Publications
643 results found
Rutter G, Firth G, Georgiadou E, et al., 2023, Impact of an SLC30A8 loss-of-function variant on the pancreatic distribution of zinc and manganese: laser ablation-ICP-MS and positron emission tomography studies in mice, Frontiers in Endocrinology, ISSN: 1664-2392
Common variants in the SLC30A8 gene, encoding the secretory granule zinc transporter ZnT8 (expressed largely in pancreatic islet alpha and beta cells), are associated with altered risk of type 2 diabetes. Unexpectedly, rare loss-of-function (LoF) variants in the gene, described in heterozygous individuals only, are protective against the disease, even though knockout of the homologous SLC30A8 gene in mice leads to unchanged or impaired glucose tolerance. Here, we aimed to determine how one or two copies of the mutant R138X allele in the mouse SLC30A8 gene impacts the homeostasis of zinc at a whole-body (using non-invasive 62Zn PET imaging to assess the acute dynamics of zinc handling) and tissue/cell level (using LA-ICP-MS to map the long-term distribution of zinc and manganese in the pancreas). Following intravenous administration of [62Zn]Zn-citrate (~7 MBq, 150 μL) in wild-type (WT), heterozygous (R138X+/-) and homozygous (R138X+/+) mutant mice (14-15 weeks old, n = 4 per genotype), zinc dynamics were measured over 60 minutes using PET. Histological, islet hormone immunohistochemistry and elemental analysis with LA-ICP-MS (Zn, Mn, P) were performed on sequential pancreas sections. Bulk Zn and Mn concentration in the pancreas was determined by solution ICP-MS. Our findings reveal that whereas uptake into organs, assessed using PET imaging of 62Zn, is largely unaffected by the R138X variant, mice homozygous of the mutant allele show a substantial lowering (to 40% of WT) of total islet zinc, as anticipated. In contrast, mice heterozygous for this allele, thus mimicking human carriers of LoF alleles, show markedly increased endocrine and exocrine zinc content (1.6-fold increase for both compared to WT), as measured by LA-ICP-MS. Both endocrine and exocrine manganese content were also sharply increased in R138X+/- mice, with smaller increases observed in R138X+/+ mice. These data challenge the view that zinc depletion from the beta cell is the likely underlying dri
Slieker R, Donnellly L, Akalestou E, et al., 2023, Identification of biomarkers for glycaemic deterioration in type 2 diabetes, Nature Communications, Vol: 14, Pages: 1-18, ISSN: 2041-1723
We identify biomarkers for disease progression in three type 2 diabetes cohorts encompassing 2,973 individuals across three molecular classes, metabolites, lipids and proteins. Homocitrulline, isoleucine and 2-aminoadipic acid, eight triacylglycerol species, and lowered sphingomyelin 42:2;2 levels are predictive of faster progression towards insulin requirement. Of ~1,300 proteins examined in two cohorts, levels of GDF15/MIC-1, IL-18Ra, CRELD1, NogoR, FAS, and ENPP7 are associated with faster progression, whilst SMAC/DIABLO, SPOCK1 and HEMK2 predict lower progression rates. In an external replication, proteins and lipids are associated with diabetes incidence and prevalence. NogoR/RTN4R injection improved glucose tolerance in high fat-fed male mice but impaired it in male db/db mice. High NogoR levels led to islet cell apoptosis, and IL-18R antagonised inflammatory IL-18 signalling towards nuclear factor kappa-B in vitro. This comprehensive, multi-disciplinary approach thus identifies biomarkers with potential prognostic utility, provides evidence for possible disease mechanisms, and identifies potential therapeutic avenues to slow diabetes progression.
Tomas Catala A, Bitsi S, Manchanda Y, et al., 2023, Divergent acute versus prolonged pharmacological GLP-1R responses in adult beta cell-specific β-arrestin 2 knockout mice, Science Advances, Vol: 9, Pages: 1-23, ISSN: 2375-2548
The glucagon-like peptide-1 receptor (GLP-1R) is a major type 2 diabetes therapeutic target. Stimulated GLP-1Rs are rapidly desensitized by β-arrestins, scaffolding proteins that not only terminate G protein interactions but also act as independent signaling mediators. Here, we have assessed in vivo glycemic responses to the pharmacological GLP-1R agonist exendin-4 in adult β cell–specific β-arrestin 2 knockout (KO) mice. KOs displayed a sex-dimorphic phenotype consisting of weaker acute responses that improved 6 hours after agonist injection. Similar effects were observed for semaglutide and tirzepatide but not with biased agonist exendin-phe1. Acute cyclic adenosine 5′-monophosphate increases were impaired, but desensitization reduced in KO islets. The former defect was attributed to enhanced β-arrestin 1 and phosphodiesterase 4 activities, while reduced desensitization co-occurred with impaired GLP-1R recycling and lysosomal targeting, increased trans-Golgi network signaling, and reduced GLP-1R ubiquitination. This study has unveiled fundamental aspects of GLP-1R response regulation with direct application to the rational design of GLP-1R–targeting therapeutics.
