Publications
673 results found
Pullen TJ, Groen N, van Oudenaarden A, et al., 2018, Identification of potential hub beta cells using single-cell RNA-Seq, Publisher: WILEY, Pages: 51-51, ISSN: 0742-3071
Martinez-Sanchez A, Nguyen-Tu MS, Cebola I, et al., 2018, Adenosine Monophosphate (AMP)-activated protein kinase (AMPK) regulates the expression of miR-184 and other miRNAs important for beta cell function, Publisher: WILEY, Pages: 48-48, ISSN: 0742-3071
Cheung R, Rolando D, Chabosseau P, et al., 2018, miR-125b is a new regulator of pancreatic beta cell function, Publisher: WILEY, Pages: 47-47, ISSN: 0742-3071
Martinez-Sanchez A, Pizza G, Marchetti P, et al., 2018, Glucose regulates miR-125b expression via AMP-activated protein kinase (AMPK), Publisher: WILEY, Pages: 49-49, ISSN: 0742-3071
Gharavy NM, Li X, Leclerc I, et al., 2018, Roles for the Type 2 diabetes-associated genes <i>C2CD4A</i> and <i>C2CD4B</i> in the control of insulin secretion, Publisher: WILEY, Pages: 40-41, ISSN: 0742-3071
Jones B, Bloom S, Buenaventura T, et al., 2018, Control of insulin secretion by GLP-1, Peptides, Vol: 100, Pages: 75-84, ISSN: 0196-9781
Stimulation of insulin secretion by glucagon-like peptide-1 (GLP-1) and other gut-derived peptides is central to the incretin response to ingesting nutriments. Analogues of GLP-1, and inhibitors of its breakdown, have found widespread clinical use for the treatment of type 2 diabetes (T2D) and obesity. The release of these peptides underlies the improvements in glycaemic control and disease remission after bariatric surgery. Given therapeutically, GLP-1 analogues can lead to side effects including nausea, which limit dosage. Greater understanding of the interactions between the GLP-1 receptor (GLP-1R) and both the endogenous and artificial ligands therefore holds promise to provide more efficacious compounds. Here, we discuss recent findings concerning the signalling and trafficking of the GLP-1R in pancreatic beta cells. Leveraging “bias” at the receptor towards cAMP generation versus the recruitment of β-arrestins and extracellular signal-regulated kinases (ERK1/2) activation may allow the development of new analogues with significantly improved clinical efficacy. We describe how, unexpectedly, relatively low-affinity agonists, which prompt less receptor internalisation than the parent compound, provoke greater insulin secretion and consequent improvements in glycaemia.
Martinez-Sanchez A, Nguyen-Tu M-S, Leclerc I, et al., 2018, Manipulation and Measurement of AMPK Activity in Pancreatic Islets., Methods Mol Biol, Vol: 1732, Pages: 413-431
The role of the energy sensor AMPK-activated protein kinase (AMPK) in the insulin-secreting β-cell remains unclear and a subject of intense research. With this chapter, we aim to provide a detailed description of the methods that our group routinely applies to the study of AMPK function in mouse and human pancreatic islets. Thus, we provide detailed protocols to isolate and/or culture mouse and human islets, to modulate and measure AMPK activity in isolated islets, and to evaluate its impact on islet function.
