scholarly journals Molecular mechanisms responsible for the sexual dimorphism in pancreatic β-cell insulin release

2021 ◽  
Vol 154 (9) ◽  
Author(s):  
Noelia Jacobo-Piqueras ◽  
Tamara Theiner ◽  
Stefanie M. Geisler ◽  
Petronel Tuluc
Keyword(s):  
Sexual Dimorphism ◽  
Electrical Activity ◽  
Insulin Release ◽  
Molecular Mechanisms ◽  
Resting Membrane Potential ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Specific Expression ◽  
Extracellular Glucose Concentration

In humans, type 2 diabetes mellitus (T2DM) has a higher incidence in males compared to females, a phenotype recapitulated by many rodent models. While the sex difference in insulin sensitivity partially accounts for this phenomenon, hitherto uncharacterized differences in pancreatic β-cell insulin release strongly contribute. Here, we show that stepwise increase in extracellular glucose concentration (2, 5, 7.5, 10, 15, 20 mM) induced electrical activity in β cells of both sexes with similar glucose sensitivity (female, EC50 = 9.45 ± 0.15 mM; male, EC50 = 9.42 ± 0.16 mM). However, female β cells’ resting membrane potential (RMP) and inter-spike potential (IP) were significantly higher compared to males (e.g., at 15 mM glucose: male RMP = −82.7 ± 6.3, IP = −74.3 ± 6.8 mV; female RMP = −50.0 ± 7.1, IP = −41.2 ± 7.3 mV). Females also showed higher frequency of trains of action potential (AP; at 10 mM glucose: male F = 1.13 ± 0.15 trains/min; female F = 1.78 ± 0.25 trains/min) and longer AP-burst duration (e.g., at 10 mM glucose: male, 241 ± 30.8 ms; female, 419 ± 60.2 ms). The higher RMP in females reduced the voltage-gated calcium channel (CaV) availability by ∼60%. This explains the paradoxical observation that, despite identical CaV expression levels and higher electrical activity, the islet Ca2+ transients were smaller in females compared to males. Interestingly, the different RMPs are not caused by altered KATP, TASK, or TALK K+ currents. However, stromatoxin-1–sensitive KV2.1 K+ current amplitude was almost double in males (IK = 130.93 ± 7.05 pA/pF) compared to females (IK = 75.85 ± 11.3 pA/pF) when measured at +80 mV. Our results are in agreement with previous findings showing that KV2.1 genetic deletion or pharmacological block leads to higher insulin release and β-cell survival. Therefore, we propose the sex-specific expression of KV2.1 to be the mechanism underlying the observed sexual dimorphism in insulin release and the incidence of T2DM.

Life and death decisions of the pancreatic β-cell: the role of fatty acids

2006 ◽  
Vol 112 (1) ◽  
pp. 27-42 ◽  
Author(s):  
Philip Newsholme ◽  
Deirdre Keane ◽  
Hannah J. Welters ◽  
Noel G. Morgan
Keyword(s):  
Fatty Acids ◽  
Insulin Release ◽  
Chronic Exposure ◽  
Cell Function ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Endogenous Fatty Acid ◽  
Gene And Protein Expression ◽  
Β Cell Function

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. Therefore changes in the levels of NEFAs are likely to be important for the regulation of β-cell function and viability under physiological conditions. In addition, the switching between endogenous fatty acid synthesis or oxidation in the β-cell, together with alterations in neutral lipid accumulation, may have critical implications for β-cell function and integrity. Long-chain acyl-CoA (formed from either endogenously synthesized or exogenous fatty acids) controls several aspects of β-cell function, including activation of specific isoenzymes of PKC (protein kinase C), modulation of ion channels, protein acylation, ceramide formation and/or NO-mediated apoptosis, and transcription factor activity. In this review, we describe the effects of exogenous and endogenous fatty acids on β-cell metabolism and gene and protein expression, and have explored the outcomes with respect to insulin secretion and β-cell integrity.

scholarly journals The Hippo kinase LATS2 impairs pancreatic β-cell survival in diabetes through the mTORC1-autophagy axis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ting Yuan ◽  
Karthika Annamalai ◽  
Shruti Naik ◽  
Blaz Lupse ◽  
Shirin Geravandi ◽  
...  
Keyword(s):  
Cell Survival ◽  
Cell Apoptosis ◽  
Molecular Mechanisms ◽  
Cell Mass ◽  
Human Islets ◽  
Hippo Signaling ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Large Tumor

