Saturated and unsaturated (including arachidonic acid) non-esterified fatty acid modulation of insulin secretion from pancreatic β-cells

2008 ◽  
Vol 36 (5) ◽  
pp. 955-958 ◽  
Author(s):  
Deirdre Keane ◽  
Philip Newsholme
Keyword(s):  
Arachidonic Acid ◽  
Insulin Secretion ◽  
Fatty Acid ◽  
Insulin Release ◽  
Chronic Exposure ◽  
Cell Metabolism ◽  
Protective Effects ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells

Both stimulatory and detrimental effects of NEFAs (non-esterified fatty acids) on pancreatic β-cells have been recognized. Acute exposure of the pancreatic β-cell to high glucose concentrations and/or saturated NEFAs results in a substantial increase in insulin release, whereas chronic exposure results in desensitization and suppression of secretion followed by induction of apoptosis. Some unsaturated NEFAs also promote insulin release acutely, but they are less toxic to β-cells during chronic exposure and can even exert positive protective effects. In the present review, we focus on exogenous and endogenous effects of NEFAs, including the polyunsaturated fatty acid, arachidonic acid (or its metabolites generated from cyclo-oxygenase activity), on β-cell metabolism, and have explored the outcomes with respect to β-cell insulin secretion.

Arachidonic acid fights palmitate: new insights into fatty acid toxicity in β-cells

2010 ◽  
Vol 120 (5) ◽  
pp. 179-181 ◽  
Author(s):  
Henrik Ortsäter
Keyword(s):  
Type 2 Diabetes ◽  
Arachidonic Acid ◽  
Fatty Acid ◽  
Saturated Fatty Acids ◽  
Cell Mass ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Self Protection

Saturated fatty acids are toxic to pancreatic β-cells. By inducing apoptosis, they contribute to a decrease in β-cell mass, a hallmark of Type 2 diabetes. In the present issue of Clinical Science, Keane and co-workers show that the polyunsaturated fatty acid arachidonic acid protects the β-cell against the toxic effects of palmitate. As Type 2 diabetes is characterized by subclinical inflammation, and arachidonic acid and metabolites thereof are produced during states of inflammation, it is possible that pancreatic β-cells use arachidonic acid as a compound for self-protection.

scholarly journals Hypoxylonol F Isolated from Annulohypoxylon annulatum Improves Insulin Secretion by Regulating Pancreatic β-cell Metabolism

Biomolecules ◽  
2019 ◽  
Vol 9 (8) ◽  
pp. 335 ◽  
Author(s):  
Dahae Lee ◽  
Buyng Su Hwang ◽  
Pilju Choi ◽  
Taejung Kim ◽  
Youngseok Kim ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Molecular Mechanisms ◽  
Cell Metabolism ◽  
Peroxisome Proliferator ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Peroxisome Proliferator Activated Receptor ◽  
Glucose Stimulated Insulin Secretion

Insulin plays a key role in glucose homeostasis and is hence used to treat hyperglycemia, the main characteristic of diabetes mellitus. Annulohypoxylon annulatum is an inedible ball-shaped wood-rotting fungus, and hypoxylon F is one of the major compounds of A. annulatum. The aim of this study is to evaluate the effects of hypoxylonol F isolated from A. annulatum on insulin secretion in INS-1 pancreatic β-cells and demonstrate the molecular mechanisms involved. Glucose-stimulated insulin secretion (GSIS) values were evaluated using a rat insulin ELISA kit. Moreover, the expression of proteins related to pancreatic β-cell metabolism and insulin secretion was evaluated using Western blotting. Hypoxylonol F isolated from A. annulatum was found to significantly enhance glucose-stimulated insulin secretion without inducing cytotoxicity. Additionally, hypoxylonol F enhanced insulin receptor substrate-2 (IRS-2) levels and activated the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway. Interestingly, it also modulated the expression of peroxisome proliferator-activated receptor γ (PPARγ) and pancreatic and duodenal homeobox 1 (PDX-1). Our findings showed that A. annulatum and its bioactive compounds are capable of improving insulin secretion by pancreatic β-cells. This suggests that A. annulatum can be used as a therapeutic agent to treat diabetes.

scholarly journals Fatty Acid and Lipopolysaccharide Effect on Beta Cells Proteostasis and its Impact on Insulin Secretion

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 884 ◽  
Author(s):  
Paloma Acosta-Montaño ◽  
Eustolia Rodríguez-Velázquez ◽  
Esmeralda Ibarra-López ◽  
Héctor Frayde-Gómez ◽  
Jaime Mas-Oliva ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Endoplasmic Reticulum ◽  
Insulin Secretion ◽  
Fatty Acid ◽  
Cell Viability ◽  
Insulin Release ◽  
Palmitoleic Acid ◽  
Cell Mass ◽  
Β Cells ◽  
Β Cell