Chabosseau P, Woodier J, Cheung R, et al., 2018, Sensors for measuring subcellular zinc pools, METALLOMICS, Vol: 10, Pages: 229-239, ISSN: 1756-5901
Nguyen-Tu M-S, Xavier GDS, Leclerc I, et al., 2018, Transcription factor-7-like 2 (TCF7L2) gene acts downstream of the Lkb1/Stk11 kinase to control mTOR signaling,beta cell growth, and insulin secretion (vol 293, pg 14178, 2018), JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 293, Pages: 18420-18420, ISSN: 0021-9258
Buenaventura T, Kanda N, Douzenis PC, et al., 2017, A targeted RNAi screen identifies endocytic trafficking factors that control GLP-1 receptor signaling in pancreatic beta cells, Diabetes, Vol: 67, Pages: 385-399, ISSN: 0012-1797
The GLP-1 receptor (GLP-1R) is a key target for type 2 diabetes (T2D) treatment. Since endocytic trafficking of agonist-bound receptors is one of the most important routes for regulation of receptor signaling, a better understanding of this process may facilitate the development of new T2D therapeutic strategies. Here, we have screened 29 proteins with known functions in G protein-coupled receptor trafficking for their role in GLP-1R potentiation of insulin secretion in pancreatic beta cells. We identify five (clathrin, dynamin1, AP2, SNX27 and SNX1) that increase and four (HIP1, HIP14, GASP-1 and Nedd4) that decrease insulin secretion from murine insulinoma MIN6B1 cells in response to the GLP-1 analogue exendin-4. The roles of Huntingtin-interacting protein 1 (HIP1) and the endosomal sorting nexins SNX1 and SNX27 were further characterized in mouse and human beta cell lines and human islets. While HIP1 was required for the coupling of cell surface GLP-1R activation with clathrin-dependent endocytosis, the sorting nexins were found to control the balance between GLP-1R plasma membrane recycling and lysosomal degradation, and, in doing so, determine the overall beta cell incretin responses. We thus identify key modulators of GLP-1R trafficking and signaling that might provide novel targets to enhance insulin secretion in T2D.
Fine NHF, Doig CL, Elhassan YS, et al., 2017, Glucocorticoids reprogram beta cell signaling to preserve insulin secretion, Diabetes, Vol: 67, Pages: 278-290, ISSN: 0012-1797
Excessive glucocorticoid exposure has been shown to be deleterious for pancreatic beta cell function and insulin release. However, glucocorticoids at physiological levels are essential for many homeostatic processes, including glycemic control. Here, we show that corticosterone and cortisol and their less active precursors, 11-dehydrocorticosterone (11-DHC) and cortisone, suppress voltage-dependent Ca2+ channel function and Ca2+ fluxes in rodent as well as human beta cells. However, insulin secretion, maximal ATP/ADP responses to glucose and beta cell identity were all unaffected. Further examination revealed the upregulation of parallel amplifying cAMP signals, and an increase in the number of membrane-docked insulin secretory granules. Effects of 11-DHC could be prevented by lipotoxicity and were associated with paracrine regulation of glucocorticoid activity, since global deletion of 11β-hydroxysteroid dehydrogenase type 1 normalized Ca2+ and cAMP responses. Thus, we have identified an enzymatically-amplified feedback loop whereby glucocorticoids boost cAMP to maintain insulin secretion in the face of perturbed ionic signals. Failure of this protective mechanism may contribute to diabetes in states of glucocorticoid excess such as Cushing's syndrome, which are associated with frank dyslipidemia.
Solimena M, Schulte AM, Marselli L, et al., 2017, Systems biology of the IMIDIA biobank from organ donors and pancreatectomised patients defines a novel transcriptomic signature of islets from individuals with type 2 diabetes., Diabetologia, Vol: 61, Pages: 641-657, ISSN: 0012-186X
AIMS/HYPOTHESIS: Pancreatic islet beta cell failure causes type 2 diabetes in humans. To identify transcriptomic changes in type 2 diabetic islets, the Innovative Medicines Initiative for Diabetes: Improving beta-cell function and identification of diagnostic biomarkers for treatment monitoring in Diabetes (IMIDIA) consortium ( www.imidia.org ) established a comprehensive, unique multicentre biobank of human islets and pancreas tissues from organ donors and metabolically phenotyped pancreatectomised patients (PPP). METHODS: Affymetrix microarrays were used to assess the islet transcriptome of islets isolated either by enzymatic digestion from 103 organ donors (OD), including 84 non-diabetic and 19 type 2 diabetic individuals, or by laser capture microdissection (LCM) from surgical specimens of 103 PPP, including 32 non-diabetic, 36 with type 2 diabetes, 15 with impaired glucose tolerance (IGT) and 20 with recent-onset diabetes (<1 year), conceivably secondary to the pancreatic disorder leading to surgery (type 3c diabetes). Bioinformatics tools were used to (1) compare the islet transcriptome of type 2 diabetic vs non-diabetic OD and PPP as well as vs IGT and type 3c diabetes within the PPP