scholarly journals Acute D-Serine Co-Agonism of β-Cell NMDA Receptors Potentiates Glucose-Stimulated Insulin Secretion and Excitatory β-Cell Membrane Activity

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 93
Author(s):  
Amber Lockridge ◽  
Eric Gustafson ◽  
Alicia Wong ◽  
Robert F. Miller ◽  
Emilyn U. Alejandro
Keyword(s):  
Insulin Secretion ◽  
Cell Membrane ◽  
Cell Function ◽  
Acute Effect ◽  
Β Cell ◽  
In Vivo Models ◽  
Β Cell Function ◽  
Glucose Stimulated Insulin Secretion

Insulin-secreting pancreatic β-cells express proteins characteristic of D-serine regulated synapses, but the acute effect of D-serine co-agonism on its presumptive β-cell target, N-methyl D-aspartate receptors (NMDARs), is unclear. We used multiple models to evaluate glucose homeostasis and insulin secretion in mice with a systemic increase in D-serine (intraperitoneal injection or DAAO mutants without D-serine catabolism) or tissue-specific loss of Grin1-encoded GluN1, the D-serine binding NMDAR subunit. We also investigated the effects of D-serine ± NMDA on glucose-stimulated insulin secretion (GSIS) and β-cell depolarizing membrane oscillations, using perforated patch electrophysiology, in β-cell-containing primary isolated mouse islets. In vivo models of elevated D-serine correlated to improved blood glucose and insulin levels. In vitro, D-serine potentiated GSIS and β-cell membrane excitation, dependent on NMDAR activating conditions including GluN1 expression (co-agonist target), simultaneous NMDA (agonist), and elevated glucose (depolarization). Pancreatic GluN1-loss females were glucose intolerant and GSIS was depressed in islets from younger, but not older, βGrin1 KO mice. Thus, D-serine is capable of acute antidiabetic effects in mice and potentiates insulin secretion through excitatory β-cell NMDAR co-agonism but strain-dependent shifts in potency and age/sex-specific Grin1-loss phenotypes suggest that context is critical to the interpretation of data on the role of D-serine and NMDARs in β-cell function.

scholarly journals In vivo imaging of β-cell function reveals glucose-mediated heterogeneity of β-cell functional development

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Jia Zhao ◽  
Weijian Zong ◽  
Yiwen Zhao ◽  
Dongzhou Gou ◽  
Shenghui Liang ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
In Vivo Imaging ◽  
Cell Function ◽  
Β Cells ◽  
Β Cell ◽  
Functional Development ◽  
Β Cell Function ◽  
Glucose Stimulated Insulin Secretion

How pancreatic β-cells acquire function in vivo is a long-standing mystery due to the lack of technology to visualize β-cell function in living animals. Here, we applied a high-resolution two-photon light-sheet microscope for the first in vivo imaging of Ca2+activity of every β-cell in Tg (ins:Rcamp1.07) zebrafish. We reveal that the heterogeneity of β-cell functional development in vivo occurred as two waves propagating from the islet mantle to the core, coordinated by islet vascularization. Increasing amounts of glucose induced functional acquisition and enhancement of β-cells via activating calcineurin/nuclear factor of activated T-cells (NFAT) signaling. Conserved in mammalians, calcineurin/NFAT prompted high-glucose-stimulated insulin secretion of neonatal mouse islets cultured in vitro. However, the reduction in low-glucose-stimulated insulin secretion was dependent on optimal glucose but independent of calcineurin/NFAT. Thus, combination of optimal glucose and calcineurin activation represents a previously unexplored strategy for promoting functional maturation of stem cell-derived β-like cells in vitro.

scholarly journals The HDAC Inhibitor Butyrate Impairs β Cell Function and Activates the Disallowed Gene Hexokinase I

2021 ◽  
Vol 22 (24) ◽  
pp. 13330
Author(s):  
Stephanie Bridgeman ◽  
Gaewyn Ellison ◽  
Philip Newsholme ◽  
Cyril Mamotte
Keyword(s):  
Insulin Secretion ◽  
Low Dose ◽  
Cell Function ◽  
High Dose ◽  
Hdac Inhibition ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function