Metabolic overload by saturated fatty acids (SFA), which comprises β-cell function, and impaired glucose-stimulated insulin secretion are frequently observed in patients suffering from obesity and type 2 diabetes mellitus. The increase of intracellular Ca2+ triggers insulin granule release, therefore several mechanisms regulate Ca2+ efflux within the β-cells, among others, the plasma membrane Ca2+-ATPase (PMCA). In this work, we describe that lipotoxicity mediated mainly by the saturated palmitic acid (PA) (16C) is associated with loss of protein homeostasis (proteostasis) and potentially cell viability, a phenomenon that was induced to a lesser extent by stearic (18C), myristic (14C) and lauric (12C) acids. PA was localized on endoplasmic reticulum, activating arms of the unfolded protein response (UPR), as also promoted by lipopolysaccharides (LPS)-endotoxins. In particular, our findings demonstrate an alteration in PMCA1/4 expression caused by PA and LPS which trigger the UPR, affecting not only insulin release and contributing to β-cell mass reduction, but also increasing reactive nitrogen species. Nonetheless, stearic acid (SA) did not show these effects. Remarkably, the proteolytic degradation of PMCA1/4 prompted by PA and LPS was avoided by the action of monounsaturated fatty acids such as oleic and palmitoleic acid. Oleic acid recovered cell viability after treatment with PA/LPS and, more interestingly, relieved endoplasmic reticulum (ER) stress. While palmitoleic acid improved the insulin release, this fatty acid seems to have more relevant effects upon the expression of regulatory pumps of intracellular Ca2+. Therefore, chain length and unsaturation of fatty acids are determinant cues in proteostasis of β-cells and, consequently, on the regulation of calcium and insulin secretion.

scholarly journals Identification and Isolation of Active Compounds from Astragalus membranaceus that Improve Insulin Secretion by Regulating Pancreatic β-Cell Metabolism

Biomolecules ◽  
2019 ◽  
Vol 9 (10) ◽  
pp. 618 ◽  
Author(s):  
Dahae Lee ◽  
Da Lee ◽  
Sungyoul Choi ◽  
Jin Lee ◽  
Dae Jang ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Cell Function ◽  
Cell Metabolism ◽  
Astragalus Membranaceus ◽  
Peroxisome Proliferator ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Peroxisome Proliferator Activated Receptor ◽  
High Blood Glucose

In type 2 diabetes (T2D), insufficient secretion of insulin from the pancreatic β-cells contributes to high blood glucose levels, associated with metabolic dysregulation. Interest in natural products to complement or replace existing antidiabetic medications has increased. In this study, we examined the effect of Astragalus membranaceus extract (ASME) and its compounds 1–9 on glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. ASME and compounds 1–9 isolated from A. membranaceus stimulated insulin secretion in INS-1 cells without inducing cytotoxicity. A further experiment showed that compounds 2, 3, and 5 enhanced the phosphorylation of total insulin receptor substrate-2 (IRS-2), phosphatidylinositol 3-kinase (PI3K), and Akt, and activated pancreatic and duodenal homeobox-1 (PDX-1) and peroxisome proliferator-activated receptor-γ (PPAR-γ), which are associated with β-cell function and insulin secretion. The data suggest that two isoflavonoids (2 and 3) and a nucleoside (compound 5), isolated from the roots of A. membranaceus, have the potential to improve insulin secretion in β-cells, representing the first step towards the development of potent antidiabetic drugs.

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

2021 ◽  
Vol 12 (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.

scholarly journals Nitric oxide interacts with cholinoceptors to modulate insulin secretion by pancreatic β cells

2020 ◽  
Vol 472 (10) ◽  
pp. 1469-1480
Author(s):  
Bashair M. Mussa ◽  
Ankita Srivastava ◽  
Abdul Khader Mohammed ◽  
Anthony J. M. Verberne
Keyword(s):  
Nitric Oxide ◽  
Insulin Secretion ◽  
Cell Viability ◽  
Combined Treatment ◽  
No Production ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Tnf Α ◽  
Ifn Γ

