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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Assistant

 

Ms Shazi Singh +44 (0)20 7594 3391

 
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Location

 

327ICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

592 results found

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, 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

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, 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

Akalestou E, Miras A, Rutter G, Le Roux Cet al., 2021, Mechanisms of weight loss after obesity surgery, Endrocrine Reviews

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

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, ISSN: 0012-186X

Journal article

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

Hu M, Cebola I, Carrat G, Jiang S, Nawaz S, Khamis A, Canouil M, Froguel P, Schulte A, Solimena M, Ibberson M, Marchetti P, Cardenas-Diaz FL, Gadue PJ, Hastoy B, Almeida-Souza L, McMahon H, Rutter GAet al., 2021, Chromatin 3D interaction analysis of the STARD10 locus unveils FCHSD2 as a regulator of insulin secretion., Cell Research, Vol: 34, Pages: 1-1, ISSN: 1001-0602

Using chromatin conformation capture, we show that an enhancer cluster in the STARD10 type 2 diabetes (T2D) locus forms a defined 3-dimensional (3D) chromatin domain. A 4.1-kb region within this locus, carrying 5 T2D-associated variants, physically interacts with CTCF-binding regions and with an enhancer possessing strong transcriptional activity. Analysis of human islet 3D chromatin interaction maps identifies the FCHSD2 gene as an additional target of the enhancer cluster. CRISPR-Cas9-mediated deletion of the variant region, or of the associated enhancer, from human pancreas-derived EndoC-βH1 cells impairs glucose-stimulated insulin secretion. Expression of both STARD10 and FCHSD2 is reduced in cells harboring CRISPR deletions, and lower expression of STARD10 and FCHSD2 is associated, the latter nominally, with the possession of risk variant alleles in human islets. Finally, CRISPR-Cas9-mediated loss of STARD10 or FCHSD2, but not ARAP1, impairs regulated insulin secretion. Thus, multiple genes at the STARD10 locus influence β cell function.

Journal article

Ghiasi SM, Rutter GA, 2021, Consequences for pancreatic beta-cell identity and function of unregulated transcript processing, Frontiers in Endocrinology, Vol: 12, Pages: 1-12, ISSN: 1664-2392

Mounting evidence suggests a role for alternative splicing (AS) of transcripts in the normal physiology and pathophysiology of the pancreatic β-cell. In the apparent absence of RNA repair systems, RNA decay pathways are likely to play an important role in controlling the stability, distribution and diversity of transcript isoforms in these cells. Around 35% of alternatively spliced transcripts in human cells contain premature termination codons (PTCs) and are targeted for degradation via nonsense-mediated decay (NMD), a vital quality control process. Inflammatory cytokines, whose levels are increased in both type 1 (T1D) and type 2 (T2D) diabetes, stimulate alternative splicing events and the expression of NMD components, and may or may not be associated with the activation of the NMD pathway. It is, however, now possible to infer that NMD plays a crucial role in regulating transcript processing in normal and stress conditions in pancreatic β-cells. In this review, we describe the possible role of Regulated Unproductive Splicing and Translation (RUST), a molecular mechanism embracing NMD activity in relationship to AS and translation of damaged transcript isoforms in these cells. This process substantially reduces the abundance of non-functional transcript isoforms, and its dysregulation may be involved in pancreatic β-cell failure in diabetes.

Journal article

López-Noriega L, Rutter GA, 2021, Long non-coding RNAs as key modulators of pancreatic β-Cell mass and function, Frontiers in Endocrinology, Vol: 11, ISSN: 1664-2392

