications

References 94 publications

Discovery of ciliary G protein-coupled receptors regulating pancreatic islet insulin and glucagon secretion

Discovery of ciliary G protein-coupled receptors regulating pancreatic islet insulin and glucagon secretion

EP3 signaling is decoupled from regulation of glucose-stimulated insulin secretion in β-cells compensating for obesity and insulin resistance

Morphogenesis of pancreas under the conditions of glutamate-induced obesity: mechanisms of correction effect of melanin

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