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3. Differential CpG methylation at Nnat in the early establishment of beta cell heterogeneity

Author

Yu, Vanessa, Yong, Fiona, Marta, Angellica, Khadayate, Sanjay, Osakwe, Adrien, Bhattacharya, Supriyo, Varghese, Sneha S., Chabosseau, Pauline, Tabibi, Sayed M., Chen, Keran, Georgiadou, Eleni, Parveen, Nazia, Suleiman, Mara, Stamoulis, Zoe, Marselli, Lorella, De Luca, Carmela, Tesi, Marta, Ostinelli, Giada, Delgadillo-Silva, Luis, Wu, Xiwei, Hatanaka, Yuki, Montoya, Alex, Elliott, James, Patel, Bhavik, Demchenko, Nikita, Whilding, Chad, Hajkova, Petra, Shliaha, Pavel, Kramer, Holger, Ali, Yusuf, Marchetti, Piero, Sladek, Robert, Dhawan, Sangeeta, Withers, Dominic J., Rutter, Guy A., and Millership, Steven J.

Published
2024
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5. Roles for the long non-coding RNA Pax6os1/PAX6-AS1 in pancreatic beta cell function

Author

Lopez-Noriega, Livia, Callingham, Rebecca, Martinez-Sánchez, Aida, Nawaz, Sameena, Pizza, Grazia, Haberman, Nejc, Cvetesic, Nevena, Nguyen-Tu, Marie-Sophie, Lenhard, Boris, Marchetti, Piero, Piemonti, Lorenzo, de Koning, Eelco, Shapiro, A.M. James, Johnson, Paul R., Leclerc, Isabelle, Hastoy, Benoit, Gauthier, Benoit R., Pullen, Timothy J., and Rutter, Guy A.

Published
2025
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9. Identification of biomarkers for glycaemic deterioration in type 2 diabetes

Author

Slieker, Roderick C., Donnelly, Louise A., Akalestou, Elina, Lopez-Noriega, Livia, Melhem, Rana, Güneş, Ayşim, Abou Azar, Frederic, Efanov, Alexander, Georgiadou, Eleni, Muniangi-Muhitu, Hermine, Sheikh, Mahsa, Giordano, Giuseppe N., Åkerlund, Mikael, Ahlqvist, Emma, Ali, Ashfaq, Banasik, Karina, Brunak, Søren, Barovic, Marko, Bouland, Gerard A., Burdet, Frédéric, Canouil, Mickaël, Dragan, Iulian, Elders, Petra J. M., Fernandez, Celine, Festa, Andreas, Fitipaldi, Hugo, Froguel, Phillippe, Gudmundsdottir, Valborg, Gudnason, Vilmundur, Gerl, Mathias J., van der Heijden, Amber A., Jennings, Lori L., Hansen, Michael K., Kim, Min, Leclerc, Isabelle, Klose, Christian, Kuznetsov, Dmitry, Mansour Aly, Dina, Mehl, Florence, Marek, Diana, Melander, Olle, Niknejad, Anne, Ottosson, Filip, Pavo, Imre, Duffin, Kevin, Syed, Samreen K., Shaw, Janice L., Cabrera, Over, Pullen, Timothy J., Simons, Kai, Solimena, Michele, Suvitaival, Tommi, Wretlind, Asger, Rossing, Peter, Lyssenko, Valeriya, Legido Quigley, Cristina, Groop, Leif, Thorens, Bernard, Franks, Paul W., Lim, Gareth E., Estall, Jennifer, Ibberson, Mark, Beulens, Joline W. J., ’t Hart, Leen M, Pearson, Ewan R., and Rutter, Guy A.

Published
2023
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12. Contributors

Author

Ali, Taqveema, primary, Balasinor, Nafisa H., additional, Campbell, Taylor S., additional, Cayir, Akin, additional, Chen, Keran, additional, Cortes, Laura R., additional, Farrell, Chloe M., additional, Forger, Nancy G., additional, He, Zhengying, additional, Hood, Lauren E., additional, Jiang, Jiachun, additional, Kaur, Kirtan, additional, Kaur, Jyotdeep, additional, Khan, Shagufta, additional, Leyrer-Jackson, Jonna M., additional, Liu, Simeiyun, additional, Liu, X. Shawn, additional, Millership, Steven J., additional, Mishra, Rakesh K., additional, Nishi, Kumari, additional, Olive, M. Foster, additional, Rahat, Beenish, additional, Robert, Valerie Jane, additional, Roth, Tania L., additional, Rutter, Guy A., additional, Shaffer, Joshua F., additional, Sharma, Renuka, additional, Sharma, Upasna, additional, Srivastava, Surabhi, additional, Stamoulis, Zoe, additional, Wang, Minglu, additional, and Yu, Vanessa, additional

