Publications
674 results found
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.
pullen T, Huising MO, Rutter GA, 2017, Analysis of purified pancreatic islet beta and alpha cell transcriptomes reveals 11β-hydroxysteroid dehydrogenase (Hsd11b1) as a novel disallowed gene, Frontiers in Genetics, ISSN: 1664-8021
Mehta ZB, Johnston NR, Nguyen-Tu M-S, et al., 2017, Remote control of glucose homeostasis in vivo using photopharmacology, Scientific Reports, Vol: 7, ISSN: 2045-2322
Photopharmacology describes the use of light to precisely deliver drug activity in space and time. Such approaches promise to improve drug specificity by reducing off-target effects. As a proof-of-concept, we have subjected the fourth generation photoswitchable sulfonylurea JB253 to comprehensive toxicology assessment, including mutagenicity and maximum/repeated tolerated dose studies, as well as in vivo testing in rodents. Here, we show that JB253 is well-tolerated with minimal mutagenicity and can be used to optically-control glucose homeostasis in anesthetized mice following delivery of blue light to the pancreas. These studies provide the first demonstration that photopharmacology may one day be applicable to the light-guided treatment of type 2 diabetes and other metabolic disease states in vivo in humans.
Nguyen-Tu MS, Leclerc I, daSilva-Xavier G, et al., 2017, The Type 2 diabetes genome-wide association study (GWAS) gene TCF7L2 modulates the response of the murine beta cell to deletion of the tumour suppressor Lkb1, DIABETIC MEDICINE, Vol: 34, Pages: 28-28, ISSN: 0742-3071
Martinez-Sanchez A, Marchetti P, Shapiro AMJ, et al., 2017, AMP-activated protein kinase (AMPK) regulates miRNA expression in beta cells, DIABETIC MEDICINE, Vol: 34, Pages: 42-43, ISSN: 0742-3071
Fine NHF, Doig CL, Elhassan Y, et al., 2017, A steroid-regulated feedback loop preserves insulin secretion in the face of perturbed beta cell function, DIABETIC MEDICINE, Vol: 34, Pages: 41-41, ISSN: 0742-3071
Buenaventura T, Kanda N, Jones B, et al., 2017, Characterisation of glucagon-like peptide-1 (GLP-1) receptor trafficking and its significance for pancreatic beta cell function, DIABETIC MEDICINE, Vol: 34, Pages: 53-53, ISSN: 0742-3071
Gao T, Chabosseau P, Rutter GA, et al., 2017, Sorcin stimulates ATF6 transcriptional activity, Publisher: WILEY, Pages: 43-43, ISSN: 0742-3071
Gharavy SNM, Li X, Martinez-Sanchez A, et al., 2017, Putative roles of the Type 2 diabetes-associated genes <i>C2CD4A</i> and <i>C2CD4B</i> in the control of insulin secretion, Publisher: WILEY, Pages: 79-79, ISSN: 0742-3071
Rutter GA, 2017, GABA signaling: A route to new pancreatic beta cells, CELL RESEARCH, Vol: 27, Pages: 309-310, ISSN: 1001-0602
An ability to convert between pancreatic islet cell types may provide a new approach to replace insulin-secreting β cells destroyed by autoimmune attack in Type 1 diabetes. Two papers, which have recently appeared in Cell, describe how this might be achieved.