Abstract Dysfunction of the pancreatic β cells leads to several chronic disorders including diabetes mellitus. Several mediators and mechanisms are known to be involved in the regulation of β cell secretory function. In this study, we propose that cytokine-induced nitric oxide (NO) production interacts with cholinergic mechanisms to modulate insulin secretion from pancreatic β cells. Using a rat insulinoma cell line INS-1, we demonstrated that β cell viability decreases significantly in the presence of SNAP (NO donor) in a concentration- and time-dependent manner. Cell viability was also found to be decreased in the presence of a combined treatment of SNAP with SMN (muscarinic receptor antagonist). We then investigated the impact of these findings on insulin secretion and found a significant reduction in glucose uptake by INS-1 cells in the presence of SNAP and SMN as compared with control. Nitric oxide synthase 3 gene expression was found to be significantly reduced in response to combined treatment with SNAP and SMN suggesting an interaction between the cholinergic and nitrergic systems. The analysis of gene and protein expression further pin-pointed the involvement of M3 muscarinic receptors in the cholinergic pathway. Upon treatment with cytokines, reduced cell viability was observed in the presence of TNF-α and IFN-γ. A significant reduction in insulin secretion was also noted after treatment with TNF-α and IFN-γ and IL1-β. The findings of the present study have shown for the first time that the inhibition of the excitatory effects of cholinergic pathways on glucose-induced insulin secretion may cause β cell injury and dysfunction of insulin secretion in response to cytokine-induced NO production.

Tolbutamide and diazoxide modulate phospholipase C-linked Ca2+ signaling and insulin secretion in β-cells

2000 ◽  
Vol 278 (4) ◽  
pp. E639-E647 ◽  
Author(s):  
Christof Schöfl ◽  
Julia Börger ◽  
Thilo Mader ◽  
Mark Waring ◽  
Alexander von zur Mühlen ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Phospholipase C ◽  
Insulin Release ◽  
Arginine Vasopressin ◽  
Bay K 8644 ◽  
Free Medium ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Activating Receptors

Arginine vasopressin (AVP), bombesin, and ACh increase cytosolic free Ca2+ and potentiate glucose-induced insulin release by activating receptors linked to phospholipase C (PLC). We examined whether tolbutamide and diazoxide, which close or open ATP-sensitive K+ channels (KATP channels), respectively, interact with PLC-linked Ca2+ signals in HIT-T15 and mouse β-cells and with PLC-linked insulin secretion from HIT-T15 cells. In the presence of glucose, the PLC-linked Ca2+ signals were enhanced by tolbutamide (3–300 μM) and inhibited by diazoxide (10–100 μM). The effects of tolbutamide and diazoxide on PLC-linked Ca2+ signaling were mimicked by BAY K 8644 and nifedipine, an activator and inhibitor of L-type voltage-sensitive Ca2+channels, respectively. Neither tolbutamide nor diazoxide affected PLC-linked mobilization of internal Ca2+ or store-operated Ca2+ influx through non-L-type Ca2+ channels. In the absence of glucose, PLC-linked Ca2+ signals were diminished or abolished; this effect could be partly antagonized by tolbutamide. In the presence of glucose, tolbutamide potentiated and diazoxide inhibited AVP- or bombesin-induced insulin secretion from HIT-T15 cells. Nifedipine (10 μM) blocked both the potentiating and inhibitory actions of tolbutamide and diazoxide on AVP-induced insulin release, respectively. In glucose-free medium, AVP-induced insulin release was reduced but was again potentiated by tolbutamide, whereas diazoxide caused no further inhibition. Thus tolbutamide and diazoxide regulate both PLC-linked Ca2+signaling and insulin secretion from pancreatic β-cells by modulating KATP channels, thereby determining voltage-sensitive Ca2+ influx.

scholarly journals L-Arginine prevents cereblon-mediated ubiquitination of glucokinase and stimulates glucose-6-phosphate production in pancreatic β-cells

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Jaeyong Cho ◽  
Yukio Horikawa ◽  
Mayumi Enya ◽  
Jun Takeda ◽  
Yoichi Imai ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Direct Stimulation ◽  
Glucose Ratio ◽  
Glucose Stimulated Insulin Secretion

Abstract We sought to determine a mechanism by which L-arginine increases glucose-stimulated insulin secretion (GSIS) in β-cells by finding a protein with affinity to L-arginine using arginine-immobilized magnetic nanobeads technology. Glucokinase (GCK), the key regulator of GSIS and a disease-causing gene of maturity-onset diabetes of the young type 2 (MODY2), was found to bind L-arginine. L-Arginine stimulated production of glucose-6-phosphate (G6P) and induced insulin secretion. We analyzed glucokinase mutants and identified three glutamate residues that mediate binding to L-arginine. One MODY2 patient with GCKE442* demonstrated lower C-peptide-to-glucose ratio after arginine administration. In β-cell line, GCKE442* reduced L-arginine-induced insulin secretion compared with GCKWT. In addition, we elucidated that the binding of arginine protects glucokinase from degradation by E3 ubiquitin ligase cereblon mediated ubiquitination. We conclude that L-arginine induces insulin secretion by increasing G6P production by glucokinase through direct stimulation and by prevention of degradation.