Histone deacetylase (HDAC) inhibitors such as butyrate have been reported to reduce diabetes risk and protect insulin-secreting pancreatic β cells in animal models. However, studies on insulin-secreting cells in vitro have found that butyrate treatment resulted in impaired or inappropriate insulin secretion. Our study explores the effects of butyrate on insulin secretion by BRIN BD-11 rat pancreatic β cells and examined effects on the expression of genes implicated in β cell function. Robust HDAC inhibition with 5 mM butyrate or trichostatin A for 24 h in β cells decreased basal insulin secretion and content, as well as insulin secretion in response to acute stimulation. Treatment with butyrate also increased expression of the disallowed gene hexokinase I, possibly explaining the impairment to insulin secretion, and of TXNIP, which may increase oxidative stress and β cell apoptosis. In contrast to robust HDAC inhibition (>70% after 24 h), low-dose and acute high-dose treatment with butyrate enhanced nutrient-stimulated insulin secretion. In conclusion, although protective effects of HDAC inhibition have been observed in vivo, potent HDAC inhibition impairs β cell function in vitro. The chronic low dose and acute high dose butyrate treatments may be more reflective of in vivo effects.

The Possible Potency of Ocimum basilicum New Constituent on Glucosestimulated Insulin Secretion In Vitro and β-cell Function In Vivo

2018 ◽  
Vol 15 (9) ◽  
pp. 969-978
Author(s):  
Huma Aslam Bhatti ◽  
Kiran Maryam ◽  
Rizwana S. Waraich ◽  
Abdul Hameed ◽  
Rahman M. Hafizur
Keyword(s):  
Insulin Secretion ◽  
Cell Function ◽  
Ocimum Basilicum ◽  
Β Cell ◽  
Β Cell Function ◽  
Insulin Secretion In Vitro

scholarly journals Inhibition of Small Maf Function in Pancreatic β-Cells Improves Glucose Tolerance Through the Enhancement of Insulin Gene Transcription and Insulin Secretion

Endocrinology ◽  
2015 ◽  
Vol 156 (10) ◽  
pp. 3570-3580 ◽  
Author(s):  
Hiroshi Nomoto ◽  
Takuma Kondo ◽  
Hideaki Miyoshi ◽  
Akinobu Nakamura ◽  
Yoko Hida ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Tolerance ◽  
High Fat Diet ◽  
Cell Function ◽  
High Fat ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function

The large-Maf transcription factor v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA) has been found to be crucial for insulin transcription and synthesis and for pancreatic β-cell function and maturation. However, insights about the effects of small Maf factors on β-cells are limited. Our goal was to elucidate the function of small-Maf factors on β-cells using an animal model of endogenous small-Maf dysfunction. Transgenic (Tg) mice with β-cell-specific expression of dominant-negative MafK (DN-MafK) experiments, which can suppress the function of all endogenous small-Mafs, were fed a high-fat diet, and their in vivo phenotypes were evaluated. Phenotypic analysis, glucose tolerance tests, morphologic examination of β-cells, and islet experiments were performed. DN-MafK-expressed MIN6 cells were also used for in vitro analysis. The results showed that DN-MafK expression inhibited endogenous small-Maf binding to insulin promoter while increasing MafA binding. DN-MafK Tg mice under high-fat diet conditions showed improved glucose metabolism compared with control mice via incremental insulin secretion, without causing changes in insulin sensitivity or MafA expression. Moreover, up-regulation of insulin and glucokinase gene expression was observed both in vivo and in vitro under DN-MafK expression. We concluded that endogenous small-Maf factors negatively regulates β-cell function by competing for MafA binding, and thus, the inhibition of small-Maf activity can improve β-cell function.