Numerous studies have sought to decipher the genetic and other mechanisms contributing to β-cell loss and dysfunction in diabetes mellitus. However, we have yet to fully understand the etiology of the disease or to develop satisfactory treatments. Since the majority of diabetes susceptibility loci are mapped to non-coding regions within the genome, understanding the functions of non-coding RNAs in β-cell biology might provide crucial insights into the pathogenesis of type 1 (T1D) and type 2 (T2D) diabetes. During the past decade, numerous studies have indicated that long non-coding RNAs play important roles in the maintenance of β-cell mass and function. Indeed, lncRNAs have been shown to be involved in controlling β-cell proliferation during development and/or β-cell compensation in response to hyperglycaemia. LncRNAs such as TUG-1 and MEG3 play a role in both β-cell apoptosis and function, while others sensitize β-cells to apoptosis in response to stress signals. In addition, several long non-coding RNAs have been shown to regulate the expression of β-cell-enriched transcription factors in cis or in trans. In this review, we provide an overview of the roles of lncRNAs in maintaining β-function and mass, and discuss their relevance in the development of diabetes.

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, NATURE COMMUNICATIONS, Vol: 12, ISSN: 2041-1723

Journal article

Mousavy Gharavy SN, Owen BM, Millership SJ, Chabosseau P, Pizza G, Martinez-Sanchez A, Tasoez E, Georgiadou E, Hu M, Fine NHF, Jacobson DA, Dickerson MT, Idevall-Hagren O, Montoya A, Kramer H, Mehta Z, Withers DJ, Ninov N, Gadue PJ, Cardenas-Diaz FL, Cruciani-Guglielmacci C, Magnan C, Ibberson M, Leclerc I, Voz M, Rutter GAet al., 2021, Sexually dimorphic roles for the type 2 diabetes-associated C2cd4b gene in murine glucose homeostasis, DIABETOLOGIA, Vol: 64, Pages: 850-864, ISSN: 0012-186X

Journal article

Chabosseau P, Rutter G, Millership S, 2021, Importance of both imprinted genes and functional heterogeneity in pancreatic beta cells: is there a link?, International Journal of Molecular Sciences, Vol: 22, ISSN: 1422-0067

Diabetes mellitus now affects more than 400 million individuals worldwide, with significant impacts on the lives of those affected and associated socio-economic costs. Although defects in insulin secretion underlie all forms of the disease, the molecular mechanisms which drive them are still poorly understood. Subsets of specialised beta cells have, in recent years, been suggested to play critical roles in “pacing” overall islet activity. The molecular nature of these cells, the means through which their identity is established and the changes which may contribute to their functional demise and “loss of influence” in both type 1 and type 2 diabetes are largely unknown. Genomic imprinting involves the selective silencing of one of the two parental alleles through DNA methylation and modified imprinted gene expression is involved in a number of diseases. Loss of expression, or loss of imprinting, can be shown in mouse models to lead to defects in beta cell function and abnormal insulin secretion. In the present review we survey the evidence that altered expression of imprinted genes contribute to loss of beta cell function, the importance of beta cell heterogeneity in normal and disease states, and hypothesise whether there is a direct link between the two.

Journal article

Jones B, McGlone ER, Fang Z, Pickford P, Corrêa IR, Oishi A, Jockers R, Inoue A, Kumar S, Görlitz F, Dunsby C, French PMW, Rutter GA, Tan TM, Tomas A, Bloom SRet al., 2021, Genetic and biased agonist-mediated reductions in β-arrestin recruitment prolong cAMP signalling at glucagon family receptors, Journal of Biological Chemistry, Vol: 296, Pages: 1-15, ISSN: 0021-9258