group; and (2) identify transcription factors driving gene co-expression modules correlated with insulin secretion ex vivo and glucose tolerance in vivo. Selected genes of interest were validated for their expression and function in beta cells. RESULTS: Comparative transcriptomic analysis identified 19 genes differentially expressed (false discovery rate ≤0.05, fold change ≥1.5) in type 2 diabetic vs non-diabetic islets from OD and PPP. Nine out of these 19 dysregulated genes were not previously reported to be dysregulated in type 2 diabetic islets. Signature genes included TMEM37, which inhibited Ca2+-influx and insulin secretion in beta cells, and ARG2 and PPP1R1A, which promoted insulin secretion. Systems biology approaches identified HNF1A, PDX1 and REST as drivers o
Rutter G, Phan K, Smith A, et al., 2017, Morphometric anatomy of the lumbar sympathetic trunk with respect to the anterolateral approach to lumbar interbody fusion: a cadaver study., J Spine Surg, Vol: 3, Pages: 419-425, ISSN: 2414-469X
BACKGROUND: An approach to lateral lumbar interbody fusion (LLIF) utilizing an oblique corridor anterior to the psoas muscle was first described by Mayer in 1997 and subsequently by other authors. The only consistent structure of note in this corridor is the lumbar sympathetic trunk (LST), which at times must be mobilized in order to perform a discectomy and interbody fusion, thereby placing the LST at risk. This study was designed to describe the morphometric anatomy of the LST in relation to surgically relevant landmarks for the anterolateral approach to the lumbar spine at L3/L4 to L5/S1. METHODS: Twenty-four embalmed cadavers (13 males, 11 females, age range, 50-89) were dissected to expose the LST. Bilateral measurements were recorded using a calliper under direct visualization, using the midsagittal plane of the lumbar spine as the reference landmark. The points were then marked with radio-opaque needles, and 14 cadavers were scanned with CT to validate the measurements. RESULTS: Of 48 LSTs, there was minimal difference in the direction of its course between sides; 14/24 specimens had concordant directions. The majority (n=28) had a medial to lateral cephalocaudal course. If osteophytes were present at the L4/L5 level, the majority of LSTs (n=7, of 8) were displaced lateral to the osteophyte. At the L5/S1 level, half of the cases with osteophytes (n=3, of 6) stretched the LST over the top of the osteophyte. The LST was adherent to the L4/L5 disc space bilaterally in 93% of cases. CONCLUSIONS: With the development of lumbar fusion techniques which utilize an oblique corridor and the retraction of psoas muscle, LST has become an important neural structure to define, protect and mobilize. In our morphometric analysis of 24 specimens, the position has been identified and quantified, and this paper notes variations, particularly distortions caused by degenerative processes. In this study, the LST ran in a medial to lateral direction from L3 to S1, and osteophytes t
Carrat G, Haythorne E, Chabosseau P, et al., 2017, Role of StarD10 in beta cell physiology, 53rd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S190-S191, ISSN: 0012-186X
Rutter GA, Hodson DJ, Chabosseau P, et al., 2017, Local and regional control of calcium dynamics in the pancreatic islet, Diabetes, Obesity and Metabolism, Vol: 19, Pages: 30-41, ISSN: 1462-8902
Ca2+ is the key intracellular regulator of insulin secretion, acting in the β-cell as the ultimate trigger for exocytosis. In response to high glucose, ATP-sensitive K+ channel closure and plasma membrane depolarization engage a sophisticated machinery to drive pulsatile cytosolic Ca2+ changes. Voltage-gated Ca2+ channels, Ca2+-activated K+ channels and Na+/Ca2+ exchange all play important roles. The use of targeted Ca2+ probes has revealed that during each cytosolic Ca2+ pulse, uptake of Ca2+ by mitochondria, endoplasmic reticulum (ER), secretory granules and lysosomes fine-tune cytosolic Ca2+ dynamics and control organellar function. For example, changes in the expression of the Ca2+-binding protein Sorcin appear to provide a link between ER Ca2+ levels and ER stress, affecting β-cell function and survival. Across the islet, intercellular communication between highly interconnected “hubs,” which act as pacemaker β-cells, and subservient “followers,” ensures efficient insulin secretion. Loss of connectivity is seen after the deletion of genes associated with type 2 diabetes (T2D) and follows metabolic and inflammatory insults that characterize this disease. Hubs, which typically comprise ~1%-10% of total β-cells, are repurposed for their specialized role by expression of high glucokinase (Gck) but lower Pdx1 and Nkx6.1 levels. Single cell-omics are poised to provide a deeper understanding of the nature of these cells and of the networks through which they communicate. New insights into the control of both the intra- and intercellular Ca2+ dynamics may thus shed light on T2D pathology and provide novel opportunities for therapy.