AbstractDiabetes results from a decline in functional pancreatic β-cells, but the molecular mechanisms underlying the pathological β-cell failure are poorly understood. Here we report that large-tumor suppressor 2 (LATS2), a core component of the Hippo signaling pathway, is activated under diabetic conditions and induces β-cell apoptosis and impaired function. LATS2 deficiency in β-cells and primary isolated human islets as well as β-cell specific LATS2 ablation in mice improves β-cell viability, insulin secretion and β-cell mass and ameliorates diabetes development. LATS2 activates mechanistic target of rapamycin complex 1 (mTORC1), a physiological suppressor of autophagy, in β-cells and genetic and pharmacological inhibition of mTORC1 counteracts the pro-apoptotic action of activated LATS2. We further show a direct interplay between Hippo and autophagy, in which LATS2 is an autophagy substrate. On the other hand, LATS2 regulates β-cell apoptosis triggered by impaired autophagy suggesting an existence of a stress-sensitive multicomponent cellular loop coordinating β-cell compensation and survival. Our data reveal an important role for LATS2 in pancreatic β-cell turnover and suggest LATS2 as a potential therapeutic target to improve pancreatic β-cell survival and function in diabetes.

scholarly journals Sfrp5 mediates glucose-induced proliferation in rat pancreatic β-cells

2016 ◽  
Vol 229 (2) ◽  
pp. 73-83 ◽  
Author(s):  
Binbin Guan ◽  
Wenyi Li ◽  
Fengying Li ◽  
Yun Xie ◽  
Qicheng Ni ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Wnt Signaling ◽  
Molecular Mechanisms ◽  
Wnt Signaling Pathway ◽  
Akt Pathway ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Promote Cell Proliferation

The cellular and molecular mechanisms of glucose-stimulated β-cell proliferation are poorly understood. Recently, secreted frizzled-related protein 5 (encoded by Sfrp5; a Wnt signaling inhibitor) has been demonstrated to be involved in β-cell proliferation in obesity. A previous study demonstrated that glucose enhanced Wnt signaling to promote cell proliferation. We hypothesized that inhibition of SFRP5 contributes to glucose-stimulated β-cell proliferation. In this study, we found that the Sfrp5 level was significantly reduced in high glucose-treated INS-1 cells, primary rat β-cells, and islets isolated from glucose-infused rats. Overexpression of SFRP5 diminished glucose-stimulated proliferation in both INS-1 cells and primary β-cells, with a concomitant inhibition of the Wnt signaling pathway and decreased cyclin D2 expression. In addition, we showed that glucose-induced Sfrp5 suppression was modulated by the PI3K/AKT pathway. Therefore, we conclude that glucose inhibits Sfrp5 expression via the PI3K/AKT pathway and hence promotes rat pancreatic β-cell proliferation.

Regulation of pancreatic β-cell electrical activity and insulin release by physiological amino acid concentrations

1997 ◽  
Vol 433 (6) ◽  
pp. 699-704 ◽  
Author(s):  
Sonia Bolea ◽  
Jose A. G. Pertusa ◽  
Franz Martín ◽  
Juan V. Sanchez-Andrés ◽  
B. Soria
Keyword(s):  
Amino Acid ◽  
Electrical Activity ◽  
Insulin Release ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Amino Acid Concentrations

scholarly journals Characterization of Signaling Pathways Associated with Pancreatic β-cell Adaptive Flexibility in Compensation of Obesity-linked Diabetes in db/db Mice

2020 ◽  
Vol 19 (6) ◽  
pp. 971-993 ◽  
Author(s):  
Taewook Kang ◽  
Brandon B. Boland ◽  
Pia Jensen ◽  
Cristina Alarcon ◽  
Arkadiusz Nawrocki ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Cell Function ◽  
Pancreatic Β Cell ◽  
Insulin Production ◽  
Metabolic Demand ◽  
Β Cells ◽  
Β Cell ◽  
Proinsulin Biosynthesis ◽  
Β Cell Function ◽  
Insight Into

