Imperial College London

ProfessorGuyRutter

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Chair in Cell Biology
 
 
 
//

Contact

 

+44 (0)20 7594 3340g.rutter Website

 
 
//

Location

 

ICTEM buildingHammersmith Campus

//

Summary

 

Publications

Publication Type
Year
to

629 results found

Bosi E, Marchetti P, Rutter GA, Eizirik DLet al., 2022, Human alpha cell transcriptomic signatures of types 1 and 2 diabetes highlight disease-specific dysfunction pathways, iScience, Vol: 25, ISSN: 2589-0042

Although glucagon secretion is perturbed in both T1D and T2D, the pathophysiological changes in individual pancreatic alpha cells are still obscure. Using recently curated single-cell RNASeq data from T1D or T2D donors and their controls, we identified alpha cell transcriptomic alterations consistent with both common and discrete pathways. Although alterations in alpha cell identity gene (ARX, MAFB) expression were conserved, cytokine-regulated genes and genes involved in glucagon biosynthesis and processing were up-regulated in T1D. Conversely, mitochondrial genes associated with ROS (COX7B, NQO2) were dysregulated in T2D. Additionally, T1D alpha cells displayed altered expression of autoimmune-induced ER stress genes (ERLEC1, HSP90), whilst those from T2D subjects showed modified glycolytic and citrate cycle gene (LDHA?, PDHB, PDK4) expression. Thus, despite conserved alterations related to loss of function, alpha cells display disease-specific gene signatures which may be secondary to the main pathogenic events in each disease, namely immune- or metabolism-mediated-stress, in T1D and T2D, respectively.

Journal article

Akalestou E, Lopez-Noriega L, Christakis I, Hu M, Miras A, Leclerc I, Rutter Get al., 2022, Vertical Sleeve Gastrectomy normalizes circulating glucocorticoid levels and lowers glucocorticoid action tissue-selectively in mice, Frontiers in Endocrinology, Vol: 13, Pages: 1-16, ISSN: 1664-2392

Objectives: Glucocorticoids produced by the adrenal cortex are essential for the maintenance of metabolic homeostasis.Glucocorticoid activation is catalysed by 11β‐hydroxysteroid dehydrogenase 1 (11β‐HSD1). Excess glucocorticoids are associatedwith insulin resistance and hyperglycaemia. A small number of studies have demonstrated effects on glucocorticoid metabolism ofbariatric surgery, a group of gastrointestinal procedures known to improve insulin sensitivity and secretion, which were assumedto result from weight loss. In this study, we hypothesize that a reduction in glucocorticoid action following bariatric surgerycontributes to the widely observed euglycemic effects of the treatment. Methods: Glucose and insulin tolerance tests wereperformed at ten weeks post operatively and circulating corticosterone was measured. Liver and adipose tissues were harvestedfrom fed mice and 11β‐HSD1 levels were measured by quantitative RT‐PCR or Western (immuno‐) blotting, respectively. 11β‐HSD1null mice (Hsd11b1-/-) were generated using CRISPR/ Cas9 genome editing. Wild type (WT) and littermate Hsd11b1-/- miceunderwent Vertical Sleeve Gastrectomy (VSG) or sham surgery. Results: WT VSG-treated mice displayed significantly improvedglucose tolerance versus sham controls, and this effect was observed in both regular chow- and HFD-fed animals. VSG lowered bodyweight in HFD but not regular chow-fed mice. Remarkably, VSG restored physiological corticosterone production in HFD mice andreduced 11β‐HSD1 expression in liver and adipose tissue post‐surgery. Elimination of the 11β‐HSD1/Hsd11b1 gene mimicked theeffects of VSG on body weight and tolerance to 1g/kg glucose challenge. However, at 3 g/kg glucose, the impact of VSG on glucoseexcursion was indistinguishable between WT and Hsd11b1-/- mice, suggesting that the euglycemic effect of VSG was superior toHsd11b1 elimination. Conclusions: Bariatric surgery improves insulin sensitivity and reduces glucocorticoi

Journal article

Parks SZ, Rutter GA, Leclerc I, 2022, Whole-body sorcin invalidation does not cause hypothalamic ER stress nor worsens obesity in C57BL/6 male mice fed a westernized diet

