454 results found
Zinc homeostasis is essential for normal cellular function, and defects in this process are associated with a number of diseases including type 2 diabetes (T2D), neurological disorders and cardiovascular disease. Thus, variants in the SLC30A8 gene, encoding the vesicular/granular zinc transporter ZnT8, are associated with altered insulin release and increased T2D risk while the zinc importer ZIP12 is implicated in pulmonary hypertension. In light of these, and findings in other diseases, recent efforts have focused on the development of refined sensors for intracellular free zinc ions that can be targeted to subcellular regions including the cytosol, endoplasmic reticulum (ER), secretory granules, Golgi apparatus, nucleus and the mitochondria. Here, we discuss recent advances in Zn2+ probe engineering and their applications to the measurement of labile subcellular zinc pools in different cell types.
Fine NHF, Doig CL, Elhassan YS, et al., 2018, Glucocorticoids Reprogram β-Cell Signaling to Preserve Insulin Secretion., Diabetes, Vol: 67, Pages: 278-290
Excessive glucocorticoid exposure has been shown to be deleterious for pancreatic β-cell function and insulin release. However, glucocorticoids at physiological levels are essential for many homeostatic processes, including glycemic control. 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 in human β-cells. However, insulin secretion, maximal ATP/ADP responses to glucose, and β-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 because 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 syndrome, which are associated with frank dyslipidemia.
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, Cebola I, et al., 2018, MiR-184 expression is regulated by AMPK in pancreatic islets., FASEB J
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.
Solimena M, Schulte AM, Marselli L, et al., 2018, 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
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
Tuncay E, Bitirim CV, Olgar Y, et al., 2018, Zn2+-transporters ZIP7 and ZnT7 play important role in progression of cardiac dysfunction via affecting sarco(endo)plasmic reticulum-mitochondria coupling in hyperglycemic cardiomyocytes., Mitochondrion
Functional contribution of S(E)R-mitochondria coupling to normal cellular processes is crucial and any alteration in S(E)R-mitochondria axis may be responsible for the onset of diseases. Mitochondrial free Zn2+level in cardiomyocytes ([Zn2+]Mit) is lower comparison to either its cytosolic or S(E)R level under physiological condition. However, there is little information about distribution of Zn2+-transporters on mitochondria and role of Zn2+-dependent mitochondrial-function associated with [Zn2+]Mit. Since we recently have shown how hyperglycemia (HG)-induced changes in ZIP7 and ZnT7 contribute to Zn2+-transport across S(E)R and contribute to S(E)R-stress in the heart, herein, we hypothesized that these transporters can also be localized to mitochondria and affect the S(E)R-mitochondria coupling, and thereby contribute to cellular Zn2+-muffling between S(E)R-mitochondria in HG-cells. Mitochondrial localizations of ZIP7 and ZnT7 were demonstrated using fluorescence technique while they were confirmed in isolated mitochondrial fractions using biochemical analysis. Markedly decreased ZIP7 and increased ZnT7 levels were measured in isolated mitochondrial fractions from either HG- or doxorubicin, DOX (as positive control)-treated cardiomyocytes. Significantly increases in [Zn2+]Mitand ROS production levels and depolarized mitochondrial membrane potential were also measured in HG cells. The expression levels of some key proteins, responsible for proper S(E)R-mitochondria coupling such as Mfn-1, Fis-1, OPA1, BAP31, STIM1 and PML in either HG- or DOX-cells were supported our above hypothesis, strongly. Overall, this study provides an important description about the role of ZIP7 and ZnT7, localized to both mitochondria and S(E)R and contribute to cellular Zn2+-muffling between cellular-compartments in HG or hypertrophic cardiomyocytes via affecting S(E)R-mitochondria coupling. Any alteration in this axis and/or cellular [Zn2+] may provide new insight for prevention/therapy o
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
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.
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
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
Carrat GR, Hu M, Nguyen-Tu M-S, 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: 0002-9297
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
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
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
Gao T, Chabosseau P, Rutter GA, et al., 2017, Sorcin stimulates ATF6 transcriptional activity, DIABETIC MEDICINE, Vol: 34, Pages: 43-43, ISSN: 0742-3071
Gerber PA, Rutter GA, 2017, The Role of Oxidative Stress and Hypoxia in Pancreatic Beta-Cell Dysfunction in Diabetes Mellitus, ANTIOXIDANTS & REDOX SIGNALING, Vol: 26, Pages: 501-+, ISSN: 1523-0864
Gharavy SNM, Li X, Martinez-Sanchez A, et al., 2017, Putative roles of the Type 2 diabetes-associated genes C2CD4A and C2CD4B in the control of insulin secretion, DIABETIC MEDICINE, Vol: 34, Pages: 79-79, ISSN: 0742-3071
Haythorne EA, Martinez-Sanchez A, Rizzuto R, et al., 2017, The mitochondrial Ca2+ uniporter (MCUa) is required for glucose-stimulated mitochondrial Ca2+ 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
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
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
Martinez-Sanchez A, Rutter GA, Latreille M, 2017, MiRNAs in beta-Cell Development, Identity, and Disease, FRONTIERS IN GENETICS, Vol: 7, ISSN: 1664-8021
Martinez-Sanchez A, Shapiro J, Marchetti P, et al., 2017, AMP-Activated Protein Kinase (AMPK) Regulates beta-Cell MicroRNA Expression, 77th Scientific Sessions of the American-Diabetes-Association, Publisher: AMER DIABETES ASSOC, Pages: A29-A29, ISSN: 0012-1797
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
Mitchell RK, Nguyen-Tu M-S, Chabosseau P, et al., 2017, The transcription factor Pax6 is required for pancreatic beta cell identity, glucose-regulated ATP synthesis, and Ca2+ dynamics in adult mice, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 292, Pages: 8892-8906, ISSN: 0021-9258
Nasteska D, Fine NHF, Rutter GA, et al., 2017, beta cell diversity is required for normal islet function, Publisher: WILEY, Pages: 12-14, ISSN: 1748-1708
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: AMER DIABETES ASSOC, Pages: A577-A577, ISSN: 0012-1797
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
Perez Y, Shorer Z, Liani-Leibson K, et al., 2017, SLC30A9 mutation affecting intracellular zinc homeostasis causes a novel cerebro-renal syndrome, BRAIN, Vol: 140, Pages: 928-939, ISSN: 0006-8950
Pullen TJ, Huising MO, Rutter GA, 2017, Analysis of Purified Pancreatic Islet Beta and Alpha Cell Transcriptomes Reveals 11 beta-Hydroxysteroid Dehydrogenase (Hsd11b1) as a Novel Disallowed Gene, FRONTIERS IN GENETICS, Vol: 8, ISSN: 1664-8021
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
Rutter GA, 2017, Controlling the identity of the adult pancreatic beta cell, NATURE REVIEWS ENDOCRINOLOGY, Vol: 13, Pages: 129-+, ISSN: 1759-5029
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