The onset of obesity-linked type 2 diabetes (T2D) is marked by an eventual failure in pancreatic β-cell function and mass that is no longer able to compensate for the inherent insulin resistance and increased metabolic load intrinsic to obesity. However, in a commonly used model of T2D, the db/db mouse, β-cells have an inbuilt adaptive flexibility enabling them to effectively adjust insulin production rates relative to the metabolic demand. Pancreatic β-cells from these animals have markedly reduced intracellular insulin stores, yet high rates of (pro)insulin secretion, together with a substantial increase in proinsulin biosynthesis highlighted by expanded rough endoplasmic reticulum and Golgi apparatus. However, when the metabolic overload and/or hyperglycemia is normalized, β-cells from db/db mice quickly restore their insulin stores and normalize secretory function. This demonstrates the β-cell's adaptive flexibility and indicates that therapeutic approaches applied to encourage β-cell rest are capable of restoring endogenous β-cell function. However, mechanisms that regulate β-cell adaptive flexibility are essentially unknown. To gain deeper mechanistic insight into the molecular events underlying β-cell adaptive flexibility in db/db β-cells, we conducted a combined proteomic and post-translational modification specific proteomic (PTMomics) approach on islets from db/db mice and wild-type controls (WT) with or without prior exposure to normal glucose levels. We identified differential modifications of proteins involved in redox homeostasis, protein refolding, K48-linked deubiquitination, mRNA/protein export, focal adhesion, ERK1/2 signaling, and renin-angiotensin-aldosterone signaling, as well as sialyltransferase activity, associated with β-cell adaptive flexibility. These proteins are all related to proinsulin biosynthesis and processing, maturation of insulin secretory granules, and vesicular trafficking—core pathways involved in the adaptation of insulin production to meet metabolic demand. Collectively, this study outlines a novel and comprehensive global PTMome signaling map that highlights important molecular mechanisms related to the adaptive flexibility of β-cell function, providing improved insight into disease pathogenesis of T2D.

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 Mouse and Human Single Pancreatic β Cell Transcriptomics Reveal Sexual Dimorphism of Transcriptomes and Identify Sex-dependent Type 2 Diabetes Altered Genes

2020 ◽  
Author(s):  
Gang Liu ◽  
Yana Li ◽  
Tengjiao Zhang ◽  
Mushan Li ◽  
Sheng Li ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Sex Differences ◽  
Sexual Dimorphism ◽  
Sexually Dimorphic ◽  
Pancreatic Β Cell ◽  
Diabetic Mice ◽  
Β Cells ◽  
Β Cell ◽  
Dependent Type

SummaryType 2 diabetes, characterized by malfunction of pancreatic β cells, is affected by multiple cues including sex differences. Nevertheless, mechanisms of sex differences in type 2 diabetes susceptibility and pathogenesis remain unclear. Using single-cell RNA sequencing (scRNA-seq) technology, we showed that sexual dimorphism of transcriptome exists in both mouse and human β cells, and differs significantly in human under diabetic condition. Our analysis further revealed the existence of sex-dependent type 2 diabetes altered genes in both mice and human beings, suggesting divergences in pathological mechanisms of type 2 diabetes between sexes. Our results indicated that sex should be taken into consideration when treating diabetes, which was further validated by the sex-matched and sex-mismatched islet transplantation in mice. Compared to sex-matched transplants, sex-mismatched transplants showed downregulation of genes involved in the longevity regulating pathway in β cells and led to impaired glucose tolerance in diabetic mice. Taken together, our findings could advance current understanding of type 2 diabetes pathogenesis with sexually dimorphic perspectives and provide new insights to the development of precision medicine.Context and SignificanceAmounting evidence has shown that sex plays a crucial role for glucose homeostasis and onset risk of diabetes. Based on pancreatic β cell transcriptome profiling at single cell resolution, we focused on identifying sexually dimorphic transcriptomes and sex-dependent type 2 diabetes genes in both mouse and human. Given the importance revealed by our study that different pathological mechanisms of type 2 diabetes exist between sexes, sex differences should be taken into consideration for innovative precision medicine when treating diabetes.HighlightsSex-biased gene expression pattern exists in both mouse and human β cells, and differs dramatically under diabetic condition in human.In both human and mouse β cells, abundant sex-dependent type 2 diabetes altered genes are identified.Sex-specific interspecies conservation of type 2 diabetes altered metabolic pathways exists.Sex-matched islet transplantation in diabetic mice yields better control of glucose homeostasis than sex-mismatched transplantation.Graphic Abstract

scholarly journals Enhanced expression of β cell CaV3.1 channels impairs insulin release and glucose homeostasis

