A5028438920- Pancreatic function and diabetes
- Metabolism, Diabetes, and Cancer
- Receptor Mechanisms and Signaling
- Diabetes Treatment and Management
- Cellular transport and secretion
- Calcium signaling and nucleotide metabolism
- Cannabis and Cannabinoid Research
- Diabetes Management and Research
- Diabetes and associated disorders
- Diet, Metabolism, and Disease
- Adenosine and Purinergic Signaling
- Cholesterol and Lipid Metabolism
- Neuropeptides and Animal Physiology
- Erythrocyte Function and Pathophysiology
- Ion channel regulation and function
- Nuclear Receptors and Signaling
- Biochemical Analysis and Sensing Techniques
- Macrophage Migration Inhibitory Factor
- GDF15 and Related Biomarkers
- Neurotransmitter Receptor Influence on Behavior
- Ion Channels and Receptors
- Adipose Tissue and Metabolism
- Regulation of Appetite and Obesity
- Neuroendocrine Tumor Research Advances
- Fibroblast Growth Factor Research
Eli Lilly (United States)
2012-2025
Karolinska Institutet
1997-2006
Eli Lilly (Germany)
2004-2006
Lomonosov Moscow State University
1994-2006
Moscow State University
2006
Karolinska University Hospital
1997-2004
University of Copenhagen
2003
Novo Nordisk (Denmark)
2002-2003
Lund University
2003
Fibroblast growth factor-21 (FGF-21) is a recently discovered metabolic regulator. Here, we investigated the effects of FGF-21 in pancreatic beta-cell. In rat islets and INS-1E cells, activated extracellular signal-regulated kinase 1/2 Akt signaling pathways. isolated from healthy rats, increased insulin mRNA protein levels but did not potentiate glucose-induced secretion. Islets cells treated with were partially protected glucolipotoxicity cytokine-induced apoptosis. diabetic rodents,...
The ATP-sensitive potassium channel is a key molecular complex for glucose-stimulated insulin secretion in pancreatic β cells. In humans, mutations either of the two subunits this channel, sulfonylurea type 1 receptor (Sur1) or Kir6.2, cause persistent hyperinsulinemic hypoglycemia infancy. We have generated and characterized <i>Sur1</i> null mice. Interestingly, these animals remain euglycemic large portion their life despite constant depolarization membrane, elevated cytoplasmic free...
The GPR119 receptor plays an important role in the secretion of incretin hormones response to nutrient consumption. We have studied ability array naturally occurring endocannabinoid-like lipids activate and identified several lipid agonists. most potent agonists were three N-acylethanolamines: oleoylethanolamine (OEA), palmitoleoylethanolamine, linoleylethanolamine (LEA), all which displayed similar potency activating GPR119. Another lipid, 2-oleoylglycerol (2-OG), also activated but with...
Liver X receptors (LXRs) alpha and beta, transcription factors of a nuclear hormone receptor family, are expressed in pancreatic islets as well glucagon-secreting insulin-secreting cell lines. Culture or MIN6 cells with LXR specific agonist T0901317 caused an increase glucose-dependent insulin secretion islet content. The stimulatory effect on was observed only after >72 h culture the compound. In cells, increased protein expression lipogenic enzymes, fatty acid synthase, acetyl-CoA...
The glucose-sensing enzyme glucokinase (GK) plays a key role in glucose metabolism. We report here the effects of novel activator, LY2121260. activator enhanced GK activity via binding to allosteric site located hinge region enzyme. LY2121260 stimulated insulin secretion glucose-dependent manner pancreatic beta-cells and increased use rat hepatocytes. In addition, incubation with resulted protein levels, suggesting that on chronic treatment may be due not only changed kinetics but also...
GPR142, a putative amino acid receptor, is expressed in pancreatic islets and the gastrointestinal tract, but ligand affinity physiological role of this receptor remain obscure. In study, we show that addition to L-Tryptophan, GPR142 signaling also activated by L-Phenylalanine not other naturally occurring acids. Furthermore, Tryptophan synthetic agonist increase insulin incretin hormones improve glucose disposal mice GPR142-dependent manner. contrast, Phenylalanine improves vivo...
