Imperial College London

ProfessorGuyRutter

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Chair in Cell Biology
 
 
 
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Contact

 

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

 
 
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Location

 

ICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

616 results found

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

Cheung R, Pizza G, Chabosseau P, Rolando D, Tomas A, Burgoyne T, Wu Z, Salowka A, Tapa 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

Impaired pancreatic β-cell function and insulin secretion are hallmarks of type 2 diabetes. MicroRNAs are short non-coding 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 miR125b-5p expression is regulated by glucose and that this miRNA mediates some of the deleterious effects of hyperglycaemia in β-cells. Here we show that islet miR-125b-5p expression is up-regulated by glucose in an AMPK-dependent manner and that short-term miR125b-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, whilst mice overexpressing miR-125b-5p selectively in β-cells (MIR125B-Tg) were hyperglycaemic and glucose intolerant. MIR125B-Tg β-cells contained enlarged lysosomal structures and showed reduced insulin content and secretion. Collectively, we identify miR-125b as a glucosecontrolled regulator of organelle dynamics that modulates insulin secretion.

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, 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

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, 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

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., J Endocrinol, Vol: 253, Pages: 1-11

Pancreatic β-cells depend on the well-balanced regulation of cytosolic zinc concentrations, providing sufficient zinc ions for the processing and storage of insulin, but avoiding toxic effects. The zinc transporter ZnT8, encoded by SLC30A8,is a key player regarding islet cell zinc homeostasis, and polymorphisms in this gene are associated with altered type 2 diabetes susceptibility in man. The objective of this study was to investigate the role of ZnT8 and zinc in situations of cellular stress as hypoxia or inflammation. Isolated islets of WT and global ZnT8-/- mice were exposed to hypoxia or cytokines and cell death was measured. To explore the role of changing intracellular Zn2+ concentrations, WT islets were exposed to different zinc concentrations using zinc chloride or the zinc chelator N,N,N',N'-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine (TPEN). Hypoxia or cytokine (TNF-α, IFN-γ, IL1-β) treatment induced islet cell death, but to a lesser extent in islets from ZnT8-/- mice, which were shown to have a reduced zinc content. Similarly, chelation of zinc with TPEN reduced cell death in WT islets treated with hypoxia or cytokines, whereas increased zinc concentrations aggravated the effects of these stressors. This study demonstrates a reduced rate of cell death in islets from ZnT8-/- mice as compared to WT islets when exposed to two distinct cellular stressors, hypoxia or cytotoxic cytokines. This protection from cell death is, in part, mediated by a reduced zinc content in islet cells of ZnT8-/- mice. These findings may be relevant for altered diabetes burden in carriers of risk SLC30A8 alleles in man.

Journal article

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

Marzook A, Chen S, Pickford P, Lucey M, Wang Y, Corrêa Jr IR, Broichhagen J, Hodson DJ, Salem V, Rutter GA, Tan TM, Bloom SR, Tomas A, Jones Bet al., 2021, Evaluation of efficacy- versus affinity-driven agonism with biased GLP-1R ligands P5 and exendin-F1, Biochemical Pharmacology, Vol: 190, Pages: 1-12, ISSN: 0006-2952

The glucagon-like peptide-1 receptor (GLP-1R) is an important regulator of glucose homeostasis and has been successfully targeted for the treatment of type 2 diabetes. Recently described biased GLP-1R agonists with selective reductions in β-arrestin versus G protein coupling show improved metabolic actions in vivo. However, two prototypical G protein-favouring GLP-1R agonists, P5 and exendin-F1, are reported to show divergent effects on insulin secretion. In this study we aimed to resolve this discrepancy by performing a side-by-side characterisation of these two ligands across a variety of in vitro and in vivo assays. Exendin-F1 showed reduced acute efficacy versus P5 for several readouts, including recruitment of mini-G proteins, G protein-coupled receptor kinases (GRKs) and β-arrestin-2. Maximal responses were also lower for both GLP-1R internalisation and the presence of active GLP-1R-mini-Gs complexes in early endosomes with exendin-F1 treatment. In contrast, prolonged insulin secretion in vitro and sustained anti-hyperglycaemic efficacy in mice were both greater with exendin-F1 than with P5. We conclude that the particularly low acute efficacy of exendin-F1 and associated reductions in GLP-1R downregulation appear to be more important than preservation of endosomal signalling to allow sustained insulin secretion responses. This has implications for the ongoing development of affinity- versus efficacy-driven biased GLP-1R agonists as treatments for metabolic disease.