Xiao J, El Eid L, Buenaventura T, et al., 2023, Control of human pancreatic beta cell kinome by glucagon-like peptide-1 receptor biased agonism, Diabetes, Obesity and Metabolism, Pages: 1-15, ISSN: 1462-8902
AimTo determine the kinase activity profiles of human pancreatic beta cells downstream of glucagon-like peptide-1 receptor (GLP-1R) balanced versus biased agonist stimulations.Materials and MethodsThis study analysed the kinomic profiles of human EndoC-βh1 cells following vehicle and GLP-1R stimulation with the pharmacological agonist exendin-4, as well as exendin-4–based biased derivatives exendin-phe1 and exendin-asp3 for acute (10-minute) versus sustained (120-minute) responses, using PamChip protein tyrosine kinase and serine/threonine kinase assays. The raw data were filtered and normalized using BioNavigator. The kinase analyses were conducted with R, mainly including kinase-substrate mapping and Kyoto Encyclopedia of Genes and Genomes pathway analysis.ResultsThe present analysis reveals that kinomic responses are distinct for acute versus sustained GLP-1R agonist exposure, with individual responses associated with agonists presenting specific bias profiles. According to pathway analysis, several kinases, including JNKs, PKCs, INSR and LKB1, are important GLP-1R signalling mediators, constituting potential targets for further research on biased GLP-1R downstream signalling.ConclusionThe results from this study suggest that differentially biased exendin-phe1 and exendin-asp3 can modulate distinct kinase interaction networks. Further understanding of these mechanisms will have important implications for the selection of appropriate anti-type 2 diabetes therapies with optimized downstream kinomic profiles.
Surekha MV, Suneetha N, Balakrishna N, et al., 2023, Impact of COVID-19 during pregnancy on placental pathology, maternal and neonatal outcome – a cross-sectional study on anemic term pregnant women from a tertiary care hospital in southern India, Frontiers in Endocrinology, Vol: 14, Pages: 1-16, ISSN: 1664-2392
BACKGROUND: SARS-CoV-2 infection during pregnancy may cause adverse maternal, neonatal and placental outcomes. While tissue hypoxia is often reported in COVID-19 patients, pregnant women with anemia are suspected to be more prone to placental hypoxia-related injuries. METHODS: This hospital-based cross-sectional study was conducted between August-November 2021, during COVID-19 second wave in India. Term pregnant women (N=212) admitted to hospital for delivery were enrolled consecutively. Since hospital admission mandated negative RT-PCR test for SARS-CoV-2 virus, none had active infection. Data on socio-demography, COVID-19 history, maternal, obstetric, and neonatal outcomes were recorded. Pre-delivery maternal and post-delivery cord blood samples were tested for hematological parameters and SARS-CoV-2 IgG. Placentae were studied for histology. RESULTS: Of 212 women, 122 (58%) were seropositive for SARS-CoV-2 IgG, but none reported COVID-19 history; 134 (63.2%) were anemic. In seropositive women, hemoglobin (p=0.04), total WBC (p=0.009), lymphocytes (p=0.005) and neutrophils (p=0.02) were significantly higher, while ferritin was high, but not significant and neutrophils to lymphocytes (p=0.12) and platelets to lymphocytes ratios (p=0.03) were lower. Neonatal outcomes were similar. All RBC parameters and serum ferritin were significantly lower in anemic mothers but not in cord blood, except RDW that was significantly higher in both, maternal (p=0.007) and cord (p=0.008) blood from seropositive anemic group compared to other groups. Placental histology showed significant increase in villous hypervascularity (p=0.000), dilated villous capillaries (p=0.000), and syncytiotrophoblasts (p=0.02) in seropositive group, typically suggesting placental hypoxia. Maternal anemia was not associated with any histological parameters. Univariate and multivariate logistic regression analyses of placental histopathological adverse outcomes showed strong association with SARS-CoV-2 sero
Chabosseau P, Yong F, Delgadillo-Silva LF, et al., 2023, Molecular phenotyping of single pancreatic islet leader beta cells by "Flash-Seq", Life Sciences, Vol: 316, ISSN: 0024-3205
AIMS: Spatially-organized increases in cytosolic Ca2+ 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 Ca2+ waves. Whether leader cells possess unique molecular features, or localisation, is unknown. MAIN METHODS: High speed confocal Ca2+ 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"). KEY FINDINGS: Distinct Ca2+ 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. Providing some support for these findings, ADCY6 immunoreactivity tended to be higher in leader than follower cells, whereas cilia number and length tended to be lower in the former. Finally, leader cells were located significantly closer to delta, but not alpha, cells in Euclidian space than were follower cells. SIGNIFICANCE: The existence of both a discrete transcriptome and unique localisation implies a role for these features in defining the specialized function of leaders. These data also raise the possibility that localised signalling between delta and leader cells contributes to the initiation and propagation of islet Ca2+ waves.