<jats:title>ABSTRACT</jats:title><jats:sec><jats:title>Background</jats:title><jats:p><jats:underline>So</jats:underline>luble <jats:underline>R</jats:underline>esistance Related <jats:underline>C</jats:underline>alcium B<jats:underline>in</jats:underline>ding Protein (sorcin) is a calcium (Ca<jats:sup>2+</jats:sup>) binding protein which has been shown to play a role in maintaining intracellular endoplasmic reticulum (ER) Ca<jats:sup>2+</jats:sup> stores and lowering ER stress. Recently, our lab has demonstrated that sorcin expression was downregulated in the islets of Langerhans of mice fed a high-fat diet or in human islets incubated with the saturated fatty acid palmitate. We also showed that overexpression of sorcin under control of the rat insulin promoter (RIP7) in C57BL/6J mice, or whole body sorcin deletion in 129S1/SvImJ mice, improves or impairs insulin secretion and pancreatic β-cell function respectively. The mechanisms behind this beneficial role of sorcin in the pancreatic β-cell might depend on protection against lipotoxic endoplasmic reticulum (ER) stress through improved ER Ca<jats:sup>2+</jats:sup> dynamics and activation of the Activating Transcription Factor 6 (ATF6) branch of the unfolded protein response (UPR). Whether sorcin is also implicated in hypothalamic ER stress during the progression of obesity is unknown. This could potentially contribute to the diminished satiety typically observed in overweight individuals.</jats:p></jats:sec><jats:sec><jats:title>Aim</jats:title><jats:p>To investigate a potential role of sorcin in hypothalamic ER stress, leptin resistance, hyperphagia and obesity.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Whole-body sorcin null mice, backcrossed onto the C57BL/6J genetic background, were u

Journal article

Tan W, Amirruddin N, Hu M, Muralidharan S, Banke P, Torta F, Ng NHJ, Rutter GA, Teo AKKet al., 2022, Mechanistic investigation into the role of type 2 diabetes-associated STARD10 in insulin secretion and pancreatic beta cells, Publisher: SPRINGER, Pages: S214-S215, ISSN: 0012-186X

Conference paper

Jones B, Burade V, Akalestou E, Manchanda Y, Ramchunder Z, Carrat G, Nguyen-Tu M-S, Marchetti P, Piemonti L, Leclerc I, Thennati R, Vilsboll T, Thorens B, Tomas A, Rutter GAet al., 2022, In vivo and in vitro characterization of GL0034, a novel long-acting glucagon-like peptide-1 receptor agonist, DIABETES OBESITY & METABOLISM, Vol: 24, Pages: 2090-2101, ISSN: 1462-8902

Journal article

Cheung R, Pizza G, Chabosseau P, Rolando D, Tomas A, Burgoyne T, Wu Z, Salowka A, Thapa A, Macklin A, Cao Y, Nguyen-Tu M-S, Dickerson MT, Jacobson DA, Marchetti P, Shapiro J, Piemonti L, de Koning E, Leclerc I, Bouzakri K, Sakamoto K, Smith DM, Rutter GA, Martinez-Sanchez Aet al., 2022, Glucose-Dependent miR-125b Is a Negative Regulator of β-Cell Function., Diabetes, Vol: 71, Pages: 1525-1545

Impaired pancreatic β-cell function and insulin secretion are hallmarks of type 2 diabetes. miRNAs are short, noncoding RNAs that silence gene expression vital for the development and function of β cells. We have previously shown that β cell-specific deletion of the important energy sensor AMP-activated protein kinase (AMPK) results in increased miR-125b-5p levels. Nevertheless, the function of this miRNA in β cells is unclear. We hypothesized that miR-125b-5p expression is regulated by glucose and that this miRNA mediates some of the deleterious effects of hyperglycemia in β cells. Here, we show that islet miR-125b-5p expression is upregulated by glucose in an AMPK-dependent manner and that short-term miR-125b-5p overexpression impairs glucose-stimulated insulin secretion (GSIS) in the mouse insulinoma MIN6 cells and in human islets. An unbiased, high-throughput screen in MIN6 cells identified multiple miR-125b-5p targets, including the transporter of lysosomal hydrolases M6pr and the mitochondrial fission regulator Mtfp1. Inactivation of miR-125b-5p in the human β-cell line EndoCβ-H1 shortened mitochondria and enhanced GSIS, whereas mice overexpressing miR-125b-5p selectively in β cells (MIR125B-Tg) were hyperglycemic and glucose intolerant. MIR125B-Tg β cells contained enlarged lysosomal structures and had reduced insulin content and secretion. Collectively, we identify miR-125b as a glucose-controlled regulator of organelle dynamics that modulates insulin secretion.

