Glucose regulates Foxo1 through insulin receptor signaling in the pancreatic islet beta-cell.


:Glucose controls islet beta-cell mass and function at least in part through the phosphatidylinositol 3-kinase (PI3K)/Akt pathway downstream of insulin signaling. The Foxo proteins, transcription factors known in other tissues to be negatively regulated by Akt activation, affect proliferation and metabolism. In this study, we tested the hypothesis that glucose regulates Foxo1 activity in the beta-cell via an autocrine/paracrine effect of released insulin on its receptor. Mouse insulinoma cells (MIN6) were starved overnight for glucose (5 mmol/l) then refed with glucose (25 mmol/l), resulting in rapid Foxo1 phosphorylation (30 min, P < 0.05 vs. untreated). This glucose response was demonstrated to be time (0.5-2 h) and dose (5-30 mmol/l) dependent. The use of inhibitors demonstrated that glucose-induced Foxo1 phosphorylation was dependent upon depolarization, calcium influx, and PI3K signaling. Additionally, increases in glucose concentration over a physiological range (2.5-20 mmol/l) resulted in nuclear to cytoplasmic translocation of Foxo1. Phosphorylation and translocation of Foxo1 following glucose refeeding were eliminated in an insulin receptor knockdown cell line, indicating that the glucose effects are mediated primarily through the insulin receptor. Activity of Foxo1 was observed to increase with decreased glucose concentrations, assessed by an IGF binding protein-1 promoter luciferase assay. Starvation of MIN6 cells identified a putative Foxo1 target, Chop, and a Chop-promoter luciferase assay in the presence of cotransfected Foxo1 supported this hypothesis. The importance of these observations was that nutritional alterations in the beta-cell are associated with changes in Foxo1 transcriptional activity and that these changes are predominantly mediated through glucose-stimulated insulin secretion acting through its own receptor.






Martinez SC,Cras-Méneur C,Bernal-Mizrachi E,Permutt MA




Has Abstract


2006-06-01 00:00:00
















  • Pancreatic islet GLUT2 glucose transporter mRNA and protein expression in humans with and without NIDDM.

    abstract::GLUT2 glucose transporter mRNA has been shown to be underexpressed in pancreatic islets of numerous animal models of non-insulin-dependent diabetes mellitus (NIDDM). It has been proposed that this molecular defect contributes to the pathogenesis of diabetes, although information concerning the expression of GLUT2 in h...


    pub_type: 杂志文章


    authors: Ferrer J,Benito C,Gomis R

    更新日期:1995-12-01 00:00:00

  • In Vivo Enrichment of Diabetogenic T Cells.

    abstract::Dysfunctional T cells can mediate autoimmunity, but the inaccessibility of autoimmune tissues and the rarity of autoimmune T cells in the blood hinder their study. We describe a method to enrich and harvest autoimmune T cells in vivo by using a biomaterial scaffold loaded with protein antigens. In model antigen system...


    pub_type: 杂志文章


    authors: Thelin MA,Kissler S,Vigneault F,Watters AL,White D,Koshy ST,Vermillion SA,Mooney DJ,Serwold T,Ali OA

    更新日期:2017-08-01 00:00:00

  • Objectively measured sedentary time may predict insulin resistance independent of moderate- and vigorous-intensity physical activity.

    abstract:OBJECTIVE:To examine the prospective association between objectively measured time spent sedentary and insulin resistance and whether this association is independent of moderate- and vigorous-intensity physical activity (MVPA) and other relevant confounders. RESEARCH DESIGN AND METHODS:This was a population-based stud...


    pub_type: 杂志文章


    authors: Helmerhorst HJ,Wijndaele K,Brage S,Wareham NJ,Ekelund U

    更新日期:2009-08-01 00:00:00

  • BH3-only molecule Bim mediates β-cell death in IRS2 deficiency.

    abstract::Irs2-deficient mice develop type 2-like diabetes due to a reduction in β-cell mass and a failure of pancreatic islets to undergo compensatory hyperplasia in response to insulin resistance. In order to define the molecular mechanisms, we knocked down Irs2 gene expression in mouse MIN6 insulinoma cells. Insulin receptor...


    pub_type: 杂志文章


    authors: Ren D,Sun J,Mao L,Ye H,Polonsky KS

    更新日期:2014-10-01 00:00:00

  • The effect of oxidation on sorbitol pathway kinetics.

    abstract::The rapid conversion of glucose to sorbitol by aldose reductase and the consequent hyperosmolarity of the cytoplasm has been shown to be the primary cause of the so-called "sugar" or "osmotic" cataract in many animal lenses. It is not as clear, however, that hyperosmolarity is the principal factor in the etiology of c...