Journal article

Nasteska D, Fine NHF, Ashford FB, Cuozzo F, Viloria K, Smith G, Dahir A, Dawson PWJ, Lai Y-C, Bastidas-Ponce A, Bakhti M, Rutter GA, Fiancette R, Nano R, Piemonti L, Lickert H, Zhou Q, Akerman I, Hodson DJet al., 2021, PDX1(LOW) MAFA(LOW) beta-cells contribute to islet function and insulin release (vol 12, 674, 2021), NATURE COMMUNICATIONS, Vol: 12, ISSN: 2041-1723

Journal article

Cheung R, Pizza G, Chabosseau P, Rolando D, Tomas A, Burgoyne T, Salowka A, Macklin A, Cao Y, Nguyen-Tu M-S, Marchetti P, Shapiro J, Piemonti L, de Koning E, Leclerc I, Sakamoto K, Smith DM, Rutter GA, Martinez-Sanchez Aet al., 2021, Glucose-dependent miR-125b is a negative regulator of β-cell function, BioRxiv

<jats:title>SUMMARY</jats:title><jats:p>Impaired pancreatic β-cell function and insulin secretion are hallmarks of type 2 diabetes. MicroRNAs are short non-coding RNAs that silence gene expression, vital for the development and function of β-cells. MiR-125b-5p (miR-125b), a highly conserved miRNA, is abundant in β-cells, though its role in these cells is unclear. Here we show that miR-125b levels in human islets correlate with body mass index (BMI), and its expression is regulated by glucose in an AMP-activated protein kinase-dependent manner. An unbiased high-throughput screen identified multiple miR-125b targets, including the transporter of lysosomal hydrolases <jats:italic>M6pr</jats:italic> and the mitochondrial fission regulator <jats:italic>Mtfp1</jats:italic>. Inactivation of miR-125b in human β-cells shortened mitochondria and enhanced glucose-stimulated insulin secretion, whilst mice over-expressing miR-125b selectively in β-cells were glucose intolerant. β-cells from these animals contained enlarged lysosomal structures and showed reduced insulin content and secretion. Thus, we identify miR125b as a glucose-controlled regulator of organelle dynamics that modulates insulin secretion.</jats:p><jats:sec id="s1"><jats:title>Highlights</jats:title><jats:list list-type="bullet"><jats:list-item><jats:p>Islet miR-125b correlates with BMI and is regulated by glucose via AMP-activated protein kinase in β-cells</jats:p></jats:list-item><jats:list-item><jats:p>miR-125b targets dozens of genes including several involved in the regulation of mitochondrial (<jats:italic>Mtfp1</jats:italic>) and lysosomal (<jats:italic>M6pr</jats:italic>) morphology or function</jats:p></jats:list-item><jats:list-item><jats:p>Deletion of miR-125b results in shorter mitochondria an

Journal article

Parks SZ, Gao T, Awuapura NJ, Ayathamattam J, Chabosseau PL, Kalvakolanu D, Valdivia HH, Rutter GA, Leclerc I, Nakatogawa Het al., 2021, The Ca2+-binding protein sorcin stimulates transcriptional activity of the unfolded protein response mediator ATF6, FEBS Letters, Vol: 595, Pages: 1782-1796, ISSN: 0014-5793

Sorcin is a calcium-binding protein involved in maintaining endoplasmic reticulum (ER) Ca2+ stores. We have previously shown that overexpressing sorcin under the rat insulin promoter was protective against high-fat diet-induced pancreatic beta-cell dysfunction in vivo. Activating transcription factor 6 (ATF6) is a key mediator of the unfolded protein response (UPR) that provides cellular protection during the progression of ER stress. Here, using nonexcitable HEK293 cells, we show that sorcin overexpression increased ATF6 signalling, whereas sorcin knock out caused a reduction in ATF6 transcriptional activity and increased ER stress. Altogether, our data suggest that sorcin downregulation during lipotoxic stress may prevent full ATF6 activation and a normal UPR during the progression of obesity and insulin resistance.