Sui L, Du Q, Romer A, et al., 2023, ZnT8 Loss of Function Mutation Increases Resistance of Human Embryonic Stem Cell-Derived Beta Cells to Apoptosis in Low Zinc Condition, CELLS, Vol: 12
Avari P, Eng PC, Hu M, et al., 2023, A novel somatic mutation implicates ATP6V0D1 in proinsulin processing, Journal of the Endocrine Society, Vol: 7, Pages: 1-5, ISSN: 2472-1972
ContextProhormone convertase 1/3 (PC1/3), encoded by protein convertase subtilisin kexin type 1 (PCSK1), converts inactive prohormones into biologically active peptides. Somatic mutations of insulinomas are associated with genetic defects interfering with control of insulin secretion from pancreatic beta cells. However, somatic mutations in proinsulinomas have not been described.ObjectiveWe report a case of a proinsulinoma, with suppressed insulin and C-peptide levels.MethodsA 70-year-old woman presented with a 20-year history of “blackouts.” During a 72-hour fast, blood glucose level dropped to 1.9 mmol/L with suppressed plasma insulin and C-peptide levels, but proinsulin levels were raised at 37 pmol/L (<10 pmol/L).ResultsImaging revealed 3 distinct DOTATATE-avid pancreatic lesions. Laparoscopic spleen-preserving distal pancreatomy was performed. In view of discordant insulin, C-peptide, and proinsulin levels, whole exome sequencing analysis was performed on the tumor. In the somatic exome of the tumor, we found mutations in PCSK expression regulators, as well as a novel truncating somatic mutation in ATP6V0D1, a subunit of the ion pump that acidifies the β-cell compartments where the PCSKs act.ConclusionAppropriately suppressed insulin levels in the context of hypoglycemia do not always indicate the absence of a neuroendocrine islet cell tumor and proinsulin levels may be indicated to solidify the diagnosis. In the context of elevated proinsulin levels, low insulin and C-peptide levels might be explained by somatic mutations that likely implicate proinsulin processing within the tumor. Furthermore, we propose several mechanistic candidates, including ATP6V0D1. Experimental validation using cellular approaches may in future confirm pathomechanisms involved in this rare condition.
Anindya R, Rutter GA, Meur G, 2023, New-onset type 1 diabetes and severe acute respiratory syndrome coronavirus 2 infection, IMMUNOLOGY AND CELL BIOLOGY, ISSN: 0818-9641
Bosi E, Marchetti P, Rutter GA, et al., 2022, Human alpha cell transcriptomic signatures of types 1 and 2 diabetes highlight disease-specific dysfunction pathways, iScience, Vol: 25, ISSN: 2589-0042
Although glucagon secretion is perturbed in both T1D and T2D, the pathophysiological changes in individual pancreatic alpha cells are still obscure. Using recently curated single-cell RNASeq data from T1D or T2D donors and their controls, we identified alpha cell transcriptomic alterations consistent with both common and discrete pathways. Although alterations in alpha cell identity gene (ARX, MAFB) expression were conserved, cytokine-regulated genes and genes involved in glucagon biosynthesis and processing were up-regulated in T1D. Conversely, mitochondrial genes associated with ROS (COX7B, NQO2) were dysregulated in T2D. Additionally, T1D alpha cells displayed altered expression of autoimmune-induced ER stress genes (ERLEC1, HSP90), whilst those from T2D subjects showed modified glycolytic and citrate cycle gene (LDHA?, PDHB, PDK4) expression. Thus, despite conserved alterations related to loss of function, alpha cells display disease-specific gene signatures which may be secondary to the main pathogenic events in each disease, namely immune- or metabolism-mediated-stress, in T1D and T2D, respectively.