    pub_type: 杂志文章


    authors: Barnett PA,González RG,Chylack LT Jr,Cheng HM

    更新日期:1986-04-01 00:00:00

  • Classification, differential diagnosis, and staging of diabetic peripheral neuropathy.

    abstract::The peripheral nerve disorders associated with diabetes are complex and probably involve a variety of causative mechanisms. This may give rise to difficulty in the classification of individual cases. A broad separation into rapidly reversible or more persistent phenomena is helpful. The former, which can be categorize...


    pub_type: 杂志文章,评审


    authors: Thomas PK

    更新日期:1997-09-01 00:00:00

  • Prevention of recurrence of IDDM in islet-transplanted diabetic NOD mice by adjuvant immunotherapy.

    abstract::Insulin-dependent diabetes mellitus (IDDM) involves the destruction of the insulin-producing cells in the islets of Langerhans. One possible cure is by transplanting the islet cells; however, transplanted islets, even between identical twins, are subject to autoimmune destruction by the disease process, resulting in d...


    pub_type: 杂志文章


    authors: Wang T,Singh B,Warnock GL,Rajotte RV

    更新日期:1992-01-01 00:00:00

  • A nonsense mutation in the inward rectifier potassium channel gene, Kir6.2, is associated with familial hyperinsulinism.

    abstract::ATP-sensitive potassium (K[ATP]) channels are an essential component of glucose-dependent insulin secretion in pancreatic islet beta-cells. These channels comprise the sulfonylurea receptor (SUR1) and Kir6.2, a member of the inward rectifier K+ channel family. Mutations in the SUR1 subunit are associated with familial...


    pub_type: 杂志文章


    authors: Nestorowicz A,Inagaki N,Gonoi T,Schoor KP,Wilson BA,Glaser B,Landau H,Stanley CA,Thornton PS,Seino S,Permutt MA

    更新日期:1997-11-01 00:00:00

  • Effects of acute, subacute, and chronic diabetes on carbohydrate and energy metabolism in rat sciatic nerve. Relation to mechanisms of peripheral neuropathy.

    abstract::To address the problem of the pathogenesis of diabetic neuropathy, rats were made diabetic by alloxan administration, and sciatic nerves were sampled for electrolyte and water content and levels of selected carbohydrates and intermediates in energy metabolism at 3, 6, and 26 weeks. Significant increases were seen in t...


    pub_type: 杂志文章


    authors: Thurston JH,McDougal DB Jr,Hauhart RE,Schulz DW

    更新日期:1995-02-01 00:00:00

  • Marked increase in white adipose tissue blood perfusion in the type 2 diabetic GK rat.

    abstract::The aim of the present study was to evaluate and cor-relate islet to brown and white adipose tissue (WAT) blood perfusion in one obese rat and one nonobese rat with type 2 diabetes (obese Zucker [OZ] and GK rats, respectively). We measured blood perfusion with a microsphere technique in anesthetized animals and subseq...


    pub_type: 杂志文章


    authors: Kampf C,Bodin B,Källskog O,Carlsson C,Jansson L

    更新日期:2005-09-01 00:00:00

  • Integrated concentration of growth hormone in juvenile-onset diabetes.

    abstract::Twenty-four-hour patterns of plasma growth hormone concentrations were evaluated during 50 studies of 42 subjects with juvenile-onset diabetes mellitus. Blood was sampled continuously over 24 h using a portable peristaltic pump under conditions in which subjects remained ambulatory and maintained their daily dietary a...


    pub_type: 杂志文章


    authors: Hayford JT,Danney MM,Hendrix JA,Thompson RG

    更新日期:1980-05-01 00:00:00

  • Otopetrin 1 protects mice from obesity-associated metabolic dysfunction through attenuating adipose tissue inflammation.

    abstract::Chronic low-grade inflammation is emerging as a pathogenic link between obesity and metabolic disease. Persistent immune activation in white adipose tissue (WAT) impairs insulin sensitivity and systemic metabolism, in part, through the actions of proinflammatory cytokines. Whether obesity engages an adaptive mechanism...


    pub_type: 杂志文章


    authors: Wang GX,Cho KW,Uhm M,Hu CR,Li S,Cozacov Z,Xu AE,Cheng JX,Saltiel AR,Lumeng CN,Lin JD

    更新日期:2014-04-01 00:00:00

  • Negative Regulation of TRPA1 by AMPK in Primary Sensory Neurons as a Potential Mechanism of Painful Diabetic Neuropathy.

    abstract::AMPK is a widely expressed intracellular energy sensor that monitors and modulates energy expenditure. Transient receptor potential ankyrin 1 (TRPA1) channel is a widely recognized chemical and thermal sensor that plays vital roles in pain transduction. In this study, we discovered a functional link between AMPK and T...


    pub_type: 杂志文章


    authors: Wang S,Kobayashi K,Kogure Y,Yamanaka H,Yamamoto S,Yagi H,Noguchi K,Dai Y

