Publications
673 results found
Gromada J, Chabosseau P, Rutter GA, 2018, The alpha-cell in diabetes mellitus, NATURE REVIEWS ENDOCRINOLOGY, Vol: 14, Pages: 694-704, ISSN: 1759-5029
Suwandhi L, Hausmann S, Braun A, et al., 2018, Chronic d-serine supplementation impairs insulin secretion, Molecular Metabolism, Vol: 16, Pages: 191-202, ISSN: 2212-8778
OBJECTIVE: The metabolic role of d-serine, a non-proteinogenic NMDA receptor co-agonist, is poorly understood. Conversely, inhibition of pancreatic NMDA receptors as well as loss of the d-serine producing enzyme serine racemase have been shown to modulate insulin secretion. Thus, we aim to study the impact of chronic and acute d-serine supplementation on insulin secretion and other parameters of glucose homeostasis. METHODS: We apply MALDI FT-ICR mass spectrometry imaging, NMR based metabolomics, 16s rRNA gene sequencing of gut microbiota in combination with a detailed physiological characterization to unravel the metabolic action of d-serine in mice acutely and chronically treated with 1% d-serine in drinking water in combination with either chow or high fat diet feeding. Moreover, we identify SNPs in SRR, the enzyme converting L-to d-serine and two subunits of the NMDA receptor to associate with insulin secretion in humans, based on the analysis of 2760 non-diabetic Caucasian individuals. RESULTS: We show that chronic elevation of d-serine results in reduced high fat diet intake. In addition, d-serine leads to diet-independent hyperglycemia due to blunted insulin secretion from pancreatic beta cells. Inhibition of alpha 2-adrenergic receptors rapidly restores glycemia and glucose tolerance in d-serine supplemented mice. Moreover, we show that single nucleotide polymorphisms (SNPs) in SRR as well as in individual NMDAR subunits are associated with insulin secretion in humans. CONCLUSION: Thus, we identify a novel role of d-serine in regulating systemic glucose metabolism through modulating insulin secretion.
Nasteska D, Rutter GA, Zhou Q, et al., 2018, Loss of beta cell heterogeneity disrupts normal islet function, 54th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S17-S17, ISSN: 0012-186X
Callingham RM, Itzkovitz S, Farack L, et al., 2018, Role for a lncRNA at the Pax6 locus in controlling beta cell identity and function, 54th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S35-S35, ISSN: 0012-186X
Hu M, Gadue PJ, Rutter GA, 2018, Impact of type 2 diabetes-associated variants at the STARD10 locus on chromatin conformation and human beta cell function, 54th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S88-S88, ISSN: 0012-186X
Meneyrol K, Bellini L, Georgiadou E, et al., 2018, Selective disruption of the very long chain fatty acid elongase 2 (ELOVL2) in the pancreatic beta cell impairs insulin release during obesity, 54th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S198-S198, ISSN: 0012-186X
Salem V, Silva LD, Suba K, et al., 2018, Glucose regulates pancreatic islet beta cell calcium dynamics and intercellular connectivity in vivo, 54th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S18-S18, ISSN: 0012-186X
Benninger RKP, Dorrell C, Hodson DJ, et al., 2018, The Impact of Pancreatic Beta Cell Heterogeneity on Type 1 Diabetes Pathogenesis, CURRENT DIABETES REPORTS, Vol: 18, ISSN: 1534-4827
Jenkins A, Lengyel I, Rutter GA, et al., 2018, Obesity, diabetes and zinc: a workshop promoting knowledge and collaboration between the UK and Israel, november 28-30, 2016 - Israel, Journal of Trace Elements in Medicine and Biology, Vol: 49, Pages: 79-85, ISSN: 0946-672X
Sponsored by the Friends of Israel Educational Foundation (FIEF)and Ben-Gurion University of the Negev and supported by the EU COSTaction Zinc-Net (COST TD1304), a three-day collaborative UK-Israelworkshop was organized by Drs Assaf Rudich, Imre Lengyel and ArieMoran. Participants from the UK and Israel met at the Desert Iris Hotel,Yeruham, Israel between the 28-30th of November 2016 for in-depthdiscussions, rather than a lecture series, to set the stage for futurecollaborative grants and projects on diabetes and zinc. Two days offormal scientific sessions with dynamic and wide-ranging discussionswas followed by a day of touring and informal networking in the Negevarea. This format was previously recognized by our sponsors as botheffective and enjoyable and all participants agreed at the end of themeeting that the 3-days provided an excellent basis for future scientificcollaboration. The discussions were centered on diabetes and obesity,already at pandemic levels, and zinc homeostasis which is related to theclinical issues and themes of the meeting. The free-flowing discussionswere based on short presentations setting the scene for the six maintopics:‘Diabetes and zinc transporters’,‘Nutrition related factors’, ‘Biomarkers’, ‘Clinical epidemiology’, ‘the Microbiome and diabetes’,and ‘Related diseases’. The abstract style summary of the sessions isfollowed by the major discussion points raised by the Authors and otherparticipants (UK: Patrik Rorsman, Oxford University; Alan Stewart,University of St Andrews and Israel: Assaf Rudich, Idit Liberty, RahelGol, Guy Las and Amos Katz, Ben-Gurion University; Sarah Zangen,Haddassa University). We hope that readers will find this discoursestimulating and some of the ideas might make their way into their re-search efforts.