Fine NHF, Doig CL, Elhassan Y, et al., 2017, Glucocorticoids re-programme the beta cell signalling cassette to preserve functional identity and insulin secretion, 53rd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S83-S83, ISSN: 0012-186X
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Nasteska D, Fine NHF, Rutter GA, et al., 2017, β cell diversity is required for normal islet function, Publisher: WILEY, Pages: 12-14, ISSN: 1748-1708
Sandhu B, Rutter G, Prendecki M, et al., 2017, HYPOXIA INDUCES ENDOPLASMIC RETICULUM STRESS AND UNFOLDED PROTEIN RESPONSES IN ISOLATED HUMAN ISLETS, Publisher: WILEY, Pages: 520-520, ISSN: 0934-0874
Hodson DJ, Nasteska D, Fine NHF, et al., 2017, Forced maturity in pancreatic beta cells impairs islet function, 53rd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S183-S183, ISSN: 0012-186X
Ralston JC, Nguyen-Tu M-S, Lyons CL, et al., 2017, A dietary switch from saturated to monounsaturated fat is protective against metabolic dysregulation, hyperinsulinaemia and beta cell dysfunction, 53rd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S267-S268, ISSN: 0012-186X
Haythorne EA, Martinez-Sanchez A, Rizzuto R, et al., 2017, The mitochondrial Ca<SUP>2+</SUP> uniporter (MCUa) is required for glucose-stimulated mitochondrial Ca<SUP>2+</SUP> uptake and insulin secretion in mouse pancreatic beta cells, 53rd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S197-S197, ISSN: 0012-186X
Tuncay E, Bitirim VC, Olgar Y, et al., 2017, Mitochondrial localization and function of Zn<SUP>2+</SUP>-transporters ZIP7 and ZnT7 in mammalian heart, Publisher: ELSEVIER SCI LTD, Pages: 62-62, ISSN: 0022-2828
Martinez-Sanchez A, Shapiro J, Marchetti P, et al., 2017, AMP-Activated Protein Kinase (AMPK) Regulates β-Cell MicroRNA Expression, 77th Scientific Sessions of the American-Diabetes-Association, Publisher: AMER DIABETES ASSOC, Pages: A29-A29, ISSN: 0012-1797
Nguyen-Tu M-S, Xavier GDS, Leclerc I, et al., 2017, The Type 2 diabetes gene TCF7L2 modulates the impact of LKB1 deletion on beta-cell function, 77th Scientific Sessions of the American-Diabetes-Association, Publisher: American Diabetes Association, Pages: A577-A577, ISSN: 0012-1797
Tuncay E, Bitirim VC, Durak A, et al., 2017, Hyperglycemia-Induced Changes in ZIP7 and ZnT7 Expression Cause Zn2+ Release From the Sarco(endo)plasmic Reticulum and Mediate ER Stress in the Heart, Diabetes, Vol: 66, Pages: 1346-1358, ISSN: 0012-1797
Changes in cellular free Zn2+ concentration, including those in the sarco(endo)plasmicreticulum [S(E)R], are primarily coordinated by Zn2+-transporters whose identity and role inthe heart is not well established. Here, we hypothesized that ZIP7 and ZnT7 transport Zn2+ inopposing directions across the S(E)R membrane in cardiomyocytes and that changes in theiractivity may play an important role in the development of ER-stress during hyperglycemia.The subcellular S(E)R-localization of ZIP7 and ZnT7 was determined in cardiomyocytes andin isolated S(E)R-preparations. Markedly increased mRNA and protein levels of ZIP7 wereobserved