568 results found
Jones B, Fang Z, Chen S, et al., 2020, Ligand-specific factors influencing GLP-1 receptor post-endocytic trafficking and degradation in pancreatic beta cells, International Journal of Molecular Sciences, ISSN: 1422-0067
Georgiadou E, Rutter GA, 2020, Control by Ca2+ of mitochondrial structure and function in pancreatic β-cells., Cell Calcium, Vol: 91
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.
Ming X, Chung ACK, Mao D, et al., 2020, Pancreatic Sirtuin 3 Deficiency Promotes Hepatic Steatosis by Enhancing 5-Hydroxytryptamine Synthesis in Diet-Induced Obese Mice., Diabetes
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.
Nguyen-Tu M-S, Martinez-Sanchez A, Leclerc I, et al., 2020, Adipocyte-specific deletion of Tcf7l2 induces dysregulated lipid metabolism and impairs glucose tolerance in mice., Diabetologia
AIMS/HYPOTHESIS: Transcription factor 7-like 2 (TCF7L2) is a downstream effector of the Wnt/β-catenin signalling pathway implicated in type 2 diabetes risk through genome-wide association studies. Although its expression is critical for adipocyte development, the potential roles of changes in adipose tissue TCF7L2 levels in diabetes risk are poorly defined. Here, we investigated whether forced changes in Tcf7l2 expression in adipocytes affect whole body glucose or lipid metabolism and crosstalk between disease-relevant tissues. METHODS: Tcf7l2 was selectively ablated in mature adipocytes in C57BL/6J mice using Cre recombinase under Adipoq promoter control to recombine Tcf7l2 alleles floxed at exon 1 (referred to as aTCF7L2 mice). aTCF7L2 mice were fed normal chow or a high-fat diet for 12 weeks. Glucose and insulin sensitivity, as well as beta cell function, were assessed in vivo and in vitro. Levels of circulating NEFA, selected hormones and adipokines were measured using standard assays. RESULTS: Reduced TCF7L2 expression in adipocytes altered glucose tolerance and insulin secretion in male but not in female mice. Thus, on a normal chow diet, male heterozygote knockout mice (aTCF7L2het) exhibited impaired glucose tolerance at 16 weeks (p = 0.03) and increased fat mass (1.4 ± 0.1-fold, p = 0.007) but no changes in insulin secretion. In contrast, male homozygote knockout (aTCF7L2hom) mice displayed normal body weight but impaired oral glucose tolerance at 16 weeks (p = 0.0001). These changes were mechanistically associated with impaired in vitro glucose-stimulated insulin secretion (decreased 0.5 ± 0.1-fold vs control mice, p = 0.02) and decreased levels of the incretins glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide (0.6 ± 0.1-fold and 0.4 ± 0.1-fold vs control mice, p =&thin
Muniangi-Muhitu H, Akalestou E, Salem V, et 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.
Rutter GA, Georgiadou E, Martinez-Sanchez A, et 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
Carrat GR, Haythorne E, Tomas A, et 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
Hu M, Cherkaoui I, Misra S, et 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.
Mao D, Tian XY, Mao D, et 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
Akalestou E, Lopez-Noriega L, Leclerc I, et al., 2020, Metabolic surgery inhibits sodium glucose co-transporter 2 (SGLT2) expression in the kidney of lean mice, Publisher: WILEY, Pages: 43-43, ISSN: 0742-3071
Akalestou E, Suba K, Lopez-Noriega L, et al., 2020, Metabolic surgery recovers Ca(2+)dynamics across pancreatic islets in obese mice, 56th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S114-S114, ISSN: 0012-186X
Ali UT, Suba K, Bitsi S, et al., 2020, Improving islet transplantation success by increasing expression of the epidermal growth factor receptor (EGFR), Publisher: WILEY, Pages: 36-36, ISSN: 0742-3071
Hu M, Cebola I, Carrat G, et al., 2020, Chromatin 3D interaction analysis of the STARD10 locus unveils FCHSD2 as a new regulator of insulin secretion, DIABETOLOGIA, Vol: 63, Pages: S110-S110, ISSN: 0012-186X
Noriega LL, Sanchez AM, Callingham R, et al., 2020, The long non-coding RNA PAX6-AS1 modulates human beta cell function, Publisher: WILEY, Pages: 38-39, ISSN: 0742-3071
Rutter GA, Georgiadou E, Rodriguez T, et al., 2020, Pancreatic beta cell-selective deletion of themitofusins 1 and 2 (Mfn1 and Mfn2) impairs glucose-stimulated insulin secretion in vitro and in vivo, 56th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S6-S7, ISSN: 0012-186X