Published
2023
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14. mTORC1 to AMPK switching underlies β-cell metabolic plasticity during maturation and diabetes

Author

Jaafar, Rami, Tran, Stella, Shah, Ajit N, Sun, Gao, Valdearcos, Martin, Marchetti, Piero, Masini, Matilde, Swisa, Avital, Giacometti, Simone, Bernal-Mizrachi, Ernesto, Matveyenko, Aleksey, Hebrok, Matthias, Dor, Yuval, Rutter, Guy A, Koliwad, Suneil K, and Bhushan, Anil

Subjects
Diabetes, Nutrition, Underpinning research, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Aetiology, Metabolic and endocrine, AMP-Activated Protein Kinases, Animals, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, Insulin Secretion, Insulin-Secreting Cells, Mechanistic Target of Rapamycin Complex 1, Mice, Mice, Knockout, Signal Transduction, Endocrinology, Medical and Health Sciences, Immunology
Abstract

Pancreatic beta cells (β-cells) differentiate during fetal life, but only postnatally acquire the capacity for glucose-stimulated insulin secretion (GSIS). How this happens is not clear. In exploring what molecular mechanisms drive the maturation of β-cell function, we found that the control of cellular signaling in β-cells fundamentally switched from the nutrient sensor target of rapamycin (mTORC1) to the energy sensor 5'-adenosine monophosphate-activated protein kinase (AMPK), and that this was critical for functional maturation. Moreover, AMPK was activated by the dietary transition taking place during weaning, and this in turn inhibited mTORC1 activity to drive the adult β-cell phenotype. While forcing constitutive mTORC1 signaling in adult β-cells relegated them to a functionally immature phenotype with characteristic transcriptional and metabolic profiles, engineering the switch from mTORC1 to AMPK signaling was sufficient to promote β-cell mitochondrial biogenesis, a shift to oxidative metabolism, and functional maturation. We also found that type 2 diabetes, a condition marked by both mitochondrial degeneration and dysregulated GSIS, was associated with a remarkable reversion of the normal AMPK-dependent adult β-cell signature to a more neonatal one characterized by mTORC1 activation. Manipulating the way in which cellular nutrient signaling pathways regulate β-cell metabolism may thus offer new targets to improve β-cell function in diabetes.

Published
2019

15. An essential role for the Zn2+ transporter ZIP7 in B cell development

Author

Anzilotti, Consuelo, Swan, David J, Boisson, Bertrand, Deobagkar-Lele, Mukta, Oliveira, Catarina, Chabosseau, Pauline, Engelhardt, Karin R, Xu, Xijin, Chen, Rui, Alvarez, Luis, Berlinguer-Palmini, Rolando, Bull, Katherine R, Cawthorne, Eleanor, Cribbs, Adam P, Crockford, Tanya L, Dang, Tarana Singh, Fearn, Amy, Fenech, Emma J, de Jong, Sarah J, Lagerholm, B Christoffer, Ma, Cindy S, Sims, David, van den Berg, Bert, Xu, Yaobo, Cant, Andrew J, Kleiner, Gary, Leahy, T Ronan, de la Morena, M Teresa, Puck, Jennifer M, Shapiro, Ralph S, van der Burg, Mirjam, Chapman, J Ross, Christianson, John C, Davies, Benjamin, McGrath, John A, Przyborski, Stefan, Santibanez Koref, Mauro, Tangye, Stuart G, Werner, Andreas, Rutter, Guy A, Padilla-Parra, Sergi, Casanova, Jean-Laurent, Cornall, Richard J, Conley, Mary Ellen, and Hambleton, Sophie

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Pediatric, Genetics, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Agammaglobulinemia, Animals, B-Lymphocytes, Cation Transport Proteins, Child, Preschool, Cytosol, Disease Models, Animal, Endoplasmic Reticulum, Female, Gene Expression Profiling, Humans, Infant, Male, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Pedigree, Zinc, Immunology, Biochemistry and cell biology
Abstract