Receptors for the peptide hormones glucagon-like peptide-1 (GLP-1R), glucose-dependent insulinotropic polypeptide (GIPR) and glucagon (GCGR) are important regulators of insulin secretion and energy metabolism. GLP-1R agonists have been successfully deployed for the treatment of type 2 diabetes, but it has been suggested that their efficacy is limited by target receptor desensitisation and downregulation due to recruitment of β-arrestins. Indeed, recently described GLP-1R agonists with reduced β-arrestin-2 recruitment have delivered promising results in preclinical and clinical studies. We therefore aimed to determine if the same phenomenon could apply to the closely related GIPR and GCGR. In HEK293 cells depleted of both β-arrestin isoforms the duration of G protein-dependent cAMP/PKA signalling was increased in response to the endogenous ligand for each receptor. Moreover, in wild-type cells, “biased” GLP-1, GCG and GIP analogues with selective reductions in β-arrestin-2 recruitment led to reduced receptor endocytosis and increased insulin secretion over a prolonged stimulation period, although the latter effect was only seen at high agonist concentrations. Biased GCG analogues increased the duration of cAMP signalling, but this did not lead to increased glucose output from hepatocytes. Our study provides a rationale for development of GLP-1R, GIPR and GCGR agonists with reduced β-arrestin recruitment, but further work is needed to maximally exploit this strategy for therapeutic purposes.

Journal article

Georgiadou E, Muralidharan C, Martinez M, Chabosseau P, Tomas A, Su Wern FY, Akalestou E, Stylianides T, Wretlind A, Legido-Quigley C, Jones B, Noriega LL, 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., 2021, Mitofusins Mfn1 and Mfn2 are required to preserve glucose-but not incretin- stimulated beta cell connectivity and insulin secretion, bioRxiv

Aims/hypothesis Mitochondrial glucose metabolism is essential for stimulated insulin release from pancreatic beta cells. Whether mitochondrial networks may be important for glucose or incretin sensing has yet to be determined.Methods Here, we generated mice with beta cell-selective, adult-restricted deletion of the mitofusin genes Mfn1 and Mfn2 (βMfn1/2 dKO). Whole or dissociated pancreatic islets were used for live beta cell fluorescence imaging of cytosolic or mitochondrial Ca2+ concentration and ATP production or GSIS in response to increasing glucose concentrations or GLP-1 receptor agonists. Serum and blood samples were collected to examine oral and i.p. glucose tolerance.Results βMfn1/2 dKO mice displayed elevated fed and fasted glycaemia (p&lt;0.01, p&lt;0.001) and a &gt;five-fold decrease (p&lt;0.0001) in plasma insulin. Mitochondrial length, glucose-induced polarisation, ATP synthesis and cytosolic Ca2+ increases were all reduced (p&lt;0.05,p&lt;0.01,p&lt;0.0001) in dKO islets, and beta cell Ca2+ dynamics were suppressed in vivo (p&lt;0.001). In contrast, oral glucose tolerance was near normal in βMfn1/2 dKO mice (p&lt;0.05, p&lt;0.01) and GLP-1 or GIP receptor agonists largely corrected defective GSIS from isolated islets through an EPAC-dependent signalling activation.Conclusions/interpretation Mitochondrial fusion and fission cycles are thus essential in the beta cell to maintain normal glucose, but not incretin, sensing. Defects in these cycles in some forms of diabetes might therefore provide opportunities for novel incretin-based or other therapies.Impact of Mfn1/2 deletion on glucose and incretin stimulated-insulin secretion in beta cells. (A) In control animals, glucose is taken up by beta cells through GLUT2 and metabolised by mitochondria (elongated structure) through the citrate (TCA) cycle, leading to an increased mitochondrial proton motive force (hyperpolarised Δψm), accelerated

Journal article

Marselli L, Piron A, Suleiman M, Colli ML, Yi X, Khamis A, Carrat GR, Rutter GA, Bugliani M, Giusti L, Ronci M, Ibberson M, Turatsinze J-V, Boggi U, De Simone P, De Tata V, Lopes M, Nasteska D, De Luca C, Tesi M, Bosi E, Singh P, Campani D, Schulte AM, Solimena M, Hecht P, Rady B, Bakaj I, Pocai A, Norquay L, Thorens B, Canouil M, Froguel P, Eizirik DL, Cnop M, Marchetti Pet al., 2020, Persistent or transient human β cell dysfunction induced by metabolic stress: specific signatures and shared gene expression with type 2 diabetes, Cell Reports, Vol: 33, ISSN: 2211-1247