Callingham RM, Leclerc I, Pullen TJ, et al., 2020, The impact of a long non-coding RNA at the Pax6 locus on beta cell identity and function, Publisher: WILEY, Pages: 38-38, ISSN: 0742-3071
Suba K, Patel Y, Alonso AM, et al., 2020, Clinical care and other categories posters: Hypoglycaemia, Publisher: WILEY, Pages: 25-25, ISSN: 0742-3071
Rutter GA, Ninov N, Salem V, et al., 2020, Comment on Satin et al. "Take Me To Your Leader": An Electrophysiological Appraisal of the Role of Hub Cells in Pancreatic Islets. Diabetes 2020;69:830-836, DIABETES, Vol: 69, Pages: E10-E11, ISSN: 0012-1797
Pickford P, Lucey M, Fang Z, et al., 2020, Signalling, trafficking and glucoregulatory properties of glucagon-like peptide-1 receptor agonists exendin-4 and lixisenatide., British Journal of Pharmacology, Vol: 177, Pages: 3905-3923, ISSN: 0007-1188
BACKGROUND AND PURPOSE: Amino acid substitutions at the N-termini of glucagon-like peptide-1 receptor agonist (GLP-1RA) peptides result in distinct patterns of intracellular signalling, sub-cellular trafficking and efficacy in vivo. Here we aimed to determine whether sequence differences at the ligand C-termini of clinically approved GLP-1RAs exendin-4 and lixisenatide lead to similar phenomena. EXPERIMENTAL APPROACH: Exendin-4, lixisenatide, and N-terminally substituted analogues with biased signalling characteristics were compared across a range of in vitro trafficking and signalling assays in different cell types. Fluorescent ligands and new time-resolved FRET approaches were developed to study agonist behaviours at the cellular and sub-cellular level. Anti-hyperglycaemic and anorectic effects of each parent ligand, and their biased derivatives, were assessed in mice. KEY RESULTS: Lixisenatide and exendin-4 showed equal binding affinity, but lixisenatide was 5-fold less potent for cAMP signalling. Both peptides induced extensive GLP-1R clustering in the plasma membrane and were rapidly endocytosed, but the GLP-1R recycled more slowly to the cell surface after lixisenatide treatment. These combined deficits resulted in reduced maximal sustained insulin secretion and reduced anti-hyperglycaemic and anorectic effects in mice with lixisenatide. N-terminal substitution of His1 by Phe1 to both ligands had favourable effects on their pharmacology, resulting in improved insulin release and lowering of blood glucose. CONCLUSION AND IMPLICATIONS: Changes to the C-terminus of exendin-4 affect signalling potency and GLP-1R trafficking via mechanisms unrelated to GLP-1R occupancy. These differences were associated with changes in their ability to control blood glucose and therefore may be therapeutically relevant.
Mostafa D, Yanagiya A, Georgiadou E, et al., 2020, Loss of beta-cell identity and diabetic phenotype in mice caused by disruption of CNOT3-dependent mRNA deadenylation, COMMUNICATIONS BIOLOGY, Vol: 3
Ralston JC, Nguyen-Tu M-S, Lyons CL, et al., 2020, Dietary substitution of SFA with MUFA within high-fat diets attenuates hyperinsulinaemia and pancreatic islet dysfunction, BRITISH JOURNAL OF NUTRITION, Vol: 124, Pages: 247-255, ISSN: 0007-1145
Amouyal C, Castel J, Guay C, et al., 2020, 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, EBioMedicine, Vol: 58, ISSN: 2352-3964
BACKGROUND: Bariatric surgery is an effective treatment for type 2 diabetes. Early post-surgical enhancement of insulin secretion is key for diabetes remission. The full complement of mechanisms responsible for improved pancreatic beta cell functionality after bariatric surgery is still unclear. Our aim was to identify pathways, evident in the islet transcriptome, that characterize the adaptive response to bariatric surgery independently of body weight changes. METHODS: We performed entero-gastro-anastomosis (EGA) with pyloric ligature in leptin-deficient ob/ob mice as a surrogate of Roux-en-Y gastric bypass (RYGB) in humans. Multiple approaches such as determination of glucose tolerance, GLP-1 and insulin secretion, whole body insulin sensitivity, ex vivo glucose-stimulated insulin secretion (GSIS) and functional multicellular Ca2+-imaging, profiling of mRNA and of miRNA expression were utilized to identify significant biological processes involved in pancreatic islet recovery. FINDINGS: EGA