Despite the known importance of zinc for human immunity, molecular insights into its roles have remained limited. Here we report a novel autosomal recessive disease characterized by absent B cells, agammaglobulinemia and early onset infections in five unrelated families. The immunodeficiency results from hypomorphic mutations of SLC39A7, which encodes the endoplasmic reticulum-to-cytoplasm zinc transporter ZIP7. Using CRISPR-Cas9 mutagenesis we have precisely modeled ZIP7 deficiency in mice. Homozygosity for a null allele caused embryonic death, but hypomorphic alleles reproduced the block in B cell development seen in patients. B cells from mutant mice exhibited a diminished concentration of cytoplasmic free zinc, increased phosphatase activity and decreased phosphorylation of signaling molecules downstream of the pre-B cell and B cell receptors. Our findings highlight a specific role for cytosolic Zn2+ in modulating B cell receptor signal strength and positive selection.

Published
2019

22. Replication and cross-validation of type 2 diabetes subtypes based on clinical variables: an IMI-RHAPSODY study

Author

Slieker, Roderick C., Donnelly, Louise A., Fitipaldi, Hugo, Bouland, Gerard A., Giordano, Giuseppe N., Åkerlund, Mikael, Gerl, Mathias J., Ahlqvist, Emma, Ali, Ashfaq, Dragan, Iulian, Festa, Andreas, Hansen, Michael K., Mansour Aly, Dina, Kim, Min, Kuznetsov, Dmitry, Mehl, Florence, Klose, Christian, Simons, Kai, Pavo, Imre, Pullen, Timothy J., Suvitaival, Tommi, Wretlind, Asger, Rossing, Peter, Lyssenko, Valeriya, Legido-Quigley, Cristina, Groop, Leif, Thorens, Bernard, Franks, Paul W., Ibberson, Mark, Rutter, Guy A., Beulens, Joline W. J., ‘t Hart, Leen M., and Pearson, Ewan R.

Published
2021
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25. Persistent or Transient Human β Cell Dysfunction Induced by Metabolic Stress: Specific Signatures and Shared Gene Expression with Type 2 Diabetes

Author

Marselli, Lorella, Piron, Anthony, Suleiman, Mara, Colli, Maikel L., Yi, Xiaoyan, Khamis, Amna, Carrat, Gaelle R., Rutter, Guy A., Bugliani, Marco, Giusti, Laura, Ronci, Maurizio, Ibberson, Mark, Turatsinze, Jean-Valery, Boggi, Ugo, De Simone, Paolo, De Tata, Vincenzo, Lopes, Miguel, Nasteska, Daniela, De Luca, Carmela, Tesi, Marta, Bosi, Emanuele, Singh, Pratibha, Campani, Daniela, Schulte, Anke M., Solimena, Michele, Hecht, Peter, Rady, Brian, Bakaj, Ivona, Pocai, Alessandro, Norquay, Lisa, Thorens, Bernard, Canouil, Mickaël, Froguel, Philippe, Eizirik, Decio L., Cnop, Miriam, and Marchetti, Piero

Published
2020
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27. The type 2 diabetes gene product STARD10 is a phosphoinositide-binding protein that controls insulin secretory granule biogenesis

Author

Carrat, Gaelle R., Haythorne, Elizabeth, Tomas, Alejandra, Haataja, Leena, Müller, Andreas, Arvan, Peter, Piunti, Alexandra, Cheng, Kaiying, Huang, Mutian, Pullen, Timothy J., Georgiadou, Eleni, Stylianides, Theodoros, Amirruddin, Nur Shabrina, Salem, Victoria, Distaso, Walter, Cakebread, Andrew, Heesom, Kate J., Lewis, Philip A., Hodson, David J., Briant, Linford J., Fung, Annie C.H., Sessions, Richard B., Alpy, Fabien, Kong, Alice P.S., Benke, Peter I., Torta, Federico, Teo, Adrian Kee Keong, Leclerc, Isabelle, Solimena, Michele, Wigley, Dale B., and Rutter, Guy A.

Published
2020
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28. A polysaccharide extract from the medicinal plant Maidong inhibits the IKK–NF-κB pathway and IL-1β–induced islet inflammation and increases insulin secretion

Author

Mao, Dandan, Tian, Xiao Yu, Mao, Di, Hung, Sze Wan, Wang, Chi Chiu, Lau, Clara Bik San, Lee, Heung Man, Wong, Chun Kwok, Chow, Elaine, Ming, Xing, Cao, Huanyi, Ma, Ronald C., Chan, Paul K.S., Kong, Alice P.S., Li, Joshua J.X., Rutter, Guy A., Tam, Wing Hung, and Chan, Juliana C.N.