Journal article

Chabosseau PL, Yong SWF, Lopez L, Leclerc I, Ali Y, Martinez-Sanchez A, Rutter GAet al., 2022, A Transcriptomic Signature of Pancreatic Islet Leader Beta Cells, Publisher: AMER DIABETES ASSOC, ISSN: 0012-1797

Conference paper

Cao H, Chung ACK, Ming X, Mao D, Lee HM, Cao X, Rutter GA, Chan JCN, Tian XY, Kong APSet al., 2022, Autotaxin signaling facilitates β cell dedifferentiation and dysfunction induced by Sirtuin 3 deficiency, Molecular Metabolism, Vol: 60, Pages: 101493-101493, ISSN: 2212-8778

OBJECTIVE: β cell dedifferentiation may underlie the reversible reduction in pancreatic β cell mass and function in type 2 diabetes (T2D). We previously reported that β cell-specific Sirt3 knockout (Sirt3f/f;Cre/+) mice developed impaired glucose tolerance and glucose-stimulated insulin secretion after feeding with high fat diet (HFD). RNA sequencing showed that Sirt3-deficient islets had enhanced expression of Enpp2 (Autotaxin, or ATX), a secreted lysophospholipase which produces lysophosphatidic acid (LPA). Here, we hypothesized that activation of the ATX/LPA pathway contributed to pancreatic β cell dedifferentiation in Sirt3-deficient β cells. METHODS: We applied LPA, or lysophosphatidylcoline (LPC), the substrate of ATX for producing LPA, to MIN6 cell line and mouse islets with altered Sirt3 expression to investigate the effect of LPA on β cell dedifferentiation and its underlying mechanisms. To examine the pathological effects of ATX/LPA pathway, we injected the β cell selective adeno-associated virus (AAV-Atx-shRNA) or negative control AAV-scramble in Sirt3f/f and Sirt3f/f;Cre/+ mice followed by 6-week of HFD feeding. RESULTS: In Sirt3f/f;Cre/+ mouse islets and Sirt3 knockdown MIN6 cells, ATX upregulation led to increased LPC with increased production of LPA. The latter not only induced reversible dedifferentiation in MIN6 cells and mouse islets, but also reduced glucose-stimulated insulin secretion from islets. In MIN6 cells, LPA induced phosphorylation of JNK/p38 MAPK which was accompanied by β cell dedifferentiation. The latter was suppressed by inhibitors of LPA receptor, JNK, and p38 MAPK. Importantly, inhibiting ATX in vivo improved insulin secretion and reduced β cell dedifferentiation in HFD-fed Sirt3f/f;Cre/+ mice. CONCLUSIONS: Sirt3 prevents β cell dedifferentiation by inhibiting ATX expression and upregulation of LPA. These findings support a long-range signaling effect of Sirt3 which modulates

Journal article

Suba K, Patel YS, Roberts A, Shrewsbury JV, Chen S, Kwok R, Kalogianni V, Liu X, Rutter GA, Jones B, Tan TM, Owen B, Drucker DJ, Bloom S, Murphy K, Salem Vet al., 2022, The Role of Intraislet Glucagon in Pulsatile Insulin Secretion, Publisher: AMER DIABETES ASSOC, ISSN: 0012-1797

Conference paper

Cruciani-Guglielmacci C, Meneyrol K, Denom J, Kassis N, Rachdi L, Makaci F, Migrenne-Li S, Daubigney F, Georgiadou E, Denis RG, Rodriguez Sanchez-Archidona A, Paul J-L, Thorens B, Rutter GA, Magnan C, Le Stunff H, Janel Net al., 2022, Homocysteine metabolism pathway is involved in the control of glucose homeostasis: a cystathionine beta synthase deficiency study in mouse, Cells, Vol: 11, ISSN: 2073-4409