We identify biomarkers for disease progression in three type 2 diabetes cohorts encompassing 2,973 individuals across molecular classes, metabolites, lipids and proteins. Homocitrulline, isoleucine 2-aminoadipic acid, eight triacylglycerol species, lowered sphingomyelin 42:2;2 levels are predictive of faster towards insulin requirement. Of ~1,300 proteins examined two cohorts, GDF15/MIC-1, IL-18Ra, CRELD1, NogoR, FAS, ENPP7 associated with progression, whilst SMAC/DIABLO, SPOCK1 HEMK2...
Insulin secretion is controlled by the β cell′s metabolic state, and ability of secretory granules to undergo exocytosis increases during glucose stimulation in a membrane potential-independent fashion. Here, we demonstrate that insulin-containing depends on phosphatidylinositol 4-kinase (PI 4-kinase) activity inhibition this enzyme suppresses glucose-stimulated insulin secretion. Intracellular application 4-phosphate 4,5-bisphosphate [PI(4,5)P 2 ] stimulated promoting priming for release...
Significance Both type 1 and 2 diabetes are associated with reduced β-cell mass or function, resulting from decreased proliferation increased apoptosis. Understanding the signals governing survival regeneration is critical for developing strategies to maintain healthy populations of these cells in individuals. forms hyperglucagonemia an plasma glucagon:insulin ratio. Glucagon excess contributes metabolic dysregulation diabetic state glucagon receptor antagonism a potential target area...
A novel imidazoline compound, RX871024, was used to investigate the mechanisms by which derivatives promote insulin secretion in rat pancreatic β-cells and HIT T15 cells. RX871024 stimulated release from cells a glucose-dependent way. This effect not related α2-adrenergic, I1-, I2-imidazoline receptors. promoted at least two modes of action. One included an increase cytoplasmic free Ca2+ concentration ([Ca2+]i), subsequent blocking ATP-dependent K+ channels, membrane depolarization,...
The Munc-18 protein (mammalian homologue of the<i>unc-18</i> gene; also called nSec1 or rbSec1) has been identified as an essential component the synaptic vesicle fusion complex. cellular and subcellular localization functional role in pancreatic β-cells was investigated. Subcellular fractionation insulin-secreting HIT-T15 cells revealed a 67-kDa both cytosol membrane fractions. Immunohistochemistry showed punctate immunoreactivity cytoplasm rat islet cells. Direct double-labeling...
d - myo -inositol 1,2,3,4,5,6-hexakisphosphate (InsP 6 ), formed via complex pathways of inositol phosphate metabolism, composes the main bulk polyphosphates in cell. Relatively little is known regarding possible biological functions for InsP . We now show that can modulate insulin exocytosis permeabilized insulin-secreting cells. Concentrations above 20 μM stimulated secretion at basal Ca 2+ -concentration (30 nM) and primed -induced (10 μM), both effects being due to activation protein...
Type 2 diabetes (T2D) is associated with defective insulin secretion and reduced β cell mass. Available treatments provide a temporary reprieve, but secondary failure rates are high, making supplementation necessary. Reversibility of key translational question. Here, we reverse engineered interrogated pancreatic islet-specific regulatory networks to discover T2D-specific subpopulations characterized by metabolic inflexibility endocrine progenitor/stem features. Single-cell gain-...
Insulin, a critical metabolic hormone to maintain blood glucose homeostasis, is synthesized and folded in the endoplasmic reticulum (ER) of pancreatic β-cells as insulin precursor proinsulin. Proinsulin misfolding aggregation detected diabetic induces ER stress obstructs normal trafficking, processing, secretion insulin, which eventually can result β-cell dedifferentiation death. We have developed quantitative methods measure misfolded aggregated proinsulin by utilizing oligomer specific...