Published
2020
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29. A surrogate of Roux-en-Y gastric bypass (the enterogastro anastomosis surgery) regulates multiple beta-cell pathways during resolution of diabetes in ob/ob mice

Author

Amouyal, Chloé, Castel, Julien, Guay, Claudiane, Lacombe, Amélie, Denom, Jessica, Migrenne-Li, Stéphanie, Rouault, Christine, Marquet, Florian, Georgiadou, Eleni, Stylianides, Theodoros, Luquet, Serge, Le Stunff, Hervé, Scharfmann, Raphael, Clément, Karine, Rutter, Guy A., Taboureau, Olivier, Magnan, Christophe, Regazzi, Romano, and Andreelli, Fabrizio

Published
2020
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32. Decreased STARD10 Expression Is Associated with Defective Insulin Secretion in Humans and Mice

Author

Carrat, Gaelle R, Hu, Ming, Nguyen-Tu, Marie-Sophie, Chabosseau, Pauline, Gaulton, Kyle J, van de Bunt, Martijn, Siddiq, Afshan, Falchi, Mario, Thurner, Matthias, Canouil, Mickaël, Pattou, Francois, Leclerc, Isabelle, Pullen, Timothy J, Cane, Matthew C, Prabhala, Priyanka, Greenwald, William, Schulte, Anke, Marchetti, Piero, Ibberson, Mark, MacDonald, Patrick E, Fox, Jocelyn E Manning, Gloyn, Anna L, Froguel, Philippe, Solimena, Michele, McCarthy, Mark I, and Rutter, Guy A

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Genetics, Biological Sciences, Human Genome, Diabetes, 2.1 Biological and endogenous factors, Metabolic and endocrine, Adaptor Proteins, Signal Transducing, Alleles, Animals, Carrier Proteins, Cloning, Molecular, Diabetes Mellitus, Type 2, GTPase-Activating Proteins, Gene Expression Regulation, Genetic Variation, Homeostasis, Humans, Insulin, Insulin Secretion, Insulin-Secreting Cells, Liver, Mice, Phosphoproteins, Proinsulin, Quantitative Trait Loci, Transcriptome, ARAP1, GWAS, STARD10, diabetes, genetics, insulin, islet, mouse, secretion, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

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.

Published
2017

33. Analysis of Purified Pancreatic Islet Beta and Alpha Cell Transcriptomes Reveals 11β-Hydroxysteroid Dehydrogenase (Hsd11b1) as a Novel Disallowed Gene

Author

Pullen, Timothy J, Huising, Mark O, and Rutter, Guy A

Subjects
Biochemistry and Cell Biology, Bioinformatics and Computational Biology, Genetics, Biological Sciences, Autoimmune Disease, Diabetes, 2.1 Biological and endogenous factors, Aetiology, Metabolic and endocrine, Hsd11b1, glucocorticoids, islets of langerhans, beta cells, alpha cells, diabetes mellitus, disallowed genes, Clinical Sciences, Law
Abstract

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.

Published
2017

35. LDHB contributes to the regulation of lactate levels and basal insulin secretion in human pancreatic β cells

Author

Cuozzo, Federica, primary, Viloria, Katrina, additional, Shilleh, Ali H., additional, Nasteska, Daniela, additional, Frazer-Morris, Charlotte, additional, Tong, Jason, additional, Jiao, Zicong, additional, Boufersaoui, Adam, additional, Marzullo, Bryan, additional, Rosoff, Daniel B., additional, Smith, Hannah R., additional, Bonner, Caroline, additional, Kerr-Conte, Julie, additional, Pattou, Francois, additional, Nano, Rita, additional, Piemonti, Lorenzo, additional, Johnson, Paul R.V., additional, Spiers, Rebecca, additional, Roberts, Jennie, additional, Lavery, Gareth G., additional, Clark, Anne, additional, Ceresa, Carlo D.L., additional, Ray, David W., additional, Hodson, Leanne, additional, Davies, Amy P., additional, Rutter, Guy A., additional, Oshima, Masaya, additional, Scharfmann, Raphaël, additional, Merrins, Matthew J., additional, Akerman, Ildem, additional, Tennant, Daniel A., additional, Ludwig, Christian, additional, and Hodson, David J., additional

Published
2024
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36. Multi-omics subgroups associated with glycaemic deterioration in type 2 diabetes: an IMI-RHAPSODY Study