resolved diabetes, increased pancreatic insulin content and GSIS despite a persistent increase in fat mass, systemic and intra-islet inflammation, and lipotoxicity. Surgery differentially regulated 193 genes in the islet, most of which were involved in the regulation of glucose metabolism, insulin secretion, calcium signaling or beta cell viability, and these were normalized alongside changes in glucose metabolism, intracellular Ca2+ dynamics and the threshold for GSIS. Furthermore, 27 islet miRNAs were differentially regulated, four of them hubs in a miRNA-gene interaction network and four others part of a blood signature of diabetes resolution in ob/ob mice and in humans. INTERPRETATION: Taken together, our data highlight novel miRNA-gene interactions in the pancreatic islet during the resolution of diabetes after bariatric surgery that form part of a blood signature of diabetes reversal. FUNDING: European Union's Horizon 2020 research and innovation programme via the Innovat
Rutter GA, McCormack JG, Halestrap AP, et al., 2020, The roles of cytosolic and intramitochondrial Ca2+ and the mitochondrial Ca2+-uniporter (MCU) in the stimulation of mammalian oxidative phosphorylation, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 295, Pages: 10506-10506, ISSN: 0021-9258
Georgiadou E, Rutter GA, 2020, Age matters: Grading granule secretion in beta cells, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 295, Pages: 8912-8913, ISSN: 0021-9258
Jones B, Pickford P, Lucey M, et al., 2020, Disconnect between signalling potency and in vivo efficacy of pharmacokinetically optimised biased glucagon-like peptide-1 receptor agonists, Molecular Metabolism, Vol: 37, ISSN: 2212-8778
ObjectiveThe objective of this study was to determine how pharmacokinetically advantageous acylation impacts on glucagon-like peptide-1 receptor (GLP-1R) signal bias, trafficking, anti-hyperglycaemic efficacy, and appetite suppression.MethodsIn vitro signalling responses were measured using biochemical and biosensor assays. GLP-1R trafficking was determined by confocal microscopy and diffusion-enhanced resonance energy transfer. Pharmacokinetics, glucoregulatory effects, and appetite suppression were measured in acute, sub-chronic, and chronic settings in mice.ResultsA C-terminally acylated ligand, [F1,K⁴⁰.C16 diacid]exendin-4, was identified that showed undetectable β-arrestin recruitment and GLP-1R internalisation. Depending on the cellular system used, this molecule was up to 1000-fold less potent than the comparator [D3,K⁴⁰.C16 diacid]exendin-4 for cyclic AMP signalling, yet was considerably more effective in vivo, particularly for glucose regulation.ConclusionsC-terminal acylation of biased GLP-1R agonists increases their degree of signal bias in favour of cAMP production and improves their therapeutic potential.
Suba K, Patel YS, Alonso AM, et al., 2020, Chronic Administration of a Long-Acting Glucagon Analogue Results in Enhanced Insulin Secretory Activity in a Directly-Observed Murine Model, 80th Scientific Sessions of the American-Diabetes-Association (ADA), Publisher: AMER DIABETES ASSOC, ISSN: 0012-1797
Akalestou E, Suba K, Noriega LL, et al., 2020, Bariatric Surgery Improves Ca2+Dynamics across Pancreatic Islets In Vivo, 80th Scientific Sessions of the American-Diabetes-Association (ADA), Publisher: AMER DIABETES ASSOC, ISSN: 0012-1797
Akalestou E, Noriega LL, Christakis I, et al., 2020, Bariatric Surgery Downregulates Glucocorticoid Signaling in Mice, 80th Scientific Sessions of the American-Diabetes-Association (ADA), Publisher: AMER DIABETES ASSOC, ISSN: 0012-1797
Georgiadou E, Chabosseau PL, Tomas A, et al., 2020, Deletion of the Mitofusins 1 and 2 (Mfn1 and Mfn2) in the Pancreatic Beta Cell Disrupts Mitochondrial Structure and Function In Vitro and Strongly Impairs Glucose-Stimulated Insulin Secretion In Vivo, 80th Scientific Sessions of the American-Diabetes-Association (ADA), Publisher: AMER DIABETES ASSOC, ISSN: 0012-1797
Salem V, Ali U, Suba K, et al., 2020, Upregulation of Pancreatic Islet EGF Receptor Improves Beta-Cell Identity and In Vivo Vascularisation in a Directly Observed Transplant Model, 80th Scientific Sessions of the American-Diabetes-Association (ADA), Publisher: AMER DIABETES ASSOC, ISSN: 0012-1797
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.