Pancreatic β cell failure is key to type 2 diabetes (T2D) onset and progression. Here, we assess whether human β cell dysfunction induced by metabolic stress is reversible, evaluate the molecular pathways underlying persistent or transient damage, and explore the relationships with T2D islet traits. Twenty-six islet preparations are exposed to several lipotoxic/glucotoxic conditions, some of which impair insulin release, depending on stressor type, concentration, and combination. The reversal of dysfunction occurs after washout for some, although not all, of the lipoglucotoxic insults. Islet transcriptomes assessed by RNA sequencing and expression quantitative trait loci (eQTL) analysis identify specific pathways underlying β cell failure and recovery. Comparison of a large number of human T2D islet transcriptomes with those of persistent or reversible β cell lipoglucotoxicity show shared gene expression signatures. The identification of mechanisms associated with human β cell dysfunction and recovery and their overlap with T2D islet traits provide insights into T2D pathogenesis, fostering the development of improved β cell-targeted therapeutic strategies.

Journal article

Jones B, Fang Z, Chen S, Manchanda Y, Bitsi S, Pickford P, David A, Shchepinova MM, Corrêa Jr IR, Hodson DJ, Broichhagen J, Tate EW, Reimann F, Salem V, Rutter GA, Tan T, Bloom SR, Tomas Aet al., 2020, Ligand-specific factors influencing GLP-1 receptor post-endocytic trafficking and degradation in pancreatic beta cells, International Journal of Molecular Sciences, Vol: 212, Pages: 1-24, ISSN: 1422-0067

The glucagon-like peptide-1 receptor (GLP-1R) is an important regulator of blood glucose homeostasis. Ligand-specific differences in membrane trafficking of the GLP-1R influence its signalling properties and therapeutic potential in type 2 diabetes. Here, we have evaluated how different factors combine to control the post-endocytic trafficking of GLP-1R to recycling versus degradative pathways. Experiments were performed in primary islet cells, INS-1 832/3 clonal beta cells and HEK293 cells, using biorthogonal labelling of GLP-1R to determine its localisation and degradation after treatment with GLP-1, exendin-4 and several further GLP-1R agonist peptides. We also characterised the effect of a rare GLP1R coding variant, T149M, and the role of endosomal peptidase endothelin-converting enzyme-1 (ECE-1), in GLP1R trafficking. Our data reveal how treatment with GLP-1 versus exendin-4 is associated with preferential GLP-1R targeting towards a recycling pathway. GLP-1, but not exendin-4, is a substrate for ECE-1, and the resultant propensity to intra-endosomal degradation, in conjunction with differences in binding affinity, contributes to alterations in GLP-1R trafficking behaviours and degradation. The T149M GLP-1R variant shows reduced signalling and internalisation responses, which is likely to be due to disruption of the cytoplasmic region that couples to intracellular effectors. These observations provide insights into how ligand- and genotype-specific factors can influence GLP-1R trafficking.

Journal article

Georgiadou E, Rutter GA, 2020, Control by Ca2+ of mitochondrial structure and function in pancreatic β-cells, Cell Calcium, Vol: 91, ISSN: 0143-4160

Mitochondria play a central role in glucose metabolism and the stimulation of insulin secretion from pancreatic β-cells. In this review, we discuss firstly the regulation and roles of mitochondrial Ca2+ transport in glucose-regulated insulin secretion, and the molecular machinery involved. Next, we discuss the evidence that mitochondrial dysfunction in β-cells is associated with type 2 diabetes, from a genetic, functional and structural point of view, and then the possibility that these changes may in part be mediated by dysregulation of cytosolic Ca2+. Finally, we review the importance of preserved mitochondrial structure and dynamics for mitochondrial gene expression and their possible relevance to the pathogenesis of type 2 diabetes.