Gardiner JV, Ma Y, Ratnasabapathy R, et al., 2018, Hypothalamic arcuate nucleus glucokinase regulates insulin secretion and glucose homeostasis, Diabetes, Obesity and Metabolism, Vol: 20, Pages: 2246-2254, ISSN: 1462-8902
AimsGlucokinase (GK) serves as a glucose sensor in several tissues including glucose‐sensitive neurons of the arcuate nucleus within the hypothalamus. We have previously demonstrated a role for arcuate GK in the regulation of food and glucose intake. However, its role in the regulation of glucose homeostasis is less clear. We therefore sought to investigate the role of arcuate GK in the regulation of glucose homeostasis.Materials and MethodsRecombinant adeno‐associated virus expressing either GK or an antisense GK construct was used to alter GK activity specifically in the hypothalamic arcuate nucleus. GK activity in this nucleus was also increased by stereotactic injection of the GK activator, compound A. The effect of altered arcuate nucleus GK activity on glucose homeostasis was subsequently investigated using glucose and insulin tolerance tests.ResultsIncreased GK activity specifically within the arcuate nucleus increased insulin secretion and improved glucose tolerance in rats during oral glucose tolerance tests. Decreased GK activity in this nucleus reduced insulin secretion and increased glucose levels during the same tests. Insulin sensitivity was not affected in either case. The effect of arcuate nucleus glucokinase was maintained in a model of type 2 diabetes.ConclusionsThese results demonstrate a role for arcuate nucleus GK in systemic glucose homeostasis.
Kleiner S, Gomez D, Megra B, et al., 2018, Mice harboring the human SLC30A8 R138X loss-of-function mutation have increased insulin secretory capacity, Proceedings of the National Academy of Sciences, Vol: 115, Pages: E7642-E7649, ISSN: 0027-8424
SLC30A8 encodes a zinc transporter that is primarily expressed in the pancreatic islets of Langerhans. In β-cells it transports zinc into insulin-containing secretory granules. Loss-of-function (LOF) mutations in SLC30A8 protect against type 2 diabetes in humans. In this study, we generated a knockin mouse model carrying one of the most common human LOF mutations for SLC30A8, R138X. The R138X mice had normal body weight, glucose tolerance, and pancreatic β-cell mass. Interestingly, in hyperglycemic conditions induced by the insulin receptor antagonist S961, the R138X mice showed a 50% increase in insulin secretion. This effect was not associated with enhanced β-cell proliferation or mass. Our data suggest that the SLC30A8 R138X LOF mutation may exert beneficial effects on glucose metabolism by increasing the capacity of β-cells to secrete insulin under hyperglycemic conditions.
Millership S, Da Silva Xavier G, Choudhury A, et al., 2018, Neuronatin regulates pancreatic beta cell insulin content and secretion, Journal of Clinical Investigation, Vol: 128, Pages: 3369-3381, ISSN: 0021-9738
Neuronatin (Nnat) is an imprinted gene implicated in human obesity and widely expressed in neuroendocrine and metabolic tissues in a hormone and nutrient-sensitive manner. However, its molecular and cellular functions and precise role in organismal physiology remain only partly defined. Here we demonstrate that mice lacking Nnat globally or specifically in β cells display impaired glucose-stimulated insulin secretion leading to defective glucose handling under conditions of nutrient-excess. In contrast, we report no evidence for any feeding or body weight phenotypes in global Nnat null mice. At the molecular level neuronatin augments insulin signal peptide cleavage by binding to the signal peptidase complex and facilitates translocation of the nascent preprohormone. Loss of neuronatin expression in β cells therefore reduces insulin content and blunts glucose-stimulated insulin secretion. Nnat expression, in turn, is glucose-regulated. This mechanism therefore represents a novel site of nutrient-sensitive control of β cell function and whole animal glucose homeostasis. These data also suggest a potential wider role for Nnat in the regulation of metabolism through the modulation of peptide processing events.