Perez Y, Leibson K, Chabosseau P, et al., 2017, SLC30A9 mutation affecting intracellular zinc homeostasis causes a novel cerebro-renal syndrome, Brain, Vol: 140, Pages: 928-939, ISSN: 0006-8950
A novel autosomal recessive cerebro-renal syndrome was identified in consanguineous Bedouin kindred: neurological deterioration was evident as of early age, progressing into severe intellectual disability, profound ataxia, camptocormia and oculomotor apraxia. Brain MRI was normal. Four of the six affected individuals had also early-onset nephropathy with features of tubulo-interstitial nephritis, hypertension and tendency for hyperkalemia, though none had rapid deterioration of renal function. Genome wide linkage analysis identified a ~18Mbsdisease-associated locus on chromosome 4(maximal logarithm of oddsscore 4.4at D4S2971; θ=0). Whole exome sequencing identified a single mutation in SLC30A9within this locus, segregating as expected within the kindred and not found in a homozygous state in 300Bedouin controls. We showed that SLC30A9(Solute Carrier Family 30, Member 9; ZnT-9) is ubiquitously expressed with high levels in cerebellum, skeletal muscle, thymus and kidney. Confocal analysis of SH-SY5Y cells overexpressing SLC30A9fused to enhanced green fluorescent proteindemonstrated vesicular cytosolic localization associated with the endoplasmic reticulum, not co-localizing with endosomal or Golgi markers. SLC30A9encodes a putative zinc transporter (by similarity) previously associated with Wnt signaling. However, using dual-luciferase reporter assay in SH-SY5Y cells we showed that Wnt signaling was not affected by the mutation. Based on protein modeling, the identified mutation is expected to affect SLC30A9’shighly conserved cation efflux domain, putatively disrupting its transmembrane helix structure. Cytosolic Zn2+measurements in HEK293 cells overexpressing wild-type and mutant SLC30A9showed lower zinc concentration within mutantratherthan wild-type SLC30A9cells. Th
Cruciani-Guglielmacci C, Bellini L, Denom J, et al., 2017, Molecular phenotyping of multiple mouse strains under metabolic challenge uncovers a role for Elovl2 in glucose-induced insulin secretion, Molecular Metabolism, Vol: 6, Pages: 340-351, ISSN: 2212-8778
Objective: In type 2 diabetes (T2D), pancreatic β cells become progressively dysfunctional, leading to a decline in insulin secretion over time. In this study, we aimed to identify key genes involved in pancreatic beta cell dysfunction by analyzing multiple mouse strains in parallel under metabolic stress. Methods: Male mice from six commonly used non-diabetic mouse strains were fed a high fat or regular chow diet for three months. Pancreatic islets were extracted and phenotypic measurements were recorded at 2 days, 10 days, 30 days, and 90 days to assess diabetes progression. RNA-Seq was performed on islet tissue at each time-point and integrated with the phenotypic data in a network-based analysis. Results: A module of co-expressed genes was selected for further investigation as it showed the strongest correlation to insulin secretion and oral glucose tolerance phenotypes. One of the predicted network hub genes was Elovl2, encoding Elongase of very long chain fatty acids 2. Elovl2 silencing decreased glucose-stimulated insulin secretion in mouse and human β cell lines. Conclusion: Our results suggest a role for Elovl2 in ensuring normal insulin secretory responses to glucose. Moreover, the large comprehensive dataset and integrative network-based approach provides a new resource to dissect the molecular etiology of β cell failure under metabolic stress.
Carrat GR, Hu M, Nguyen-Tu MS, et al., 2017, Decreased STARD10 expression is associated with defective insulin secretion in humans and mice, American Journal of Human Genetics, Vol: 100, Pages: 238-256, ISSN: 1537-6605
Genetic variants near ARAP1 (CENTD2) and STARD10 influence type 2 diabetes (T2D) risk. The risk alleles impair glucose-induced insulin secretion and, paradoxically but characteristically, are associated with decreased proinsulin:insulin ratios, indicating improved proinsulin conversion. Neither the identity of the causal variants nor the gene(s) through which risk is conferred have been firmly established. Whereas ARAP1 encodes a GTPase activating protein, STARD10 is a member of the steroidogenic acute regulatory protein (StAR)-related lipid transfer protein family. By integrating genetic fine-mapping and epigenomic annotation data and performing promoter-reporter and chromatin conformational capture (3C) studies in β cell lines, we localize the causal variant(s) at this locus to a 5 kb region that overlaps a stretch-enhancer active in islets. This region contains several highly correlated T2D-risk variants, including the rs140130268 indel. Expression QTL analysis of islet transcriptomes from three independent subject groups demonstrated that T2D-risk allele carriers displayed reduced levels of STARD10 mRNA, with no concomitant change in ARAP1 mRNA levels. Correspondingly, β-cell-selective deletion of StarD10 in mice led to impaired glucose-stimulated Ca2+ dynamics and insulin secretion and recapitulated the pattern of improved proinsulin processing observed at the human GWAS signal. Conversely, overexpression of StarD10 in the adult β cell improved glucose tolerance in high fat-fed animals. In contrast, manipulation of Arap1 in β cells had no impact on insulin secretion or proinsulin conversion in mice. This convergence of human and murine data provides compelling evidence that the T2D risk associated with variation at this locus is mediated through reduction in STARD10 expression in the β cell.