Author

Li, Shiying, primary, Dragan, Iulian, additional, Tran, Van Du T., additional, Fung, Chun Ho, additional, Kuznetsov, Dmitry, additional, Hansen, Michael K., additional, Beulens, Joline W. J., additional, Hart, Leen M. ‘t, additional, Slieker, Roderick C., additional, Donnelly, Louise A., additional, Gerl, Mathias J., additional, Klose, Christian, additional, Mehl, Florence, additional, Simons, Kai, additional, Elders, Petra J. M., additional, Pearson, Ewan R., additional, Rutter, Guy A., additional, and Ibberson, Mark, additional

Published
2024
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37. Sexually dimorphic roles for the type 2 diabetes-associated C2cd4b gene in murine glucose homeostasis

Author

Mousavy Gharavy, S. Neda, Owen, Bryn M., Millership, Steven J., Chabosseau, Pauline, Pizza, Grazia, Martinez-Sanchez, Aida, Tasoez, Emirhan, Georgiadou, Eleni, Hu, Ming, Fine, Nicholas H. F., Jacobson, David A., Dickerson, Matthew T., Idevall-Hagren, Olof, Montoya, Alex, Kramer, Holger, Mehta, Zenobia, Withers, Dominic J., Ninov, Nikolay, Gadue, Paul J., Cardenas-Diaz, Fabian L., Cruciani-Guglielmacci, Céline, Magnan, Christophe, Ibberson, Mark, Leclerc, Isabelle, Voz, Marianne, and Rutter, Guy A.

Published
2021
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40. An omics-based machine learning approach to predict diabetes progression: a RHAPSODY study

Author

Circulatory Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Cardiometabolic Health, Slieker, Roderick C., Münch, Magnus, Donnelly, Louise A., Bouland, Gerard A., Dragan, Iulian, Kuznetsov, Dmitry, Elders, Petra J.M., Rutter, Guy A., Ibberson, Mark, Pearson, Ewan R., ’t Hart, Leen M., van de Wiel, Mark A., Beulens, Joline W.J., Circulatory Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Cardiometabolic Health, Slieker, Roderick C., Münch, Magnus, Donnelly, Louise A., Bouland, Gerard A., Dragan, Iulian, Kuznetsov, Dmitry, Elders, Petra J.M., Rutter, Guy A., Ibberson, Mark, Pearson, Ewan R., ’t Hart, Leen M., van de Wiel, Mark A., and Beulens, Joline W.J.

Published
2024

41. An omics-based machine learning approach to predict diabetes progression: a RHAPSODY study

Author

Slieker, Roderick C. (author), Münch, Magnus (author), Donnelly, Louise A. (author), Bouland, G.A. (author), Dragan, Iulian (author), Kuznetsov, Dmitry (author), Elders, Petra J.M. (author), Rutter, Guy A. (author), Ibberson, Mark (author), Slieker, Roderick C. (author), Münch, Magnus (author), Donnelly, Louise A. (author), Bouland, G.A. (author), Dragan, Iulian (author), Kuznetsov, Dmitry (author), Elders, Petra J.M. (author), Rutter, Guy A. (author), and Ibberson, Mark (author)

Abstract

Aims/hypothesis: People with type 2 diabetes are heterogeneous in their disease trajectory, with some progressing more quickly to insulin initiation than others. Although classical biomarkers such as age, HbA1c and diabetes duration are associated with glycaemic progression, it is unclear how well such variables predict insulin initiation or requirement and whether newly identified markers have added predictive value. Methods: In two prospective cohort studies as part of IMI-RHAPSODY, we investigated whether clinical variables and three types of molecular markers (metabolites, lipids, proteins) can predict time to insulin requirement using different machine learning approaches (lasso, ridge, GRridge, random forest). Clinical variables included age, sex, HbA1c, HDL-cholesterol and C-peptide. Models were run with unpenalised clinical variables (i.e. always included in the model without weights) or penalised clinical variables, or without clinical variables. Model development was performed in one cohort and the model was applied in a second cohort. Model performance was evaluated using Harrel’s C statistic. Results: Of the 585 individuals from the Hoorn Diabetes Care System (DCS) cohort, 69 required insulin during follow-up (1.0–11.4 years); of the 571 individuals in the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) cohort, 175 required insulin during follow-up (0.3–11.8 years). Overall, the clinical variables and proteins were selected in the different models most often, followed by the metabolites. The most frequently selected clinical variables were HbA1c (18 of the 36 models, 50%), age (15 models, 41.2%) and C-peptide (15 models, 41.2%). Base models (age, sex, BMI, HbA1c) including only clinical variables performed moderately in both the DCS discovery cohort (C statistic 0.71 [95% CI 0.64, 0.79]) and the GoDARTS replication cohort (C 0.71 [95% CI 0.69, 0.75]). A more extensive model including HD, Pattern Recognition and Bioinformatics