Kimura T, Obata A, Shimoda M, et al., 2018, Down-regulation of vascular GLP-1 receptor expression in human subjects with obesity, Scientific Reports, Vol: 8, ISSN: 2045-2322
It has been thought that incretin signaling prevents arteriosclerosis, and very recently anti-arteriosclerotic effects through GLP-1 receptor were finally demonstrated in clinical human study. The purpose of this study was to investigate how vascular GLP-1 receptor expression is influenced in human subjects. First, we evaluated GLP-1 receptor expression in human arteries in immunostaining. Next, we separated the artery into the intima and media, and evaluated gene expression levels of various factors. We divided the subjects into obesity and non-obesity group and compared their expression levels between them. Finally, we evaluated which factors determine vascular GLP-1 receptor expression. GLP-1 receptor expression in intima and media was lower in obesity group compared to non-obesity group which was correlated with the alteration of TCF7L2 expression. Multiple regression analyses showed that BMI was an independent determining factor for GLP-1 receptor expression in the intima and media. Furthermore, using small interfering RNA method and TCF7L2-EGFP adenovirus, we showed that TCF7L2 was involved in GLP-1 receptor expression in human vascular cells. Taken together, vascular GLP-1 receptor and TCF7L2 expression was significantly down-regulated in human subjects with obesity. In addition, it is likely that TCF7L2 functions as a modulator of vascular GLP-1 receptor expression.
Nguyen-Tu M-S, da Silva Xavier G, Leclerc I, et al., 2018, Transcription factor-7-like 2 (TCF7L2) gene acts downstream of the Lkb1/Stk11 kinase to control mTOR signaling, β cell growth, and insulin secretion, Journal of Biological Chemistry, Vol: 293, Pages: 14178-14189, ISSN: 0021-9258
Variants in the transcription factor-7-like 2 (TCF7L2/TCF4) gene, involved in Wnt signalling, are associated with type 2 diabetes. Loss of Tcf7l2 selectively from the β cell in mice has previously been shown to cause glucose intolerance and to lower β cell mass. Deletion of the tumour suppressor liver kinase B1 (LKB1/STK11) leads to β cell hyperplasia and enhanced glucose-stimulated insulin secretion, providing a convenient genetic model for increased β cell growth and function. The aim of this study was to explore the possibility that Tcf7l2 may be required for the effects of Lkb1 deletion on insulin secretion in the mouse β cell. Mice bearing floxed Lkb1 and/or Tcf7l2 alleles were bred with knock-in mice bearing Cre recombinase inserted at the Ins1 locus (Ins1Cre), allowing highly β cell-selective deletion of either or both genes. Oral glucose tolerance was unchanged by the further deletion of a single Tcf7l2 allele in these cells. By contrast, mice lacking both Tcf7l2 alleles on this background showed improved oral glucose tolerance and insulin secretion in vivo and in vitro compared to mice lacking a single Tcf7l2 allele. Bi-allelic Tcf7l2 deletion also enhanced β cell proliferation, increased β cell mass and caused changes in polarity as revealed by the "rosette-like" arrangement of β cells. Tcf7l2 deletion also increased signalling by Target of Rapamycin (mTOR), augmenting phospho-ribosomal S6 levels. We identified a novel signalling mechanism through which a modifier gene, Tcf7l2, lies on a pathway through which LKB1 acts in the β cell to restrict insulin secretion.