Rutter GA, 2017, Diabetes: Controlling the identity of the adult pancreatic β cell., Nature Reviews Endocrinology, Vol: 13, Pages: 129-130, ISSN: 1759-5029
Understanding how pancreatic β cells achieve and maintain functional identity as insulin-secreting cells is a major roadblock in our understanding of the aetiology of diabetes mellitus. Three new papers reveal the roles, in the adult β cell, of four transcription factors that are crucial for reprogramming a multipotent endocrine progenitor.
Martinez-Sanchez A, Rutter GA, Latreille M, 2017, MiRNAs in β-Cell development, identity, and disease., Frontiers in Genetics, Vol: 7, ISSN: 1664-8021
Pancreatic β-cells regulate glucose metabolism by secreting insulin, which in turn stimulates the utilization or storage of the sugar by peripheral tissues. Insulin insufficiency and a prolonged period of insulin resistance are usually the core components of type 2 diabetes (T2D). Although, decreased insulin levels in T2D have long been attributed to a decrease in β-cell function and/or mass, this model has recently been refined with the recognition that a loss of β-cell "identity" and dedifferentiation also contribute to the decline in insulin production. MicroRNAs (miRNAs) are key regulatory molecules that display tissue-specific expression patterns and maintain the differentiated state of somatic cells. During the past few years, great strides have been made in understanding how miRNA circuits impact β-cell identity. Here, we review current knowledge on the role of miRNAs in regulating the acquisition of the β-cell fate during development and in maintaining mature β-cell identity and function during stress situations such as obesity, pregnancy, aging, or diabetes. We also discuss how miRNA function could be harnessed to improve our ability to generate β-cells for replacement therapy for T2D.
Ralston JC, Nguyen-Tu MS, Lyons CL, et al., 2017, Pancreatic islet dysfunction is partially attenuated by replacement of dietary saturated fatty acids with monounsaturated fatty acids, Publisher: CAMBRIDGE UNIV PRESS, Pages: E55-E55, ISSN: 0029-6651
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Merriman C, Huang Q, Rutter GA, et al., 2016, Lipid-tuned zinc transport activity of human ZnT8 protein correlates with risk for Type-2 diabetes, Journal of Biological Chemistry, Vol: 291, Pages: 26950-26957, ISSN: 0021-9258
Zinc is a critical element for insulin storage in the secretory granules of pancreatic beta cells. The islet-specific zinc transporter ZnT8 mediates granular sequestration of zinc ions. A genetic variant of human ZnT8 arising from a single nonsynonymous nucleotide change contributes to increased susceptibility to type-2 diabetes (T2D), but it remains unclear how the high risk variant (Arg-325), which is also a higher frequency (>50%) allele, is correlated with zinc transport activity. Here, we compared the activity of Arg-325 with that of a low risk ZnT8 variant (Trp-325). The Arg-325 variant was found to be more active than the Trp-325 form following induced expression in HEK293 cells. We further examined the functional consequences of changing lipid conditions to mimic the impact of lipid remodeling on ZnT8 activity during insulin granule biogenesis. Purified ZnT8 variants in proteoliposomes exhibited more than 4-fold functional tunability by the anionic phospholipids, lysophosphatidylcholine and cholesterol. Over a broad range of permissive lipid compositions, the Arg-325 variant consistently exhibited accelerated zinc transport kinetics versus the Trp-form. In agreement with the human genetic finding that rare loss-of-function mutations in ZnT8 are associated with reduced T2D risk, our results suggested that the common high risk Arg-325 variant is hyperactive, and thus may be targeted for inhibition to reduce T2D risk in the general populations.