scholarly journals The adaptor protein APPL2 controls glucose-stimulated insulin secretion via F-actin remodeling in pancreatic β-cells

2020 ◽  
Vol 117 (45) ◽  
pp. 28307-28315
Author(s):  
Baile Wang ◽  
Huige Lin ◽  
Xiaomu Li ◽  
Wenqi Lu ◽  
Jae Bum Kim ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Adaptor Protein ◽  
Hek293 Cells ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Actin Remodeling ◽  
Actin Depolymerization ◽  
Glucose Stimulated Insulin Secretion

Filamentous actin (F-actin) cytoskeletal remodeling is critical for glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells, and its dysregulation causes type 2 diabetes. The adaptor protein APPL1 promotes first-phase GSIS by up-regulating solubleN-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein expression. However, whether APPL2 (a close homology of APPL1 with the same domain organization) plays a role in β-cell functions is unknown. Here, we show that APPL2 enhances GSIS by promoting F-actin remodeling via the small GTPase Rac1 in pancreatic β-cells. β-cell specific abrogation of APPL2 impaired GSIS, leading to glucose intolerance in mice. APPL2 deficiency largely abolished glucose-induced first- and second-phase insulin secretion in pancreatic islets. Real-time live-cell imaging and phalloidin staining revealed that APPL2 deficiency abolished glucose-induced F-actin depolymerization in pancreatic islets. Likewise, knockdown of APPL2 expression impaired glucose-stimulated F-actin depolymerization and subsequent insulin secretion in INS-1E cells, which were attributable to the impairment of Ras-related C3 botulinum toxin substrate 1 (Rac1) activation. Treatment with the F-actin depolymerization chemical compounds or overexpression of gelsolin (a F-actin remodeling protein) rescued APPL2 deficiency-induced defective GSIS. In addition, APPL2 interacted with Rac GTPase activating protein 1 (RacGAP1) in a glucose-dependent manner via the bin/amphiphysin/rvs-pleckstrin homology (BAR-PH) domain of APPL2 in INS-1E cells and HEK293 cells. Concomitant knockdown of RacGAP1 expression reverted APPL2 deficiency-induced defective GSIS, F-actin remodeling, and Rac1 activation in INS-1E cells. Our data indicate that APPL2 interacts with RacGAP1 and suppresses its negative action on Rac1 activity and F-actin depolymerization thereby enhancing GSIS in pancreatic β-cells.

Time-resolved metabolomics analysis of β-cells implicates the pentose phosphate pathway in the control of insulin release

2013 ◽  
Vol 450 (3) ◽  
pp. 595-605 ◽  
Author(s):  
Peter Spégel ◽  
Vladimir V. Sharoyko ◽  
Isabel Goehring ◽  
Anders P. H. Danielsson ◽  
Siri Malmgren ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pentose Phosphate Pathway ◽  
Metabolic Response ◽  
Cell Metabolism ◽  
Pentose Phosphate ◽  
Β Cells ◽  
Β Cell ◽  
Time Resolved ◽  
Atp Production ◽  
Rat Islets

Insulin secretion is coupled with changes in β-cell metabolism. To define this process, 195 putative metabolites, mitochondrial respiration, NADP+, NADPH and insulin secretion were measured within 15 min of stimulation of clonal INS-1 832/13 β-cells with glucose. Rapid responses in the major metabolic pathways of glucose occurred, involving several previously suggested metabolic coupling factors. The complexity of metabolite changes observed disagreed with the concept of one single metabolite controlling insulin secretion. The complex alterations in metabolite levels suggest that a coupling signal should reflect large parts of the β-cell metabolic response. This was fulfilled by the NADPH/NADP+ ratio, which was elevated (8-fold; P<0.01) at 6 min after glucose stimulation. The NADPH/NADP+ ratio paralleled an increase in ribose 5-phosphate (>2.5-fold; P<0.001). Inhibition of the pentose phosphate pathway by trans-dehydroepiandrosterone (DHEA) suppressed ribose 5-phosphate levels and production of reduced glutathione, as well as insulin secretion in INS-1 832/13 β-cells and rat islets without affecting ATP production. Metabolite profiling of rat islets confirmed the glucose-induced rise in ribose 5-phosphate, which was prevented by DHEA. These findings implicate the pentose phosphate pathway, and support a role for NADPH and glutathione, in β-cell stimulus-secretion coupling.

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