Glutamate has been implicated as an intracellular messenger in the regulation of insulin secretion response to glucose. Here we demonstrate by measurements cell capacitance rat pancreatic β‐cells that glutamate (1 mM) enhanced Ca 2+ ‐dependent exocytosis. also stimulated from permeabilized β‐cells. The effect was dose‐dependent (half‐maximum at 5.1 and maximal 10 mM glutamate. Glutamate‐induced exocytosis stronger clonal INS‐1E cells compared isolated mice parental INS‐1 cells, which...
Liver X receptors (LXRalpha and LXRbeta) regulate glucose lipid metabolism. Pancreatic beta-cells INS-1E insulinoma cells express only the LXRbeta isoform. Activation of with synthetic agonist T0901317 increased glucose-induced insulin secretion content, whereas deletion receptor in knockout mice severely blunted secretion. Analysis gene expression LXR agonist-treated islets from LXRbeta-deficient revealed that positively regulated ATP-binding cassette transporter A1 (ABCA1), sterol...
Oxytocin (OXT) has been shown to suppress appetite, induce weight loss, and improve glycemic control lipid metabolism in several species, including humans, monkeys, rodents. However, OXT's short half-life circulation lack of receptor selectivity limit its application efficacy. In this study, we report an OXT peptide analog (OXTGly) that is potent selective for the (OXTR). OXT, but not OXTGly, activated vasopressin receptors vitro acutely increased blood pressure vivo when administered IP....
The insulinotropic activity of the novel imidazoline compound BL11282 was investigated. Intravenous administration (0.3 mg · kg–1 min–1) to anesthetized rats did not change blood glucose and insulin levels under basal conditions, but produced a higher increase in faster removal from after infusion. Similarly, isolated Wistar rat pancreatic islets, 0.1–100 μmol/l potently stimulated glucose-induced secretion modulate secretion. Unlike previously described imidazolines, block ATP-dependent K+...
Membrane homeostasis is maintained by exocytosis and endocytosis. The molecular mechanisms regulating the interplay between these two processes are not clear. Inositol hexakisphosphate (InsP(6)) under metabolic control serves as a signal in pancreatic beta cell stimulus-secretion coupling increasing Ca(2+)-channel activity insulin exocytosis. We now show that InsP(6) also promotes dynamin I-mediated endocytosis cell. This effect of depends on calcineurin-induced dephosphorylation accounted...
Cytosolic free Ca 2+ plays an important role in the molecular mechanisms leading to regulated insulin secretion by pancreatic β cell. A number of -binding proteins have been implicated this process. Here, we define protein neuronal sensor-1 (NCS-1) secretion. In cells, NCS-1 increases exocytosis promoting priming secretory granules for release and increasing residing readily releasable pool. The effect on is mediated through increase phosphatidylinositol (PI) 4-kinase activity generation...
Liver X receptors (LXRs) form functional heterodimers with the retinoid (RXRs) and regulate cholesterol, lipid, glucose metabolism. We demonstrated previously that activation of LXR modulates insulin secretion in MIN6 cells pancreatic islets. In this study we investigated effects agonist T0901317 RXR 9-cis-retinoic acid (9cRA) on cell proliferation apoptosis cells. Whereas showed no effect cells, combination 9cRA inhibited proliferation. Flow cytometry analysis cycle LXR/RXR prevented from...
Extracellular ATP released from pancreatic β-cells acts as a potent insulinotropic agent through activation of P2 purinergic receptors. Ectonucleotidases, family membrane-bound nucleotide-metabolizing enzymes, regulate extracellular levels by degrading and related nucleotides. Ectonucleotidase activity affects the relative proportion its metabolites, which in turn will impact level receptor stimulation exerted ATP. Therefore, we investigated expression role ectonucleotidases β-cells. Of...
GPR142 agonists are being pursued as novel diabetes therapies by virtue of their insulin secretagogue effects. But it is undetermined whether GPR142's functions in pancreatic islets limited to regulating secretion. The current study expands research on its action. We demonstrated situ hybridization and immunostaining that expressed not only β cells but also a subset α cells. Stimulation selective agonist increased glucagon secretion both human mouse islets. More importantly, the potentiated...