Hamilton A, Zhang Q, Salehi A, et al., 2018, Adrenaline stimulates glucagon secretion by Tpc2-dependent Ca2+ mobilization from acidic stores in pancreatic α-Cells, Diabetes, Vol: 67, Pages: 1128-1139, ISSN: 0012-1797
Adrenaline is a powerful stimulus of glucagon secretion. It acts by activation of β-adrenergic receptors but the downstream mechanisms have only been partially elucidated. Here we have examined the effects of adrenaline in mouse and human α-cells by a combination of electrophysiology, imaging of Ca2+ and PKA activity and hormone release measurements. We found that stimulation of glucagon secretion correlated with a PKA- and EPAC2-dependent (inhibited by PKI and ESI-05, respectively) elevation of [Ca2+]i in α-cells, which occurred without stimulation of electrical activity, persisted in the absence of extracellular Ca2+ but was sensitive to ryanodine, bafilomycin and thapsigargin. Adrenaline also increased [Ca2+]i in α-cells in human islets. Genetic or pharmacological inhibition of Tpc2 channel (that mediates Ca2+ release from acidic intracellular stores) abolished the stimulatory effect of adrenaline on glucagon secretion and reduced the elevation of [Ca2+]i. Furthermore, in Tpc2-deficient islets, ryanodine exerted no additive inhibitory effect. These data suggest that β-adrenergic stimulation of glucagon secretion is controlled by a hierarchy of [Ca2+]i signaling in the α-cell that is initiated by cAMP-induced Tpc2-dependent Ca2+ release from the acidic stores and further amplified by Ca2+-induced Ca2+ release from the sarco/endoplasmic reticulum.
Sandhu B, Prendecki M, Vallant N, et al., 2018, Hypoxia Results in Endoplasmic Reticulum Stress and Activation of the Unfolded Protein Response in Isolated Human Islets and Human Donor Pancreases., American Transplant Congress, Publisher: WILEY, Pages: 603-603, ISSN: 1600-6135
Martinez-Sanchez A, Nguyen-Tu M-S, Cebola I, et al., 2018, MiR-184 expression is regulated by AMPK in pancreatic islets., FASEB Journal, Vol: 32, Pages: 2587-2600, ISSN: 0892-6638
AMPK is a critical energy sensor and target for widely used antidiabetic drugs. In β-cells, elevated glucose concentrations lower AMPK activity, and the ablation of both catalytic subunits (βAMPKdKO mice) impairs insulin secretion in vivo and β-cell identity. MicroRNAs (miRNAs) are small RNAs that silence gene expression that are essential for pancreatic β-cell function and identity and altered in diabetes. Here, we have explored the miRNAs acting downstream of AMPK in mouse and human β-cells. We identified 14 down-regulated and 9 up-regulated miRNAs in βAMPKdKO vs. control islets. Gene ontology analysis of targeted transcripts revealed enrichment in pathways important for β-cell function and identity. The most down-regulated miRNA was miR-184 (miR-184-3p), an important regulator of β-cell function and compensatory expansion that is controlled by glucose and reduced in diabetes. We demonstrate that AMPK is a potent regulator and an important mediator of the negative effects of glucose on miR-184 expression. Additionally, we reveal sexual dimorphism in miR-184 expression in mouse and human islets. Collectively, these data demonstrate that glucose-mediated changes in AMPK activity are central for the regulation of miR-184 and other miRNAs in islets and provide a link between energy status and gene expression in β-cells.-Martinez-Sanchez, A., Nguyen-Tu, M.-S., Cebola, I., Yavari, A., Marchetti, P., Piemonti, L., de Koning, E., Shapiro, A. M. J., Johnson, P., Sakamoto, K., Smith, D. M., Leclerc, I., Ashrafian, H., Ferrer, J., Rutter, G. A. MiR-184 expression is regulated by AMPK in pancreatic islets.
Jones B, Buenaventura T, Kanda N, et al., 2018, Targeting GLP-1 receptor trafficking to improve agonist efficacy, Nature Communications, Vol: 9, ISSN: 2041-1723
Glucagon-like peptide-1 receptor (GLP-1R) activation promotes insulin secretion from pancreatic beta cells, causes weight loss, and is an important pharmacological target in type 2 diabetes (T2D). Like other G protein-coupled receptors, the GLP-1R undergoes agonist-mediated endocytosis, but the functional and therapeutic consequences of modulating GLP-1R endocytic trafficking have not been clearly defined. Here, we investigate a novel series of biased GLP-1R agonists with variable propensities for GLP-1R internalization and recycling. Compared to a panel of FDA-approved GLP-1 mimetics, compounds that retain GLP-1R at the plasma membrane produce greater long-term insulin release, which is dependent on a reduction in β-arrestin recruitment and faster agonist dissociation rates. Such molecules elicit glycemic benefits in mice without concomitant increases in signs of nausea, a common side effect of GLP-1 therapies. Our study identifies a set of agents with specific GLP-1R trafficking profiles and the potential for greater efficacy and tolerability as T2D treatments.