Published
2024
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43. The pore-forming subunit MCU of the mitochondrial Ca2+ uniporter is required for normal glucose-stimulated insulin secretion in vitro and in vivo in mice

Author

Georgiadou, Eleni, Haythorne, Elizabeth, Dickerson, Matthew T., Lopez-Noriega, Livia, Pullen, Timothy J., da Silva Xavier, Gabriela, Davis, Samuel P. X., Martinez-Sanchez, Aida, Semplici, Francesca, Rizzuto, Rosario, McGinty, James A., French, Paul M., Cane, Matthew C., Jacobson, David A., Leclerc, Isabelle, and Rutter, Guy A.

Published
2020
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46. PDX1LOW MAFALOW β-cells contribute to islet function and insulin release

Author

Nasteska, Daniela, Fine, Nicholas H. F., Ashford, Fiona B., Cuozzo, Federica, Viloria, Katrina, Smith, Gabrielle, Dahir, Aisha, Dawson, Peter W. J., Lai, Yu-Chiang, Bastidas-Ponce, Aimée, Bakhti, Mostafa, Rutter, Guy A., Fiancette, Remi, Nano, Rita, Piemonti, Lorenzo, Lickert, Heiko, Zhou, Qiao, Akerman, Ildem, and Hodson, David J.

Published
2021
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50. Engineered mini-G proteins block the internalization of cognate GPCRs and disrupt downstream intracellular signaling.

Author

Manchanda, Yusman, ElEid, Liliane, Oqua, Affiong I., Ramchunder, Zenouska, Choi, Jiyoon, Shchepinova, Maria M., Rutter, Guy A., Inoue, Asuka, Tate, Edward W., Jones, Ben, and Tomas, Alejandra

Subjects
G protein coupled receptors, GLUCAGON-like peptide 1, PROTEIN overexpression, PEPTIDE receptors, ARRESTINS, PROTEINS, PROTEIN engineering
Abstract

Mini-G proteins are engineered, thermostable variants of Gα subunits designed to stabilize G protein–coupled receptors (GPCRs) in their active conformations. Because of their small size and ease of use, they are popular tools for assessing GPCR behaviors in cells, both as reporters of receptor coupling to Gα subtypes and for cellular assays to quantify compartmentalized signaling at various subcellular locations. Here, we report that overexpression of mini-G proteins with their cognate GPCRs disrupted GPCR endocytic trafficking and associated intracellular signaling. In cells expressing the Gαs-coupled GPCR glucagon-like peptide 1 receptor (GLP-1R), coexpression of mini-Gs, a mini-G protein derived from Gαs, blocked β-arrestin 2 recruitment and receptor internalization and disrupted endosomal GLP-1R signaling. These effects did not involve changes in receptor phosphorylation or lipid nanodomain segregation. Moreover, we found that mini-G proteins derived from Gαi and Gαq also inhibited the internalization of GPCRs that couple to them. Finally, we developed an alternative intracellular signaling assay for GLP-1R using a nanobody specific for active Gαs:GPCR complexes (Nb37) that did not affect GLP-1R internalization. Our results have important implications for designing methods to assess intracellular GPCR signaling. Editor's summary: Mini-G proteins are engineered forms of Gα subunits that stably interact with activated G protein–coupled receptors (GPCRs) and are often used to investigate GPCR signaling from specific subcellular compartments. Manchanda et al. found that mini-G proteins interfered with GPCR internalization and compartmentalized signaling. Overexpression of a mini-G protein derived from Gαs prevented agonist-induced β-arrestin 2 recruitment to the glucagon-like peptide 1 receptor (GLP-1R), which inhibited receptor internalization and signaling at endosomes. Other GPCRs also showed reduced internalization when the mini-G versions of their cognate Gα subunits were overexpressed. These potentially confounding effects indicate that results from experiments using mini-G proteins to measure compartmentalized GPCR signaling should be interpreted cautiously. —Annalisa M. VanHook [ABSTRACT FROM AUTHOR]

Published
2024
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