in ventricular cardiomyocytes from diabetic rats or high glucose-treated H9c2 cellswhilst ZnT7 expression was low. Additionally, we observed increased ZIP7-phosphorylationin response to high glucose in vivo and in vitro. Using recombinant targeted FRET-basedsensors, we showed that hyperglycemia induced a marked redistribution of cellular free Zn2+,increasing cytosolic free Zn2+ and lowering free Zn2+ in the S(E)R. These changes involvealterations in ZIP7-phosphorylation and were suppressed by siRNA-mediated silencing ofCK2α. Opposing changes in the expression of ZIP7 and ZnT7 were also observed inhyperglycemia. We conclude that sub-cellular free Zn2+ re-distribution in the hyperglycemicheart, resulting from altered ZIP7 and ZnT7 activity, contributes to cardiac dysfunction indiabetes.
Sandhu B, Prendecki M, Crawley J, et al., 2017, Cytotopic thrombin inhibition prior to cold ischaemia attenuates microvascular endothelial ischaemia-reperfusion injury, American Transplant Congress, Publisher: Wiley, Pages: 731-731, ISSN: 1600-6135
Sandhu B, Prendecki M, Rutter G, et al., 2017, Hypoxia induces tissue factor upregulation in isolated human islets, American Transplant Congress, Publisher: Wiley, Pages: 461-461, ISSN: 1600-6135
pullen T, Huising MO, Rutter GA, 2017, Analysis of purified pancreatic islet beta and alpha cell transcriptomesreveals 11β-hydroxysteroid dehydrogenase (Hsd11b1) as a noveldisallowed gene, Frontiers in Genetics, Vol: 8, ISSN: 1664-8021
We and others have previously identified a group of genes, dubbed “disallowed,” whose expression is markedly lower in pancreatic islets than in other mammalian cell types. Forced mis-expression of several members of this family leads to defective insulin secretion, demonstrating the likely importance of disallowance for normal beta cell function. Up to now, transcriptomic comparisons have been based solely on data from whole islets. This raises the possibilities that (a) there may be important differences in the degree of disallowance of family members between beta and other either neuroendocrine cells; (b) beta (or alpha) cell disallowed genes may have gone undetected. To address this issue, we survey here recent massive parallel sequencing (RNA-Seq) datasets from purified mouse and human islet cells. Our analysis reveals that the most strongly disallowed genes are similar in beta and alpha cells, with 11β-hydroxysteroid dehydrogenase (Hsd11b1) mRNA being essentially undetectable in both cell types. The analysis also reveals that several genes involved in cellular proliferation, including Yap1 and Igfbp4, and previously assumed to be disallowed in both beta and alpha cells, are selectively repressed only in the beta cell. The latter finding supports the view that beta cell growth is selectively restricted in adults, providing a mechanism to avoid excessive insulin production and the risk of hypoglycaemia. Approaches which increase the expression or activity of selected disallowed genes in the beta cell may provide the basis for novel regenerative therapies in type 2 diabetes.