Janjuha S, Singh SP, Tsakmaki A, et al., 2018, Age-related islet inflammation marks the proliferative decline of pancreatic beta-cells in zebrafish, eLife, Vol: 7, ISSN: 2050-084X
The pancreatic islet, a cellular community harboring the insulin-producing beta-cells, is known to undergo age-related alterations. However, only a handful of signals associated with aging have been identified. By comparing beta-cells from younger and older zebrafish, here we show that the aging islets exhibit signs of chronic inflammation. These include recruitment of tnfα-expressing macrophages and the activation of NF-kB signaling in beta-cells. Using a transgenic reporter, we show that NF-kB activity is undetectable in juvenile beta-cells, whereas cells from older fish exhibit heterogeneous NF-kB activity. We link this heterogeneity to differences in gene expression and proliferation. Beta-cells with high NF-kB signaling proliferate significantly less compared to their neighbors with low activity. The NF-kB signalinghi cells also exhibit premature upregulation of socs2, an age-related gene that inhibits beta-cell proliferation. Together, our results show that NF-kB activity marks the asynchronous decline in beta-cell proliferation with advancing age.
Salem V, Suba K, Martin Alonso A, et al., 2018, Real-Time In Vivo Imaging of Whole Islet Ca2+ Dynamics Reveals Glucose-Induced Changes in Beta-Cell Connectivity in Mouse and Human Islets, American Diabetes Association, 78th Scientific Sessions, Publisher: American Diabetes Association, ISSN: 0012-1797
Rutter GA, Hodson DJ, 2018, Beta cell connectivity in pancreatic islets: a type 2 diabetes target? (vol 72, pg 453, 2015), CELLULAR AND MOLECULAR LIFE SCIENCES, Vol: 75, Pages: 1303-1305, ISSN: 1420-682X
Carrat GR, Haythorne E, Chabosseau P, et al., 2018, The Type 2 diabetes genome-wide association study (GWAS) gene STARD10 controls beta cell granule morphogenesis and proinsulin release, Diabetes UK, Publisher: WILEY, Pages: 46-46, ISSN: 0742-3071
Suba K, Nguyen-Tu MS, Chabosseau P, et al., 2018, Measuring real-time islet blood vessel responses to hormonal challenges using the platform of transplanted islets in the anterior chamber of the murine eye, Diabetes UK, Publisher: WILEY, Pages: 49-49, ISSN: 0742-3071
Khan R, Kanda N, Bloom SR, et al., 2018, An investigation into the role of compound 5d in incretin-dependent pancreatic beta cell function, Publisher: WILEY, Pages: 54-54, ISSN: 0742-3071
Nguyen-Tu MS, Rutter GA, Xavier GD, 2018, Adipose tissue-selective deletion of the Type 2 diabetes Genome-wide association studies (GWAS) gene <i>Tcf7l2</i> in mice impairs insulin sensitivity and secretion, Publisher: WILEY, Pages: 83-84, ISSN: 0742-3071
Callingham RM, Pullen TJ, Rutter GA, 2018, The role of a long non-coding RNA at the <i>Pax6</i> locus in controlling beta cell identity and function, Publisher: WILEY, Pages: 50-50, ISSN: 0742-3071
Chabosseau P, Cheung R, Rutter GA, 2018, CRISPR/Cas9-mediated engineering of insulin-secreting cells to study Type 2 diabetes risk variants of the gene <i>SLC30A8</i>/ZnT8 the Zn2+transporter, Publisher: WILEY, Pages: 45-45, ISSN: 0742-3071
Scott F, Parks S, Gao T, et al., 2018, The calcium sensor sorcin maintains activating transcription factor 6 (ATF6) transcriptional activity while lowering ER stress, Publisher: WILEY, Pages: 44-44, ISSN: 0742-3071
Laughlin WE, Buenaventura T, Oqua AI, et al., 2018, Control of glucagon-like peptide-1 receptor (GLP-1R) palmitoylation, lipid raft partitioning, clustering and signalling by biased agonism, Publisher: WILEY, Pages: 54-55, ISSN: 0742-3071
Rutter GA, Haythorne EA, Georgiadou E, et al., 2018, Pancreatic beta cell-selective deletion of the mitochondrial calcium uniporter (MCU) impairs glucose-stimulated insulin secretion <i>in vitro</i> but not <i>in vivo</i>, Publisher: WILEY, Pages: 42-42, ISSN: 0742-3071
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