Akalestou E, Lopez-Noriega L, Christakis I, et al., 2022, Vertical Sleeve Gastrectomy normalizes circulating glucocorticoid levels and lowers glucocorticoid action tissue-selectively in mice, Frontiers in Endocrinology, Vol: 13, Pages: 1-16, ISSN: 1664-2392
Objectives: Glucocorticoids produced by the adrenal cortex are essential for the maintenance of metabolic homeostasis.Glucocorticoid activation is catalysed by 11β‐hydroxysteroid dehydrogenase 1 (11β‐HSD1). Excess glucocorticoids are associatedwith insulin resistance and hyperglycaemia. A small number of studies have demonstrated effects on glucocorticoid metabolism ofbariatric surgery, a group of gastrointestinal procedures known to improve insulin sensitivity and secretion, which were assumedto result from weight loss. In this study, we hypothesize that a reduction in glucocorticoid action following bariatric surgerycontributes to the widely observed euglycemic effects of the treatment. Methods: Glucose and insulin tolerance tests wereperformed at ten weeks post operatively and circulating corticosterone was measured. Liver and adipose tissues were harvestedfrom fed mice and 11β‐HSD1 levels were measured by quantitative RT‐PCR or Western (immuno‐) blotting, respectively. 11β‐HSD1null mice (Hsd11b1-/-) were generated using CRISPR/ Cas9 genome editing. Wild type (WT) and littermate Hsd11b1-/- miceunderwent Vertical Sleeve Gastrectomy (VSG) or sham surgery. Results: WT VSG-treated mice displayed significantly improvedglucose tolerance versus sham controls, and this effect was observed in both regular chow- and HFD-fed animals. VSG lowered bodyweight in HFD but not regular chow-fed mice. Remarkably, VSG restored physiological corticosterone production in HFD mice andreduced 11β‐HSD1 expression in liver and adipose tissue post‐surgery. Elimination of the 11β‐HSD1/Hsd11b1 gene mimicked theeffects of VSG on body weight and tolerance to 1g/kg glucose challenge. However, at 3 g/kg glucose, the impact of VSG on glucoseexcursion was indistinguishable between WT and Hsd11b1-/- mice, suggesting that the euglycemic effect of VSG was superior toHsd11b1 elimination. Conclusions: Bariatric surgery improves insulin sensitivity and reduces glucocorticoi
Parks SZ, Rutter GA, Leclerc I, 2022, Whole-body sorcin invalidation does not cause hypothalamic ER stress nor worsens obesity in C57BL/6 male mice fed a westernized diet
<jats:title>ABSTRACT</jats:title><jats:sec><jats:title>Background</jats:title><jats:p><jats:underline>So</jats:underline>luble <jats:underline>R</jats:underline>esistance Related <jats:underline>C</jats:underline>alcium B<jats:underline>in</jats:underline>ding Protein (sorcin) is a calcium (Ca<jats:sup>2+</jats:sup>) binding protein which has been shown to play a role in maintaining intracellular endoplasmic reticulum (ER) Ca<jats:sup>2+</jats:sup> stores and lowering ER stress. Recently, our lab has demonstrated that sorcin expression was downregulated in the islets of Langerhans of mice fed a high-fat diet or in human islets incubated with the saturated fatty acid palmitate. We also showed that overexpression of sorcin under control of the rat insulin promoter (RIP7) in C57BL/6J mice, or whole body sorcin deletion in 129S1/SvImJ mice, improves or impairs insulin secretion and pancreatic β-cell function respectively. The mechanisms behind this beneficial role of sorcin in the pancreatic β-cell might depend on protection against lipotoxic endoplasmic reticulum (ER) stress through improved ER Ca<jats:sup>2+</jats:sup> dynamics and activation of the Activating Transcription Factor 6 (ATF6) branch of the unfolded protein response (UPR). Whether sorcin is also implicated in hypothalamic ER stress during the progression of obesity is unknown. This could potentially contribute to the diminished satiety typically observed in overweight individuals.</jats:p></jats:sec><jats:sec><jats:title>Aim</jats:title><jats:p>To investigate a potential role of sorcin in hypothalamic ER stress, leptin resistance, hyperphagia and obesity.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Whole-body sorcin null mice, backcrossed onto the C57BL/6J genetic background, were u
Tan W, Amirruddin N, Hu M, et al., 2022, Mechanistic investigation into the role of type 2 diabetes-associated STARD10 in insulin secretion and pancreatic beta cells, Publisher: SPRINGER, Pages: S214-S215, ISSN: 0012-186X
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 beta-Cell Function, DIABETES, Vol: 71, Pages: 1525-1545, ISSN: 0012-1797
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
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
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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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
Zheng X, Ho QWC, Chua M, et 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
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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
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