Tuncay E, Bitirim V, Durak A, et al., 2016, Both Reactive ROS and RNS Contribute to Intracellular Free Zn<SUP>2+</SUP> Regulation in Cardiomyocytes Via Zinc Transporter ZIP7 Under Hyperglycemia, Publisher: ELSEVIER SCIENCE INC, Pages: S153-S153, ISSN: 0891-5849
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Kanda N, Buenaventura T, Correa Jr IR, et al., 2016, Co-operation between Epidermal Growth Factor Receptor and Glucagon-like Peptide 1 Receptor in Pancreatic Beta Cell Survival during Oxidative stress, EMJ Diabetes, ISSN: 2054-6181
Johnston NR, Mitchell RK, Haythorne E, et al., 2016, Beta cell hubs dictate pancreatic islet responses to glucose, Cell Metabolism, Vol: 24, Pages: 389-401, ISSN: 1932-7420
The arrangement of beta cells within islets of Langerhans is critical for insulin release through thegeneration of rhythmic activity. A privileged role for individual beta cells in orchestrating theseresponses has long-been suspected, but not directly demonstrated. We show here that the beta cellpopulation in situ is operationally heterogeneous. Mapping of islet functional architecturerevealed the presence of hub cells with pacemaker properties, which remain stable over recordingperiods of 2-3 hours. Using a dual optogenetic/photopharmacological strategy, silencing of hubsabolished coordinated islet responses to glucose, whereas specific stimulation restoredcommunication patterns. Hubs were metabolically-adapted and targeted by both proinflammatoryand glucolipotoxic insults to induce widespread beta cell dysfunction. Thus, theislet is wired by hubs, whose failure may contribute to type 2 diabetes mellitus.
Rutter GA, 2016, Modeling type 2 diabetes GWAS candidate gene function in hESCs., Cell Stem Cell, Vol: 19, Pages: 281-282, ISSN: 1934-5909
Type 2 diabetes is a complex polygenic disorder that affects about 1 in 12 adults. In this issue of Cell Stem Cell, Zeng et al. (2016) elegantly combine CRISPR-based gene editing in hESCs with directed β cell differentiation to investigate the functions of genes highlighted by genome-wide association studies (GWAS) for this disease.
Mehta ZB, FIne N, Pullen TJ, et al., 2016, Changes in the expression of the type 2 diabetes-associated gene VPS13C in the β cell are associated with glucose intolerance in humans and mice, American Journal of Physiology-Endocrinology and Metabolism, Vol: 311, Pages: E488-E507, ISSN: 1522-1555
Single nucleotide polymorphisms (SNPs) close to the VPS13C, C2CD4A and C2CD4B genes on chromosome 15q are associated with impaired fasting glucose and increased risk of type 2 diabetes. eQTL analysis revealed an association between possession of risk (C) alleles at a previously implicated causal SNP, rs7163757, and lowered VPS13C and C2CD4A levels in islets from female (n = 40, P < 0.041) but not from male subjects. Explored using promoter-reporter assays in β-cells and other cell lines, the risk variant at rs7163757 lowered enhancer activity. Mice deleted for Vps13c selectively in the β-cell were generated by crossing animals bearing a floxed allele at exon 1 to mice expressing Cre recombinase under Ins1 promoter control (Ins1Cre). Whereas Vps13cfl/fl:Ins1Cre (βVps13cKO) mice displayed normal weight gain compared with control littermates, deletion of Vps13c had little effect on glucose tolerance. Pancreatic histology revealed no significant change in β-cell mass in KO mice vs. controls, and glucose-stimulated insulin secretion from isolated islets was not altered in vitro between control and βVps13cKO mice. However, a tendency was observed in female null mice for lower insulin levels and β-cell function (HOMA-B) in vivo. Furthermore, glucose-stimulated increases in intracellular free Ca2+ were significantly increased in islets from female KO mice, suggesting impaired Ca2+ sensitivity of the secretory machinery. The present data thus provide evidence for a limited role for changes in VPS13C expression in conferring altered disease risk at this locus, particularly in females, and suggest that C2CD4A may also be involved.