Lipid-induced pancreatic β-cell dysfunction: focus on in vivo studies

2011 ◽  
Vol 300 (2) ◽  
pp. E255-E262 ◽  
Author(s):  
Adria Giacca ◽  
Changting Xiao ◽  
Andrei I. Oprescu ◽  
Andre C. Carpentier ◽  
Gary F. Lewis
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Cell Function ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Β Cell Function

The phenomenon of lipid-induced pancreatic β-cell dysfunction (“lipotoxicity”) has been very well documented in numerous in vitro experimental systems and has become widely accepted. In vivo demonstration of β-cell lipotoxicity, on the other hand, has not been consistently demonstrated, and there remains a lack of consensus regarding the in vivo effects of chronically elevated free fatty acids (FFA) on β-cell function. Much of the disagreement relates to how insulin secretion is quantified in vivo and in particular whether insulin secretion is assessed in relation to whole body insulin sensitivity, which is clearly reduced by elevated FFA. By correcting for changes in in vivo insulin sensitivity, we and others have shown that prolonged elevation of FFA impairs β-cell secretory function. Prediabetic animal models and humans with a positive family history of type 2 diabetes are more susceptible to this impairment, whereas those with severe impairment of β-cell function (such as individuals with type 2 diabetes) demonstrate no additional impairment of β-cell function when FFA are experimentally raised. Glucolipotoxicity (i.e., the combined β-cell toxicity of elevated glucose and FFA) has been amply demonstrated in vitro and in some animal studies but not in humans, perhaps because there are limitations in experimentally raising plasma glucose to sufficiently high levels for prolonged periods of time. We and others have shown that therapies directed toward diminishing oxidative stress and ER stress have the potential to reduce lipid-induced β-cell dysfunction in animals and humans. In conclusion, lipid-induced pancreatic β-cell dysfunction is likely to be one contributor to the complex array of genetic and metabolic insults that result in the relentless decline in pancreatic β-cell function in those destined to develop type 2 diabetes, and mechanisms involved in this lipotoxicity are promising therapeutic targets.

scholarly journals In Vitro Studies to Assess the α-Glucosidase Inhibitory Activity and Insulin Secretion Effect of Isorhamnetin 3-O-Glucoside and Quercetin 3-O-Glucoside Isolated from Salicornia herbacea

Processes ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 483
Author(s):  
Dahae Lee ◽  
Jun Yeon Park ◽  
Sanghyun Lee ◽  
Ki Sung Kang
Keyword(s):  
Insulin Secretion ◽  
Cell Function ◽  
Ethanolic Extract ◽  
Ethyl Acetate Fraction ◽  
Gradient Elution ◽  
Glucosidase Activity ◽  
Β Cell Function ◽  
Glucose Stimulated Insulin Secretion ◽  
Salicornia Herbacea

In this study, we examined the effect of ethanolic extract of Salicornia herbacea (ESH), isorhamnetin 3-O-glucoside (I3G), quercetin 3-O-glucoside (Q3G), quercetin, and isorhamnetin on α-glucosidase activity and glucose-stimulated insulin secretion (GSIS) in insulin-secreting rat insulinoma (INS-1) cells. A portion of the ethyl acetate fraction of ESH was chromatographed on a silica gel by a gradient elution with chloroform and methanol to provide Q3G and I3G. ESH, Q3G, and quercetin inhibited α-glucosidase activity, and quercetin (IC50 value was 29.47 ± 3.36 μM) inhibited the activity more effectively than Q3G. We further demonstrated that ESH, Q3G, quercetin, I3G, and isorhamnetin promote GSIS in INS-1 pancreatic β-cells without inducing cytotoxicity. Among them, I3G was the most effective in enhancing GSIS. I3G enhanced the phosphorylation of total extracellular signal-regulated kinase (ERK), insulin receptor substrate-2 (IRS-2), phosphatidylinositol 3-kinase (PI3K), Akt, and activated pancreatic and duodenal homeobox-1 (PDX-1), which are associated with insulin secretion and β-cell function. As components of ESH, Q3G has the potential to regulate blood glucose by inhibiting α-glucosidase activity, and I3G enhances the insulin secretion, but its bioavailability should be considered in determining biological importance.

scholarly journals Bioactive Phytochemicals Isolated from Akebia quinata Enhances Glucose-Stimulated Insulin Secretion by Inducing PDX-1