Cystathionine beta synthase (CBS) catalyzes the first step of the transsulfuration pathway from homocysteine to cystathionine, and its deficiency leads to hyperhomocysteinemia (HHcy) in humans and rodents. To date, scarce information is available about the HHcy effect on insulin secretion, and the link between CBS activity and the setting of type 2 diabetes is still unknown. We aimed to decipher the consequences of an inborn defect in CBS on glucose homeostasis in mice. We used a mouse model heterozygous for CBS (CBS+/-) that presented a mild HHcy. Other groups were supplemented with methionine in drinking water to increase the mild to intermediate HHcy, and were submitted to a high-fat diet (HFD). We measured the food intake, body weight gain, body composition, glucose homeostasis, plasma homocysteine level, and CBS activity. We evidenced a defect in the stimulated insulin secretion in CBS+/- mice with mild and intermediate HHcy, while mice with intermediate HHcy under HFD presented an improvement in insulin sensitivity that compensated for the decreased insulin secretion and permitted them to maintain a glucose tolerance similar to the CBS+/+ mice. Islets isolated from CBS+/- mice maintained their ability to respond to the elevated glucose levels, and we showed that a lower parasympathetic tone could, at least in part, be responsible for the insulin secretion defect. Our results emphasize the important role of Hcy metabolic enzymes in insulin secretion and overall glucose homeostasis.

Journal article

Akalestou E, Lopez-Noriega L, Tough IR, Hu M, Leclerc I, Cox HM, Rutter GAet al., 2022, Vertical sleeve gastrectomy lowers SGLT2/Slc5a2 expression in the mouse kidney, Diabetes, Vol: 71, ISSN: 0012-1797

Bariatric surgery improves glucose homeostasis but the underlying mechanisms are not fully elucidated. Here, we show that the expression of sodium glucose cotransporter-2 (SGLT2/Slc5a2) is reduced in the kidney of lean and obese mice following vertical sleeve gastrectomy (VSG). Indicating an important contribution of altered cotransporter expression to the impact of surgery, inactivation of the SGLT2/Slc5a2 gene by CRISPR/Cas9 attenuated the effects of VSG, with glucose excursions following intraperitoneal injection lowered by ∼30% in wild-type mice but by ∼20% in SGLT2 null animals. The effects of the SGLT2 inhibitor dapaglifozin were similarly blunted by surgery. Unexpectedly, effects of dapaglifozin were still observed in SGLT2 null mice, consistent with the existence of metabolically beneficial off-target effects of SGLT2 inhibitors. Thus, we describe a new mechanism involved in mediating the glucose lowering effects of bariatric surgery.

Journal article

Rodriguez T, 2022, DRP1 levels determine the apoptotic threshold during embryonic differentiation through a mitophagy dependent mechanism, Developmental Cell, Vol: 57, Pages: 1316-1330.e7, ISSN: 1534-5807

The changes that drive differentiation facilitate the emergence of abnormal cells that need to be removed before they contribute to further development or the germline. Consequently, in mice in the lead-up to gastrulation, ∼35% of embryonic cells are eliminated. This elimination is caused by hypersensitivity to apoptosis, but how it is regulated is poorly understood. Here, we show that upon exit of naive pluripotency, mouse embryonic stem cells lower their mitochondrial apoptotic threshold, and this increases their sensitivity to cell death. We demonstrate that this enhanced apoptotic response is induced by a decrease in mitochondrial fission due to a reduction in the activity of dynamin-related protein 1 (DRP1). Furthermore, we show that in naive pluripotent cells, DRP1 prevents apoptosis by promoting mitophagy. In contrast, during differentiation, reduced mitophagy levels facilitate apoptosis. Together, these results indicate that during early mammalian development, DRP1 regulation of mitophagy determines the apoptotic response.