2019 ◽  
Vol 117 (1) ◽  
pp. 448-453 ◽  
Author(s):  
Jia Yu ◽  
Yue Shi ◽  
Kaixuan Zhao ◽  
Guang Yang ◽  
Lina Yu ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Release ◽  
Glucose Homeostasis ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Recombinant Adenovirus ◽  
Β Cells ◽  
Β Cell ◽  
Nuclear Retention ◽  
Enhanced Expression

Voltage-gated calcium 3.1 (CaV3.1) channels are absent in healthy mouse β cells and mediate minor T-type Ca2+currents in healthy rat and human β cells but become evident under diabetic conditions. Whether more active CaV3.1 channels affect insulin secretion and glucose homeostasis remains enigmatic. We addressed this question by enhancing de novo expression of β cell CaV3.1 channels and exploring the consequent impacts on dynamic insulin secretion and glucose homeostasis as well as underlying molecular mechanisms with a series of in vitro and in vivo approaches. We now demonstrate that a recombinant adenovirus encoding enhanced green fluorescent protein–CaV3.1 subunit (Ad-EGFP-CaV3.1) efficiently transduced rat and human islets as well as dispersed islet cells. The resulting CaV3.1 channels conducted typical T-type Ca2+currents, leading to an enhanced basal cytosolic-free Ca2+concentration ([Ca2+]i). Ad-EGFP-CaV3.1-transduced islets released significantly less insulin under both the basal and first phases following glucose stimulation and could no longer normalize hyperglycemia in recipient rats rendered diabetic by streptozotocin treatment. Furthermore, Ad-EGFP-CaV3.1 transduction reduced phosphorylated FoxO1 in the cytoplasm of INS-1E cells, elevated FoxO1 nuclear retention, and decreased syntaxin 1A, SNAP-25, and synaptotagmin III. These effects were prevented by inhibiting CaV3.1 channels or the Ca2+-dependent phosphatase calcineurin. Enhanced expression of β cell CaV3.1 channels therefore impairs insulin release and glucose homeostasis by means of initial excessive Ca2+influx, subsequent activation of calcineurin, consequent dephosphorylation and nuclear retention of FoxO1, and eventual FoxO1-mediated down-regulation of β cell exocytotic proteins. The present work thus suggests an elevated expression of CaV3.1 channels plays a significant role in diabetes pathogenesis.

scholarly journals The T1D-associated lncRNA Lnc13 modulates human pancreatic β cell inflammation by allele-specific stabilization of STAT1 mRNA

2020 ◽  
Vol 117 (16) ◽  
pp. 9022-9031 ◽  
Author(s):  
Itziar Gonzalez-Moro ◽  
Ane Olazagoitia-Garmendia ◽  
Maikel L. Colli ◽  
Nadia Cobo-Vuilleumier ◽  
Thomas S. Postler ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Functional Characterization ◽  
Mirror Image ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Polycytidylic Acid ◽  
Specific Manner ◽  
Allele Specific ◽  
The Stability

The vast majority of type 1 diabetes (T1D) genetic association signals lie in noncoding regions of the human genome. Many have been predicted to affect the expression and secondary structure of long noncoding RNAs (lncRNAs), but the contribution of these lncRNAs to the pathogenesis of T1D remains to be clarified. Here, we performed a complete functional characterization of a lncRNA that harbors a single nucleotide polymorphism (SNP) associated with T1D, namely, Lnc13. Human pancreatic islets harboring the T1D-associated SNP risk genotype in Lnc13 (rs917997*CC) showed higher STAT1 expression than islets harboring the heterozygous genotype (rs917997*CT). Up-regulation of Lnc13 in pancreatic β-cells increased activation of the proinflammatory STAT1 pathway, which correlated with increased production of chemokines in an allele-specific manner. In a mirror image, Lnc13 gene disruption in β-cells partially counteracts polyinosinic-polycytidylic acid (PIC)-induced STAT1 and proinflammatory chemokine expression. Furthermore, we observed that PIC, a viral mimetic, induces Lnc13translocation from the nucleus to the cytoplasm promoting the interaction of STAT1 mRNA with (poly[rC] binding protein 2) (PCBP2). Interestingly, Lnc13-PCBP2 interaction regulates the stability of the STAT1 mRNA, sustaining inflammation in β-cells in an allele-specific manner. Our results show that the T1D-associated Lnc13 may contribute to the pathogenesis of T1D by increasing pancreatic β-cell inflammation. These findings provide information on the molecular mechanisms by which disease-associated SNPs in lncRNAs influence disease pathogenesis and open the door to the development of diagnostic and therapeutic approaches based on lncRNA targeting.

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