Mitchell RK, Nguyen-Tu MS, Chabosseau P, et al., 2017, The transcription factor Pax6 is required for pancreatic β cell identity, glucose-regulated ATP synthesis and Ca2+ dynamics in adult mice., Journal of Biological Chemistry, Vol: 292, Pages: 8892-8906, ISSN: 1083-351X
Heterozygous mutations in the human paired box gene PAX6 lead to impaired glucose tolerance. Although embryonic deletion of the Pax6 gene in mice leads to the loss of most pancreatic islet cell types, the functional consequences of Pax6 loss in adults are poorly defined. Here, we developed a mouse line in which Pax6 was selectively inactivated in β cells by crossing animals with floxed Pax6 alleles to mice expressing the inducible Pdx1CreERT transgene. Pax6 deficiency, achieved by tamoxifen injection, caused progressive hyperglycemia. While β-cell mass was preserved 8 days post injection, total insulin content and insulin:chromogranin A immunoreactivity were reduced by ~60%, and glucose-stimulated insulin secretion was eliminated. RNAseq and qRT-PCR analyses revealed that whereas the expression of key β cell genes including Ins2, Slc30a8, MafA, Slc2a2, G6pc2 and Glp1r was reduced after Pax6 deletion, that of several genes which are usually selectively repressed ("disallowed") in β-cells, including Slc16a1, was increased. Assessed in intact islets, glucose-induced ATP:ADP increases were significantly reduced (p<0.05) in βPax6KO versus control β cells, and the former displayed attenuated increases in cytosolic Ca2+. Unexpectedly, glucose-induced increases in intercellular connectivity were enhanced after Pax6 deletion, consistent with increases in the expression of the glucose sensor glucokinase, but decreases in that of two transcription factors usually expressed in fully differentiated β-cells, Pdx1 and Nkx6.1, as observed in islet "hub" cells. These results indicate that Pax6 is required for the functional identity of adult β cells. Furthermore, deficiencies in β cell glucose-sensing are likely to contribute to defective insulin secretion in human carriers of PAX6 mutations.
Da Silva Xavier G, Mondragon A, Mourougavelou V, et al., 2017, Pancreatic alpha cell-selective deletion of Tcf7l2 impairs glucagon secretion and counter-regulatory responses in mice, Diabetologia, Vol: 60, Pages: 1043-1050, ISSN: 0012-186X
Aims/hypothesisTranscription factor 7-like 2 (TCF7L2) is a high mobility group (HMG) box-containing transcription factor and downstream effector of the Wnt signalling pathway. SNPs in the TCF7L2 gene have previously been associated with an increased risk of type 2 diabetes in genome-wide association studies. In animal studies, loss of Tcf7l2 function is associated with defective islet beta cell function and survival. Here, we explore the role of TCF7L2 in the control of the counter-regulatory response to hypoglycaemia by generating mice with selective deletion of the Tcf7l2 gene in pancreatic alpha cells.MethodsAlpha cell-selective deletion of Tcf7l2 was achieved by crossing mice with floxed Tcf7l2 alleles to mice bearing a Cre recombinase transgene driven by the preproglucagon promoter (PPGCre), resulting in Tcf7l2AKO mice. Glucose homeostasis and hormone secretion in vivo and in vitro, and islet cell mass were measured using standard techniques.ResultsWhile glucose tolerance was unaffected in Tcf7l2AKO mice, glucose infusion rates were increased (AUC for glucose during the first 60 min period of hyperinsulinaemic–hypoglycaemic clamp test was increased by 1.98 ± 0.26-fold [p < 0.05; n = 6] in Tcf7l2AKO mice vs wild-type mice) and glucagon secretion tended to be lower (plasma glucagon: 0.40 ± 0.03-fold vs wild-type littermate controls [p < 0.01; n = 6]). Tcf7l2AKO mice displayed reduced fasted plasma glucose concentration. Glucagon release at low glucose was impaired in islets isolated from Tcf7l2AKO mice (0.37 ± 0.02-fold vs islets from wild-type littermate control mice [p < 0.01; n = 6). Alpha cell mass was also reduced (72.3 ± 20.3% [p < 0.05; n = 7) in Tcf7l2AKO mice compared with wild-type mice.Conclusions/interpretationThe present findings demonstrate an alpha cell-autonomous role for Tcf7l2 in the control of pancreatic glucagon secretion and the maintenance of alpha cell mass and function.
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