Journal article

Georgiadou E, Muralidharan C, Martinez M, Chabosseau P, Akalestou E, Tomas A, Yong Su Wern F, Stylianides T, Wretlind A, Legido-Quigley C, Jones B, Lopez Noriega L, Xu Y, Gu G, Alsabeeh N, Cruciani-Guglielmacci C, Magnan C, Ibberson M, Leclerc I, Ali Y, Soleimanpour SA, Linnemann AK, Rodriguez TA, Rutter GAet al., 2022, Mitofusins Mfn1 and Mfn2 are required to preserve glucose- but not incretin-stimulated beta cell connectivity and insulin secretion, Diabetes, Vol: 71, Pages: 1472-1489, ISSN: 0012-1797

Mitochondrial glucose metabolism is essential for stimulated insulin release from pancreatic beta cells. Whether mitofusin gene expression, and hence mitochondrial network integrity, is important for glucose or incretin signalling has not previously been explored. Here, we generated mice with beta cell-selective, adult-restricted deletion of the mitofusin genes Mfn1 and Mfn2 (βMfn1/2 dKO). βMfn1/2 dKO mice displayed elevated fed and fasted glycaemia and a >five-fold decrease in plasma insulin. Mitochondrial length, glucose-induced polarisation, ATP synthesis, cytosolic and mitochondrial Ca2+ increases were all reduced in dKO islets. In contrast, oral glucose tolerance was more modestly affected in βMfn1/2 dKO mice and GLP-1 or GIP receptor agonists largely corrected defective GSIS through enhanced EPAC-dependent signalling. Correspondingly, cAMP increases in the cytosol, as measured with an Epac-camps based sensor, were exaggerated in dKO mice. Mitochondrial fusion and fission cycles are thus essential in the beta cell to maintain normal glucose, but not incretin, sensing. These findings broaden our understanding of the roles of mitofusins in beta cells, the potential contributions of altered mitochondrial dynamics to diabetes development and the impact of incretins on this process.

Journal article

Rutter G, Georgiadou E, 2022, Mitofusins Mfn1 and Mfn2 are required to preserve glucose- but not incretin-stimulated beta cell connectivity and insulin secretion, Diabetes, ISSN: 0012-1797

Journal article

Bitsi S, Manchanda Y, ElEid L, Mohamed N, Hansen B, Suba K, Rutter GA, Salem V, Jones B, Tomas Aet al., 2022, Divergent acute <i>versus</i> prolonged pharmacological GLP-1R responses in adult beta cell-selective β-arrestin 2 knockout mice

<jats:title>Abstract</jats:title><jats:p>The glucagon-like peptide-1 receptor (GLP-1R) is a major therapeutic target in type 2 diabetes (T2D) and obesity. Following activation, GLP-1Rs are rapidly desensitised by β-arrestins, scaffolding proteins that terminate G protein interactions but also act as independent signalling mediators. While GLP-1R interacts with β-arrestins 1 and 2, expression of the latter is greatly enhanced in beta cells, making this the most relevant isoform. Here, we have assessed <jats:italic>in vivo</jats:italic> glycaemic responses to the pharmacological GLP-1R agonist exendin-4 in adult beta cell-selective β-arrestin 2 knockout (KO) mice. Lean female and high-fat, high-sucrose-fed KO mice of both sexes displayed worse acute responses <jats:italic>versus</jats:italic> control littermates, an effect that was inverted 6 hours post-agonist injection, resulting in prolonged <jats:italic>in vivo</jats:italic> cell-cell connectivity in KO islets implanted in mouse eyes. Similar effects were observed for the clinically relevant semaglutide and tirzepatide but not with exendin-phe1, an agonist biased away from β-arrestin recruitment. <jats:italic>Ex vivo</jats:italic> acute cAMP was impaired, but overnight desensitisation was reduced in KO islets. The acute signalling defect was attributed to enhanced β-arrestin 1 and phosphodiesterase (PDE) 4 activity in the absence of β-arrestin 2, while the reduced desensitisation correlated with altered GLP-1R trafficking, involving impaired recycling and lysosomal targeting and increased trans-Golgi network (TGN) localisation and signalling, as well as reduced GLP-1R ubiquitination by the E3 ubiquitin ligase NEDD4. This study has unveiled fundamental aspects of the role of β-arrestin 2 in regulating pharmacological GLP-1R responses with direct application to the rational design of improved GLP-1R-targeting therape

Journal article

Karsai M, Zuellig RA, Lehmann R, Cuozzo F, Nasteska D, Luca E, Hantel C, Hodson DJ, Spinas GA, Rutter GA, Gerber PAet al., 2022, Lack of ZnT8 protects pancreatic islets from hypoxia- and cytokine-induced cell death, JOURNAL OF ENDOCRINOLOGY, Vol: 253, Pages: 1-11, ISSN: 0022-0795