Journal article

Ming X, Chung ACK, Mao D, Cao H, Fan B, Wong WKK, Ho CC, Lee HM, Schoonjans K, Auwerx J, Rutter GA, Chan JCN, Tian XY, Kong APSet al., 2020, Pancreatic Sirtuin 3 deficiency promotes hepatic steatosis by enhancing 5-hydroxytryptamine synthesis in diet-induced Obese mice, Diabetes, Vol: 70, Pages: 119-131, ISSN: 0012-1797

Sirtuin 3 (SIRT3) is a protein deacetylase regulating beta cell function through inhibiting oxidative stress in obese and diabetic mice, but the detailed mechanism and potential effect of beta cell specific SIRT3 on metabolic homeostasis, and its potential effect on other metabolic organs are unknown. We found glucose tolerance and glucose stimulated insulin secretion (GSIS) were impaired in high fat diet (HFD)-fed beta cell selective Sirt3 knockout (Sirt3f/f;Cre/+) mice. In addition, Sirt3f/f;Cre/+ mice had more severe hepatic steatosis than Sirt3f/f mice upon HFD feeding. RNA sequencing (RNA-Seq) of islets suggested that Sirt3 deficiency over-activated 5-hydroxytryptamine (5-HT) synthesis as evidenced by up-regulation of tryptophan hydroxylase 1 (TPH1). 5-HT concentration was increased in both islets and serum of Sirt3f/f;Cre/+ mice. 5-HT also facilitated the effect of palmitate to increase lipid deposition. Treatment with TPH1 inhibitor ameliorated hepatic steatosis and reduced weight gain in HFD-fed Sirt3f/f;Cre/+ mice. These data suggested that under HFD feeding, SIRT3 deficiency in beta cells not only regulates insulin secretion but also modulates hepatic lipid metabolism via the release of 5-HT.

Journal article

Nguyen-Tu M-S, Martinez-Sanchez A, Leclerc I, Rutter GA, da Silva Xavier Get al., 2020, Adipocyte-specific deletion of Tcf7l2 induces dysregulated lipid metabolism and impairs glucose tolerance in mice, DIABETOLOGIA, Vol: 64, Pages: 129-141, ISSN: 0012-186X

Journal article

Muniangi-Muhitu H, Akalestou E, Salem V, Misra S, Oliver NS, Rutter GAet al., 2020, Covid-19 and diabetes: a complex bidirectional relationship, Frontiers in Endocrinology, Vol: 11, ISSN: 1664-2392

Covid-19 is a recently-emerged infectious disease caused by the novel severe acute respiratory syndrome coronavirus SARS-CoV2. SARS-CoV2 differs from previous coronavirus infections (SARS and MERS) due to its high infectivity (reproduction value, R0, typically 2-4) and pre- or asymptomatic transmission, properties that have contributed to the current global Covid-19 pandemic. Identified risk factors for disease severity and death from SARS-Cov2 infection include older age, male sex, diabetes, obesity and hypertension. The reasons for these associations are still largely obscure. Evidence is also emerging that SARS-CoV2 infection exacerbates the underlying pathophysiology of hyperglycemia in people with diabetes. Here, we discuss potential mechanisms through which diabetes may affect the risk of more severe outcomes in Covid-19 and, additionally, how diabetic emergencies and longer term pathology may be aggravated by infection with the virus. We consider roles for the immune system, the observed phenomenon of microangiopathy in severe Covid-19 infection and the potential for direct viral toxicity on metabolically-relevant tissues including pancreatic beta cells and targets of insulin action.