Journal article

So WY, Liu WN, Teo AKK, Rutter GA, Han Wet al., 2021, Paired box 6 programs essential exocytotic genes in the regulation of glucose-stimulated insulin secretion and glucose homeostasis, Science Translational Medicine, Vol: 13, Pages: 1-14, ISSN: 1946-6234

The paired box 6 (PAX6) transcription factor is crucial for normal pancreatic islet development and function. Heterozygous mutations of PAX6 are associated with impaired insulin secretion and early-onset diabetes mellitus in humans. However, the molecular mechanism of PAX6 in controlling insulin secretion in human beta cells and its pathophysiological role in type 2 diabetes (T2D) remain ambiguous. We investigated the molecular pathway of PAX6 in the regulation of insulin secretion and the potential therapeutic value of PAX6 in T2D by using human pancreatic beta cell line EndoC-βH1, the db/db mouse model, and primary human pancreatic islets. Through loss- and gain-of-function approaches, we uncovered a mechanism by which PAX6 modulates glucose-stimulated insulin secretion (GSIS) through a cAMP response element–binding protein (CREB)/Munc18-1/2 pathway. Moreover, under diabetic conditions, beta cells and pancreatic islets displayed dampened PAX6/CREB/Munc18-1/2 pathway activity and impaired GSIS, which were reversed by PAX6 replenishment. Adeno-associated virus–mediated PAX6 overexpression in db/db mouse pancreatic beta cells led to a sustained amelioration of glycemic perturbation in vivo but did not affect insulin resistance. Our study highlights the pathophysiological role of PAX6 in T2D-associated beta cell dysfunction in humans and suggests the potential of PAX6 gene transfer in preserving and restoring beta cell function.

Journal article

Slieker RC, Donnelly LA, Fitipaldi H, Bouland GA, Giordano GN, Akerlund M, Gerl MJ, Ahlqvist E, Ali A, Dragan I, Festa A, Hansen MK, Mansour Aly D, Kim M, Kuznetsov D, Mehl F, Klose C, Simons K, Pavo I, Pullen TJ, Suvitaival T, Wretlind A, Rossing P, Lyssenko V, Legido-Quigley C, Groop L, Thorens B, Franks PW, Ibberson M, Rutter GA, Beulens JWJ, 't Hart LM, Pearson ERet al., 2021, Replication and cross-validation of type 2 diabetes subtypes based on clinical variables: an IMI-RHAPSODY study, DIABETOLOGIA, Vol: 64, Pages: 1982-1989, ISSN: 0012-186X

Journal article

Bitsi S, Suba K, Mohamed N, Leclerc I, Rutter GA, Salem V, Jones B, Tomas Aet al., 2021, beta-arrestin-2 Deletion Influences GLP-1 Receptor Signaling in Pancreatic beta Cells In Vivo, Publisher: AMER DIABETES ASSOC, ISSN: 0012-1797

Conference paper

Manchanda Y, Ben J, Carrat G, Ramchunder Z, Marchetti P, Leclerc I, Thennati R, Burade VS, Tomas A, Rutter GAet al., 2021, Binding Kinetics, Bias, Receptor Internalization, and Effects on Insulin Secretion for a Novel GLP1R-GIPR Dual Agonist, HISHS-2001, Publisher: AMER DIABETES ASSOC, ISSN: 0012-1797

Conference paper

Chabosseau PL, Martinez-Sanchez A, Leclerc I, Salem V, Rutter GAet al., 2021, Repetitive Ca2+Waves Emanate from a Stable Leader Cell in Mouse Islets, Publisher: AMER DIABETES ASSOC, ISSN: 0012-1797

Conference paper

Georgiadou E, Muralidharan C, Chabosseau PL, Tomas A, Stylianides T, Legido-Quigley C, Alsabeeh N, Cruciani-Guglielmacci C, Magnan C, Ibberson M, Leclerc I, Linnemann AK, Ali Y, Rodriguez T, Rutter GAet al., 2021, Deletion of the Mitofusins 1 and 2 (Mfn1 and Mfn2) from the Pancreatic Beta Cell Disrupts Mitochondrial Structure and Impairs Glucose-, but Not Incretinut-, Stimulated Insulin Secretion, Publisher: AMER DIABETES ASSOC, ISSN: 0012-1797

Conference paper

Amouyal C, Castel J, Guay C, Lacombe A, Denom J, Migrenne-Li S, Rouault C, Marquet F, Georgiadou E, Stylianides T, Luquet S, Le Stunff H, Scharfmann R, Clement K, Rutter GA, Taboureau O, Magnan C, Regazzi R, Andreelli Fet al., 2021, 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 (vol 58, 102895, 2020), EBIOMEDICINE, Vol: 66, ISSN: 2352-3964

Journal article

Cheung R, Pizza G, Chabosseau P, Rolando D, Salowska A, Burgoyne T, Leclerc I, Tomas A, Rutter GA, Martinez-Sanchez Aet al., 2021, miR-125b impairs beta cell function in vivo by targeting lysosomal and mitochondrial genes, Publisher: WILEY, ISSN: 0742-3071

Conference paper

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