Journal article

Nguyen-Tu M-S, Harris J, Martinez-Sanchez A, Chabosseau P, Hu M, Georgiadou E, Pollard A, Otero P, Lopez-Noriega L, Leclerc I, Sakamoto K, Schmoll D, Smith DM, Carling D, Rutter GAet al., 2022, Opposing effects on regulated insulin secretion of acute vs chronic stimulation of AMP-activated protein kinase, DIABETOLOGIA, Vol: 65, Pages: 997-1011, ISSN: 0012-186X

Journal article

Zheng X, Ho QWC, Chua M, Stelmashenko O, Yeo XY, Muralidharan S, Torta F, Chew EGY, Lian MM, Foo JN, Jung S, Wong SH, Tan NS, Tong N, Rutter GA, Wenk MR, Silver DL, Berggren P-O, Ali Yet al., 2022, Destabilization of beta Cell FIT2 by saturated fatty acids alter lipid droplet numbers and contribute to ER stress and diabetes, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 119, ISSN: 0027-8424

Journal article

Cherkaoui I, Colclough K, Sessions RB, Rutter GA, Misra Set al., 2022, No family history of diabetes: Could it still be Maturity Onset Diabetes of the Young (MODY)?, Publisher: WILEY, ISSN: 0742-3071

Conference paper

Akalestou E, Miras A, Rutter G, Le Roux Cet al., 2022, Mechanisms of weight loss after obesity surgery, Endrocrine Reviews, Vol: 43, Pages: 19-34, ISSN: 0163-769X

Obesity surgery remains the most effective treatment for obesity and its complications.Weight loss was initially attributed to decreased energy absorption from the gut buthave since been linked to reduced appetitive behaviour and potentially increasedenergy expenditure. Implicated mechanisms associating rearrangement of thegastrointestinal tract with these metabolic outcomes include central appetite control,release of gut peptides, change in microbiota and bile acids. However, the exactcombination and timing of signals remain largely unknown. In this review, we surveyrecent research investigating these mechanisms, and seek to provide insights onunanswered questions over how weight loss is achieved following bariatric surgerywhich may eventually lead to safer, nonsurgical weight-loss interventions orcombinations of medications with surgery

Journal article

Manchanda Y, Ramchunder Z, Shchepinova MM, Rutter GA, Inoue A, Tate EW, Jones B, Tomas Aet al., 2021, Expression of mini-G proteins specifically halt cognate GPCR trafficking and intracellular signalling

<jats:title>Abstract</jats:title><jats:p>Mini-G proteins are engineered thermostable variants of Gα subunits designed to specifically stabilise G protein-coupled receptors (GPCRs) in their active conformation for structural analyses. Due to their smaller size and ease of use, they have become popular tools in recent years to assess specific GPCR behaviours in cells, both as reporters of receptor coupling to each G protein subtype and for in-cell assays designed to quantify compartmentalised receptor signalling from a range of subcellular locations. Here, we describe a previously unappreciated consequence of the co-expression of mini-G proteins with their cognate GPCRs, namely a profound disruption in GPCR trafficking and intracellular signalling caused by the co-expression of the specific mini-G subtype coupled to the affected receptor. We studied the Gαs-coupled pancreatic beta cell class B GPCR glucagon-like peptide-1 receptor (GLP-1R) as a model to describe in detail the molecular consequences derived from this effect, including a complete halt in β-arrestin-2 recruitment and receptor internalisation, despite near-normal levels of receptor GRK2 recruitment and lipid nanodomain segregation, as well as the disruption of endosomal GLP-1R signalling by mini-G<jats:sub>s</jats:sub> co-expression. We also extend our analysis to a range of other prototypical GPCRs covering the spectrum of Gα subtype coupling preferences, to unveil a widely conserved phenomenon of GPCR internalisation blockage by specific mini-G proteins coupled to a particular receptor. Our results have important implications for the design of methods to assess intracellular GPCR signalling. We also present an alternative adapted bystander intracellular signalling assay for the GLP-1R in which we substitute the mini-G<jats:sub>s</jats:sub> by a nanobody, Nb37, with specificity for active Gαs:GPCR complexes and no deleterious effect o