Carrat GR, Nguyen-Tu M-S, Hu M, et al., 2016, Deletion of the type 2 diabetes-associated gene product StarD10 in mice impairs insulin secretion and action, 52nd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S88-S88, ISSN: 0012-186X
Agha-Jaffar R, Misra S, Oliver N, et al., 2016, Ethnic variations in glucose and the interaction with fetal growth in a multi-ethnic inner city antenatal cohort, 52nd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: Springer Verlag, Pages: S447-S448, ISSN: 0012-186X
Nguyen-Tu M-S, Leclerc I, da Silva-Xavier G, et al., 2016, Role of the type 2 diabetes GWAS gene TCF7L2 in LKB1-mediated regulation of insulin secretion in the murine beta cell, 52nd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: Springer Verlag, Pages: S169-S169, ISSN: 0012-186X
Kanda N, Buenaventura T, Correa IR, et al., 2016, Oxidative stress-induced EGF and GLP-1 receptors cooperate towards pancreatic beta cell survival in response to inflammatory cytokines and glucolipotoxicity, 52nd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S189-S189, ISSN: 0012-186X
Jones B, Buenaventura T, Owen B, et al., 2016, Biased agonism alters GLP-1 receptor trafficking and glucose homeostasis, 52nd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S72-S73, ISSN: 0012-186X
Rutter GA, Mitchell RK, Hodson DJ, 2016, Pax6 is required for the functional identity of the adult pancreatic beta cell, 52nd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: Springer Verlag, Pages: S168-S169, ISSN: 0012-186X
Frank JA, Yushchenko DA, Hodson DJ, et al., 2016, Photoswitchable diacylglycerols enable optical control of protein kinase C., Nature Chemical Biology, Vol: 12, Pages: 755-762, ISSN: 1552-4469
Increased levels of the second messenger lipid diacylglycerol (DAG) induce downstream signaling events including the translocation of C1-domain-containing proteins toward the plasma membrane. Here, we introduce three light-sensitive DAGs, termed PhoDAGs, which feature a photoswitchable acyl chain. The PhoDAGs are inactive in the dark and promote the translocation of proteins that feature C1 domains toward the plasma membrane upon a flash of UV-A light. This effect is quickly reversed after the termination of photostimulation or by irradiation with blue light, permitting the generation of oscillation patterns. Both protein kinase C and Munc13 can thus be put under optical control. PhoDAGs control vesicle release in excitable cells, such as mouse pancreatic islets and hippocampal neurons, and modulate synaptic transmission in Caenorhabditis elegans. As such, the PhoDAGs afford an unprecedented degree of spatiotemporal control and are broadly applicable tools to study DAG signaling.
Solomou A, Philippe E, Chabosseau P, et al., 2016, Over-expression of Slc30a8/ZnT8 selectively in the mouse α cell impairs glucagon release and responses to hypoglycemia, Nutrition and Metabolism, Vol: 13, ISSN: 0029-6678
BackgroundThe human SLC30A8 gene encodes the secretory granule-localised zinc transporter ZnT8 whose expression is chiefly restricted to the endocrine pancreas. Single nucleotide polymorphisms (SNPs) in the human SLC30A8 gene have been associated, through genome-wide studies, with altered type 2 diabetes risk. In addition to a role in the control of insulin release, recent studies involving targeted gene ablation from the pancreatic α cell (Solomou et al., J Biol Chem 290(35):21432-42) have also implicated ZnT8 in the control of glucagon release. Up to now, however, the possibility that increased levels of the transporter in these cells may impact glucagon secretion has not been explored.MethodsHere, we use a recently-developed reverse tetracyline transactivator promoter-regulated ZnT8 transgene to drive the over-expression of human ZnT8 selectively in the α cell in adult mice. Glucose homeostasis and glucagon secretion were subsequently assessed both in vivo during hypoglycemic clamps and from isolated islets in vitro.ResultsDoxyclin-dependent human ZnT8 mRNA expression was apparent in both isolated islets and in fluorescence-activated cell sorting- (FACS) purified α cells. Examined at 12 weeks of age, intraperitoneal glucose (1 g/kg) tolerance was unchanged in transgenic mice versus wild-type littermates (n = 8-10 mice/genotype, p > 0.05) and sensitivity to intraperitoneal insulin (0.75U/kg) was similarly unaltered in transgenic animals. In contrast, under hyperinsulinemic-hypoglycemic clamp, a ~45 % (p < 0.001) reduction in glucose infusion rate was apparent, and glucagon release was significantly (~40 %, p < 0.01) impaired, in transgenic mice. Correspondingly, examined in vitro, glucagon secretion was significantly reduced (~30 %, p < 0.05) from transgenic versus control islets at low, stimulatory glucose concentrations (1 mM, p < 0.05) but not at
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