Plants ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 1087
Author(s):  
Dahae Lee ◽  
Jin Su Lee ◽  
Jurdas Sezirahiga ◽  
Hak Cheol Kwon ◽  
Dae Sik Jang ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Cell Function ◽  
Experimental Studies ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Etoh Extract ◽  
Chemical Structures ◽  
Β Cell Function ◽  
Glucose Stimulated Insulin Secretion ◽  
Phosphoinositide 3 Kinase

Chocolate vine (Akebia quinata) is consumed as a fruit and is also used in traditional medicine. In order to identify the bioactive components of A. quinata, a phytosterol glucoside stigmasterol-3-O-β-d-glucoside (1), three triterpenoids maslinic acid (2), scutellaric acid (3), and hederagenin (4), and three triterpenoidal saponins akebia saponin PA (5), hederacoside C (6), and hederacolchiside F (7) were isolated from a 70% EtOH extract of the fruits of A. quinata (AKQU). The chemical structures of isolates 1–7 were determined by analyzing the 1D and 2D nuclear magnetic resonance (NMR) spectroscopic data. Here, we evaluated the effects of AKQU and compounds 1–7 on insulin secretion using the INS-1 rat pancreatic β-cell line. Glucose-stimulated insulin secretion (GSIS) was evaluated in INS-1 cells using the GSIS assay. The expression levels of the proteins related to pancreatic β-cell function were detected by Western blotting. Among the isolates, stigmasterol-3-O-β-d-glucoside (1) exhibited strong GSIS activity and triggered the overexpression of pancreas/duodenum homeobox protein-1 (PDX-1), which is implicated in the regulation of pancreatic β-cell survival and function. Moreover, isolate 1 markedly induced the expression of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), insulin receptor substrate-2 (IRS-2), phosphoinositide 3-kinase (PI3K), and Akt, which regulate the transcription of PDX-1. The results of our experimental studies indicated that stigmasterol-3-O-β-d-glucoside (1) isolated from the fruits of A. quinata can potentially enhance insulin secretion, and might alleviate the reduction in GSIS during the development of T2DM.

scholarly journals Rice Bran Phenolic Extracts Modulate Insulin Secretion and Gene Expression Associated with β-Cell Function

Nutrients ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1889 ◽  
Author(s):  
Nancy Saji ◽  
Nidhish Francis ◽  
Lachlan J. Schwarz ◽  
Christopher L. Blanchard ◽  
Abishek B. Santhakumar
Keyword(s):  
Insulin Secretion ◽  
Rice Bran ◽  
Cell Function ◽  
Β Cell ◽  
Free Radical Damage ◽  
Glucose Transporter 2 ◽  
Expression Of Genes ◽  
Β Cell Function ◽  
Glucose Stimulated Insulin Secretion ◽  
Phenolic Extracts

Oxidative stress is known to modulate insulin secretion and initiate gene alterations resulting in impairment of β-cell function and type 2 diabetes mellitus (T2DM). Rice bran (RB) phenolic extracts contain bioactive properties that may target metabolic pathways associated with the pathogenesis of T2DM. This study aimed to examine the effect of stabilized RB phenolic extracts on the expression of genes associated with β-cell function such as glucose transporter 2 (Glut2), pancreatic and duodenal homeobox 1 (Pdx1), sirtuin 1 (Sirt1), mitochondrial transcription factor A (Tfam), and insulin 1 (Ins1) in addition to evaluating its impact on glucose-stimulated insulin secretion. It was observed that treatment with different concentrations of RB phenolic extracts (25-250 µg/mL) significantly increased the expression of Glut2, Pdx1, Sirt1, Tfam, and Ins1 genes and glucose-stimulated insulin secretion under both normal and high glucose conditions. RB phenolic extracts favourably modulated the expression of genes involved in β-cell dysfunction and insulin secretion via several mechanisms such as synergistic action of polyphenols targeting signalling molecules, decreasing free radical damage by its antioxidant activity, and stimulation of effectors or survival factors of insulin secretion.

scholarly journals Protein restriction in early life is associated with changes in insulin sensitivity and pancreatic β-cell function during pregnancy