Journal article

Jha MK, Passero J, Rawat A, Ament XH, Yang F, Vidensky S, Collins SL, Horton MR, Hoke A, Rutter GA, Latremoliere A, Rothstein JD, Morrison BMet al., 2021, Macrophage monocarboxylate transporter 1 promotes peripheral nerve regeneration after injury in mice, JOURNAL OF CLINICAL INVESTIGATION, Vol: 131, ISSN: 0021-9738

Journal article

de Jesus DS, Mak TCS, Wang Y-F, von Ohlen Y, Bai Y, Kane E, Chabosseau P, Chahrour CM, Distaso W, Salem V, Tomas A, Stoffel M, Rutter GA, Latreille Met al., 2021, Dysregulation of the Pdx1/Ovol2/Zeb2 axis in dedifferentiated β-cells triggers the induction of genes associated with epithelial-mesenchymal transition in diabetes, Molecular Metabolism, Vol: 53, ISSN: 2212-8778

OBJECTIVE: β-cell dedifferentiation has been revealed as a pathological mechanism underlying pancreatic dysfunction in diabetes. We previously showed that increased miR-7 levels trigger β-cell dedifferentiation and diabetes. We used β-cell-specific miR-7 overexpressing mice (Tg7) to test the hypothesis that loss of β-cell identity triggered by miR-7 overexpression alters islet gene expression and islet microenvironment in diabetes. METHODS: We performed bulk and single-cell RNA sequencing (RNA-seq) in islets obtained from β-cell-specific miR-7 overexpressing mice (Tg7). We carried out loss- and gain-of-function experiments in MIN6 and EndoC-bH1 cell lines. We analysed previously published mouse and human T2D data sets. RESULTS: Bulk RNA-seq revealed that β-cell dedifferentiation is associated with the induction of genes associated with epithelial-to-mesenchymal transition (EMT) in prediabetic (2-week-old) and diabetic (12-week-old) Tg7 mice. Single-cell RNA-seq (scRNA-seq) indicated that this EMT signature is enriched specifically in β-cells. These molecular changes are associated with a weakening of β-cell: β-cell contacts, increased extracellular matrix (ECM) deposition, and TGFβ-dependent islet fibrosis. We found that the mesenchymal reprogramming of β-cells is explained in part by the downregulation of Pdx1 and its inability to regulate a myriad of epithelial-specific genes expressed in β-cells. Notable among genes transactivated by Pdx1 is Ovol2, which encodes a transcriptional repressor of the EMT transcription factor Zeb2. Following compromised β-cell identity, the reduction in Pdx1 gene expression causes a decrease in Ovol2 protein, triggering mesenchymal reprogramming of β-cells through the induction of Zeb2. We provided evidence that EMT signalling associated with the upregulation of Zeb2 expression is a molecular feature of islets in T2D subjects. CONCLUSIONS: Our study indicates that m

Journal article

Akalestou E, Suba K, Lopez-Noriega L, Georgiadou E, Chabosseau P, Gallie A, Wretlind A, Legido-Quigley C, Leclerc I, Salem V, Rutter GAet al., 2021, Intravital imaging of islet Ca2+ dynamics reveals enhanced beta cell connectivity after bariatric surgery in mice (vol 12, 5165, 2021), Nature Communications, Vol: 12, Pages: 1-1, ISSN: 2041-1723

Journal article

Slieker RC, Donnelly LA, Lopez-Noriega L, Giordano GN, Akerlund M, Pavo I, Lyssenko V, Quigley CL, Groop L, Ibberson M, Beulens JWJ, ' t Hart LM, Pearson ER, Rutter GAet al., 2021, Novel biomarkers for glycaemic deterioration in type 2 diabetes: an IMI RHAPSODY study, Publisher: SPRINGER, Pages: 108-108, ISSN: 0012-186X

Conference paper

Martinez-Sanchez A, Cheung R, Pizza G, Rolando D, Chabosseau P, Tomas A, Salowska A, Burgoyne T, Leclerc I, Rutter GAet al., 2021, Beta cell miR-125b controls glucose homeostasis by targeting lysosomal and mitochondrial genes, Publisher: SPRINGER, Pages: 158-158, ISSN: 0012-186X

