Publications
673 results found
Chabosseau P, Yong F, Delgadillo-Silva LF, et al., 2022, Molecular phenotyping of single pancreatic islet leader beta cells by “Flash-Seq”
<jats:title>Abstract</jats:title><jats:sec><jats:title>Aims</jats:title><jats:p>Spatially-organised increases in cytosolic Ca<jats:sup>2+</jats:sup>within pancreatic beta cells in the pancreatic islet underlie the stimulation of insulin secretion by high glucose. Recent data have revealed the existence of subpopulations of beta cells including “leaders” which initiate Ca<jats:sup>2+</jats:sup>waves. Whether leader cells possess unique molecular features, or localisation, is unknown.</jats:p></jats:sec><jats:sec><jats:title>Main methods</jats:title><jats:p>High speed confocal Ca<jats:sup>2+</jats:sup>imaging was used to identify leader cells and connectivity analysis, running under MATLAB and Python, to identify highly connected “hub” cells. To explore transcriptomic differences between beta cell sub-groups, individual leaders or followers were labelled by photo-activation of the cryptic fluorescent protein PA-mCherry and subjected to single cell RNA sequencing (“Flash-Seq”).</jats:p></jats:sec><jats:sec><jats:title>Key findings</jats:title><jats:p>Distinct Ca<jats:sup>2+</jats:sup>wave types were identified in individual islets, with leader cells present in 73 % (28 of 38 islets imaged). Scale-free, power law-adherent behaviour was also observed in 29% of islets, though “hub” cells in these islets did not overlap with leaders. Transcripts differentially expressed (295; padj<0.05) between leader and follower cells included genes involved in cilium biogenesis and transcriptional regulation. Functionally validating these findings, cilia number and length tended to be lower in leader<jats:italic>vs</jats:italic>follower cells. Leader cells were also located significantly closer to delta cells in Euclidian space than were follower cells.</jats:p>
Jones B, Burade V, Akalestou E, et al., 2022, In vivo and in vitro characterization of GL0034, a novel long-acting glucagon-like peptide-1 receptor agonist, Diabetes, Obesity and Metabolism: a journal of pharmacology and therapeutics, Vol: 24, Pages: 2090-2101, ISSN: 1462-8902
AimsTo describe the in vitro characteristics and antidiabetic in vivo efficacy of the novel glucagon-like peptide-1 receptor agonist (GLP-1RA) GL0034.Materials and MethodsGlucagon-like peptide-1 receptor (GLP-1R) kinetic binding parameters, cyclic adenosine monophosphate (cAMP) signalling, endocytosis and recycling were measured using HEK293 and INS-1832/3 cells expressing human GLP-1R. Insulin secretion was measured in vitro using INS-1832/3 cells, mouse islets and human islets. Chronic administration studies to evaluate weight loss and glycaemic effects were performed in db/db and diet-induced obese mice.ResultsCompared to the leading GLP-1RA semaglutide, GL0034 showed increased binding affinity and potency-driven bias in favour of cAMP over GLP-1R endocytosis and β-arrestin-2 recruitment. Insulin secretory responses were similar for both ligands. GL0034 (6 nmol/kg) led to at least as much weight loss and lowering of blood glucose as did semaglutide at a higher dose (14 nmol/kg).ConclusionsGL0034 is a G protein-biased agonist that shows powerful antidiabetic effects in mice, and may serve as a promising new GLP-1RA for obese patients with type 2 diabetes.
Cheung R, Pizza G, Chabosseau P, et al., 2022, Glucose-Dependent miR-125b Is a Negative Regulator of β-Cell Function, DIABETES, Vol: 71, Pages: 1525-1545, ISSN: 0012-1797
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- Citations: 4
Cao H, Chung ACK, Ming X, et 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
Chabosseau PL, Yong SWF, Lopez L, et al., 2022, A Transcriptomic Signature of Pancreatic Islet Leader Beta Cells, Publisher: AMER DIABETES ASSOC, ISSN: 0012-1797
Suba K, Patel YS, Roberts A, et al., 2022, The Role of Intraislet Glucagon in Pulsatile Insulin Secretion, Publisher: AMER DIABETES ASSOC, ISSN: 0012-1797
Nguyen-Tu M-S, Harris J, Martinez-Sanchez A, et 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
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- Citations: 3
Cruciani-Guglielmacci C, Meneyrol K, Denom J, et 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.