Journal article

Carrat GR, Haythorne E, Tomas A, Haataja L, Müller A, Arvan P, Piunti A, Cheng K, Huang M, Pullen TJ, Georgiadou E, Stylianides T, Amirruddin NS, Salem V, Distaso W, Cakebread A, Heesom KJ, Lewis PA, Hodson DJ, Briant LJ, Fung ACH, Sessions RB, Alpy F, Kong APS, Benke PI, Torta F, Keong Teo AK, Leclerc I, Solimena M, Wigley DB, Rutter GAet al., 2020, The type 2 diabetes gene product STARD10 is a phosphoinositide-binding protein that controls insulin secretory granule biogenesis, Molecular Metabolism, Vol: 40, ISSN: 2212-8778

OBJECTIVE: Risk alleles for type 2 diabetes at the STARD10 locus are associated with lowered STARD10 expression in the β-cell, impaired glucose-induced insulin secretion, and decreased circulating proinsulin:insulin ratios. Although likely to serve as a mediator of intracellular lipid transfer, the identity of the transported lipids and thus the pathways through which STARD10 regulates β-cell function are not understood. The aim of this study was to identify the lipids transported and affected by STARD10 in the β-cell and the role of the protein in controlling proinsulin processing and insulin granule biogenesis and maturation. METHODS: We used isolated islets from mice deleted selectively in the β-cell for Stard10 (βStard10KO) and performed electron microscopy, pulse-chase, RNA sequencing, and lipidomic analyses. Proteomic analysis of STARD10 binding partners was executed in the INS1 (832/13) cell line. X-ray crystallography followed by molecular docking and lipid overlay assay was performed on purified STARD10 protein. RESULTS: βStard10KO islets had a sharply altered dense core granule appearance, with a dramatic increase in the number of "rod-like" dense cores. Correspondingly, basal secretion of proinsulin was increased versus wild-type islets. The solution of the crystal structure of STARD10 to 2.3 Å resolution revealed a binding pocket capable of accommodating polyphosphoinositides, and STARD10 was shown to bind to inositides phosphorylated at the 3' position. Lipidomic analysis of âStard10KO islets demonstrated changes in phosphatidylinositol levels, and the inositol lipid kinase PIP4K2C was identified as a STARD10 binding partner. Also consistent with roles for STARD10 in phosphoinositide signalling, the phosphoinositide-binding proteins Pirt and Synaptotagmin 1 were amongst the differentially expressed genes in βStard10KO islets. CONCLUSION: Our data indicate that STARD10 binds to, and may transp

Journal article

Rutter GA, Georgiadou E, Martinez-Sanchez A, Pullen TJet al., 2020, Metabolic and functional specialisations of the pancreatic beta cell: gene disallowance, mitochondrial metabolism and intercellular connectivity, DIABETOLOGIA, Vol: 63, Pages: 1990-1998, ISSN: 0012-186X

Journal article

Hu M, Cherkaoui I, Misra S, Rutter GAet al., 2020, Functional genomics in pancreatic β cells: recent advances in gene deletion and genome editing technologies for diabetes research., Front Endocrinol (Lausanne), Vol: 11, Pages: 1-20, ISSN: 1664-2392

The inheritance of variants that lead to coding changes in, or the mis-expression of, genes critical to pancreatic beta cell function can lead to alterations in insulin secretion and increase the risk of both type 1 and type 2 diabetes. Recently developed clustered regularly interspaced short palindromic repeats (CRISPR/Cas9) gene editing tools provide a powerful means of understanding the impact of identified variants on cell function, growth, and survival and might ultimately provide a means, most likely after the transplantation of genetically "corrected" cells, of treating the disease. Here, we review some of the disease-associated genes and variants whose roles have been probed up to now. Next, we survey recent exciting developments in CRISPR/Cas9 technology and their possible exploitation for β cell functional genomics. Finally, we will provide a perspective as to how CRISPR/Cas9 technology may find clinical application in patients with diabetes.

Journal article

Mao D, Tian XY, Mao D, Hung SW, Wang CC, Lau CBS, Lee HM, Wong CK, Chow E, Ming X, Cao H, Ma RC, Chan PKS, Kong APS, Li JJX, Rutter GA, Tam WH, Chan JCNet al., 2020, A polysaccharide extract from the medicinal plant Maidong inhibits the IKK-NF-kappa B pathway and IL-1 beta-induced islet inflammation and increases insulin secretion, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 295, Pages: 12573-12587, ISSN: 0021-9258

Journal article

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