Conference paper

Akalestou E, Lopez-Noriega L, Hu M, Leclerc I, Rutter GAet al., 2021, SGLT2 contributes to glucoregulatory improvements following vertical sleeve gastrectomy in mice, Publisher: SPRINGER, Pages: 222-222, ISSN: 0012-186X

Conference paper

Thennati R, Burade V, Garcia-Ocana A, Pratley RE, Rutter GA, Vilsboll T, Thorens Bet al., 2021, A novel, long-acting dual agonist for GIPR/GLP-1R, HISHS-2001, demonstrates effects on HbA(1c) and weight loss in the db/db mouse model of type 2 diabetes, Publisher: SPRINGER, Pages: 242-242, ISSN: 0012-186X

Conference paper

Akalestou E, Suba K, Lopez-Noriega L, Georgiadou E, Chabosseau P, Gallie A, Wretlind A, Quigley C, Leclerc I, Salem V, Rutter GAet al., 2021, Intravital imaging of islet Ca2+ dynamics reveals enhanced beta cell connectivity after bariatric surgery in mice, Nature Communications, Vol: 12, Pages: 1-13, ISSN: 2041-1723

Bariatric surgery improves both insulin sensitivity and secretion and can induce diabetes remission. However, the mechanisms and time courses of these changes, particularly the impact on β cell function, are difficult to monitor directly. In this study, we investigated the effect of Vertical Sleeve Gastrectomy (VSG) on β cell function in vivo by imaging Ca2+ dynamics in islets engrafted into the anterior eye chamber. Mirroring its clinical utility, VSG in mice results in significantly improved glucose tolerance, and enhanced insulin secretion. We reveal that these benefits are underpinned by augmented β cell function and coordinated activity across the islet. These effects involve changes in circulating GLP-1 levels which may act both directly and indirectly on the β cell, in the latter case through changes in body weight. Thus, bariatric surgery leads to time-dependent increases in β cell function and intra-islet connectivity which are likely to contribute to diabetes remission.

Journal article

Slieker RC, Donnelly LA, Fitipaldi H, Bouland GA, Giordano GN, Åkerlund M, Gerl MJ, Ahlqvist E, Ali A, Dragan I, Elders P, Festa A, Hansen MK, van der Heijden AA, Aly DM, Kim M, Kuznetsov D, Mehl F, Klose C, Simons K, Pavo I, Pullen TJ, Suvitaival T, Wretlind A, Rossing P, Lyssenko V, Quigley CL, Groop L, Thorens B, Franks PW, Ibberson M, Rutter GA, Beulens JW, 't Hart LM, Pearson ERet al., 2021, Distinct molecular signatures of clinical clusters in people with Type 2 diabetes: an IMIRHAPSODY study., Diabetes, Vol: 70, Pages: 2683-2693, ISSN: 0012-1797

Type 2 diabetes is a multifactorial disease with multiple underlying aetiologies. To address this heterogeneity a previous study clustered people with diabetes into five diabetes subtypes. The aim of the current study is to investigate the aetiology of these clusters by comparing their molecular signatures. In three independent cohorts, in total 15,940 individuals were clustered based on five clinical characteristics. In a subset, genetic- (N=12828), metabolomic- (N=2945), lipidomic- (N=2593) and proteomic (N=1170) data were obtained in plasma. In each datatype each cluster was compared with the other four clusters as the reference. The insulin resistant cluster showed the most distinct molecular signature, with higher BCAAs, DAG and TAG levels and aberrant protein levels in plasma enriched for proteins in the intracellular PI3K/Akt pathway. The obese cluster showed higher cytokines. A subset of the mild diabetes cluster with high HDL showed the most beneficial molecular profile with opposite effects to those seen in the insulin resistant cluster. This study showed that clustering people with type 2 diabetes can identify underlying molecular mechanisms related to pancreatic islets, liver, and adipose tissue metabolism. This provides novel biological insights into the diverse aetiological processes that would not be evident when type 2 diabetes is viewed as a homogeneous disease.

Journal article

This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.

Request URL: http://wlsprd.imperial.ac.uk:80/respub/WEB-INF/jsp/search-html.jsp Request URI: /respub/WEB-INF/jsp/search-html.jsp Query String: respub-action=search.html&id=00462876&limit=30&person=true