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.
Akalestou E, Lopez-Noriega L, Tough IR, et 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.
Georgiadou E, Muralidharan C, Martinez M, et 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.
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
Bitsi S, Manchanda Y, ElEid L, et 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
Karsai M, Zuellig RA, Lehmann R, et 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
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- Citations: 5
Zheng X, Ho QWC, Chua M, et al., 2022, Destabilization of β 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
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- Citations: 8
Cherkaoui I, Colclough K, Sessions RB, et al., 2022, No family history of diabetes: Could it still be Maturity Onset Diabetes of the Young (MODY)?, Publisher: WILEY, ISSN: 0742-3071
Akalestou E, Miras A, Rutter G, et 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
Yu V, Stamoulis Z, Chen K, et al., 2022, Genomic imprinting and developmental physiology: intrauterine growth and postnatal period, Perinatal and Developmental Epigenetics: Volume 32 in Translational Epigenetics, Pages: 115-136, ISBN: 9780128217863
In therian mammals, genomic imprinting, typically via methylation of either the paternal or maternal allele, results in a monoallelic and parent-of-origin expression pattern of a subset of genes. Careful maintenance of the expression of these “imprinted” genes is crucial to mammalian development, with misexpression in humans or model organisms evidenced in a series of prenatal, neonatal, and postnatal growth and developmental phenotypes that impact adult metabolic health. Imprinted genes exert their effects in utero via both placental and embryonic tissues, with their dysregulation leading to fetal growth defects and abnormal control of placental resources. In the neonatal and postnatal period, they govern the feeding, thermoregulation, and social behaviors in both the offspring and the mother. Furthermore, metabolic syndrome in adulthood is a consequence of gene-environment interactions via altered imprinted gene expression in the postnatal period, demonstrating the importance of tightly controlled growth and development in early life.
Manchanda Y, Ramchunder Z, Shchepinova MM, et 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
Jha MK, Passero J, Rawat A, et al., 2021, Macrophage monocarboxylate transporter 1 promotes peripheral nerve regeneration after injury in mice, JOURNAL OF CLINICAL INVESTIGATION, Vol: 131, ISSN: 0021-9738
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- Citations: 16
de Jesus DS, Mak TCS, Wang Y-F, et 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
Akalestou E, Suba K, Lopez-Noriega L, et 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
Slieker RC, Donnelly LA, Fitipaldi H, et 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
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- Citations: 27
Martinez-Sanchez A, Cheung R, Pizza G, et al., 2021, Beta cell miR-125b controls glucose homeostasis by targeting lysosomal and mitochondrial genes, Publisher: SPRINGER, Pages: 158-158, ISSN: 0012-186X
Akalestou E, Lopez-Noriega L, Hu M, et al., 2021, SGLT2 contributes to glucoregulatory improvements following vertical sleeve gastrectomy in mice, Publisher: SPRINGER, Pages: 222-222, ISSN: 0012-186X
Thennati R, Burade V, Garcia-Ocana A, et al., 2021, A novel, long-acting dual agonist for GIPR/GLP-1R, HISHS-2001, demonstrates effects on HbA<sub>1c</sub> and weight loss in the db/db mouse model of type 2 diabetes, Publisher: SPRINGER, Pages: 242-242, ISSN: 0012-186X
Slieker RC, Donnelly LA, Lopez-Noriega L, et al., 2021, Novel biomarkers for glycaemic deterioration in type 2 diabetes: an IMI RHAPSODY study, Publisher: SPRINGER, Pages: 108-108, ISSN: 0012-186X
Akalestou E, Suba K, Lopez-Noriega L, et 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.
Slieker RC, Donnelly LA, Fitipaldi H, et 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.
Marzook A, Chen S, Pickford P, et 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.
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