2012 ◽  
Vol 109 (2) ◽  
pp. 236-247 ◽  
Author(s):  
Letícia Martins Ignácio-Souza ◽  
Sílvia Regina Reis ◽  
Vanessa Cristina Arantes ◽  
Bárbara Laet Botosso ◽  
Roberto Vilela Veloso ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Protein Kinase ◽  
Early Life ◽  
Cell Function ◽  
Secretory Process ◽  
Insulin Biosynthesis ◽  
Β Cell ◽  
Pregnant Rats ◽  
Β Cell Function ◽  
Glucose Stimulated Insulin Secretion

Malnutrition in early life impairs glucose-stimulated insulin secretion in adulthood. Conversely, pregnancy is associated with a significant increase in glucose-stimulated insulin secretion under conditions of normoglycaemia. A failure in β-cell adaptive changes may contribute to the onset of diabetes. Thus, glucose homeostasis and β-cell function were evaluated in control-fed pregnant (CP) and non-pregnant (CNP) or protein-restricted pregnant (LPP) and non-pregnant (LPNP) rats, from fetal to adult life, and in protein-restricted rats that were recovered after weaning (RP and RNP). The typical insulin resistance of pregnancy was not observed in the RP rats, nor did pregnancy increase the insulin content/islet in the LPP group. The glucose dose–response curves from pregnant rats were shifted to the left in relation to the non-pregnant rats, except in the recovered group. Glucose utilisation but not oxidation in islets from the RP and LPP groups was reduced at a concentration of 8·3 mm-glucose compared with islets from the CP group. Cyclic AMP content and the potentiation of glucose-stimulated insulin secretion by isobutylmethylxanthine at a concentration of 2·8 mm-glucose indicated increased adenylyl cyclase 3 activity but reduced protein kinase A-α activity in islets from the RP and LPP rats. Protein kinase C (PKC)-α but not phospholipase C (PLC)-β1 expression was reduced in islets from the RP group. Phorbol-12-myristate 13-acetate produced a less potent stimulation of glucose-stimulated insulin secretion in the RP group. Thus, the alterations exhibited by islets from the LPP group appeared to be due to reduced islet mass and/or insulin biosynthesis. In the RP group the loss of the adaptive capacity apparently resulted from uncoupling between glucose metabolism and the amplifying signals of the secretory process, as well as a severe attenuation of the PLC/PKC pathway.

scholarly journals Spontaneous restoration of functional β-cell mass in obese SM/J mice

2020 ◽  
Author(s):  
Mario A Miranda ◽  
Caryn Carson ◽  
Celine L St Pierre ◽  
Juan F Macias-Velasco ◽  
Jing W Hughes ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Mitotic Index ◽  
Cell Function ◽  
Cell Mass ◽  
Β Cell ◽  
Physiological Mechanisms ◽  
Β Cell Function ◽  
Basal Insulin Secretion ◽  
Glucose Stimulated Insulin Secretion ◽  
Mass Expansion

AbstractMaintenance of functional β-cell mass is critical to preventing diabetes, but the physiological mechanisms that cause β-cell populations to thrive or fail in the context of obesity are unknown. High fat-fed SM/J mice spontaneously transition from hyperglycemic-obese to normoglycemic-obese with age, providing a unique opportunity to study β-cell adaptation. Here, we characterize insulin homeostasis, islet morphology, and β-cell function during SM/J’s diabetic remission. As they resolve hyperglycemia, obese SM/J mice dramatically increase circulating and pancreatic insulin levels while improving insulin sensitivity. Immunostaining of pancreatic sections reveals that obese SM/J mice selectively increase β-cell mass but not α-cell mass. Obese SM/J mice do not show elevated β-cell mitotic index, but rather elevated α-cell mitotic index. Functional assessment of isolated islets reveals that obese SM/J mice increase glucose stimulated insulin secretion, decrease basal insulin secretion, and increase islet insulin content. These results establish that β-cell mass expansion and improved β-cell function underlie the resolution of hyperglycemia, indicating that obese SM/J mice are a valuable tool for exploring how functional β-cell mass can be recovered in the context of obesity.

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