    更新日期:2018-01-01 00:00:00

  • Effects of calcium antagonists on insulin-mediated glucose metabolism in skeletal muscle.

    abstract::The effect of three calcium antagonists (verapamil, diltiazem, and nifedipine) on insulin effects was investigated in isolated rat soleus muscles. Soleus muscles were incubated in the presence of insulin (100 microU/ml), a concentration that stimulates the rates of lactate formation and glycogen synthesis half-maximal...


    pub_type: 杂志文章


    authors: Foot EA,Leighton B

    更新日期:1994-01-01 00:00:00

  • Antiobesity effect of eicosapentaenoic acid in high-fat/high-sucrose diet-induced obesity: importance of hepatic lipogenesis.

    abstract:OBJECTIVE:Given the pleiotropic effect of eicosapentaenoic acid (EPA), it is interesting to know whether EPA is capable of improving obesity. Here we examined the anti-obesity effect of EPA in mice with two distinct models of obesity. RESEARCH DESIGN AND METHODS:Male C57BL/6J mice were fed a high-fat/high-sucrose diet...


    pub_type: 杂志文章


    authors: Sato A,Kawano H,Notsu T,Ohta M,Nakakuki M,Mizuguchi K,Itoh M,Suganami T,Ogawa Y

    更新日期:2010-10-01 00:00:00

  • Insulin receptor-related receptor is expressed in pancreatic beta-cells and stimulates tyrosine phosphorylation of insulin receptor substrate-1 and -2.

    abstract::The receptor-type protein tyrosine kinases in murine pancreatic islets were screened to identify possible growth/differentiation factors in pancreatic beta-cells. The analysis revealed that insulin receptor-related receptor (IRR) is highly expressed in the islets as well as in several highly differentiated beta-cell l...


    pub_type: 杂志文章


    authors: Hirayama I,Tamemoto H,Yokota H,Kubo SK,Wang J,Kuwano H,Nagamachi Y,Takeuchi T,Izumi T

    更新日期:1999-06-01 00:00:00

  • Higher cord C-peptide concentrations are associated with slower growth rate in the 1st year of life in girls but not in boys.

    abstract:OBJECTIVE:To understand the relationships between maternal glycemia during pregnancy and prenatal and early postnatal growth by evaluating cord C-peptide and IGF-I as mediating biomarkers in boys and girls separately. RESEARCH DESIGN AND METHODS:We evaluated 342 neonates within the EDEN mother-child cohort study born ...


    pub_type: 杂志文章


    authors: Regnault N,Botton J,Heude B,Forhan A,Hankard R,Foliguet B,Hillier TA,Souberbielle JC,Dargent-Molina P,Charles MA,EDEN Mother-Child Cohort Study Group.

    更新日期:2011-08-01 00:00:00

  • Insulin sensitivity of isolated perfused rat liver.

    abstract::The responsiveness of the isolated perfused rat liver to different metabolic effects of insulin was investigated during recycling perfusion. Infusion of porcine insulin at rates of 6, 9, 16 and 33 mU/hr. resulted in stable perfusate insulin levels averaging 41, 72, 120 and 229 muU/ml., respectively. Since the portal v...


    pub_type: 杂志文章


    authors: Mondon CE,Dolkas CB,Olefsky JM,Reaven GM

    更新日期:1975-02-01 00:00:00

  • The human GLP-1 analogs liraglutide and semaglutide: absence of histopathological effects on the pancreas in nonhuman primates.

    abstract::Increased pancreas mass and glucagon-positive adenomas have been suggested to be a risk associated with sitagliptin or exenatide therapy in humans. Novo Nordisk has conducted extensive toxicology studies, including data on pancreas weight and histology, in Cynomolgus monkeys dosed with two different human glucagon-lik...


    pub_type: 杂志文章


    authors: Gotfredsen CF,Mølck AM,Thorup I,Nyborg NC,Salanti Z,Knudsen LB,Larsen MO

    更新日期:2014-07-01 00:00:00

  • A Mendelian Randomization Study of Circulating Uric Acid and Type 2 Diabetes.

    abstract::We aimed to investigate the causal effect of circulating uric acid concentrations on type 2 diabetes risk. A Mendelian randomization study was performed using a genetic score with 24 uric acid-associated loci. We used data of the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort ...


    pub_type: 杂志文章


    authors: Sluijs I,Holmes MV,van der Schouw YT,Beulens JW,Asselbergs FW,Huerta JM,Palmer TM,Arriola L,Balkau B,Barricarte A,Boeing H,Clavel-Chapelon F,Fagherazzi G,Franks PW,Gavrila D,Kaaks R,Khaw KT,Kühn T,Molina-Montes E,Mo

    更新日期:2015-08-01 00:00:00

  • Identification of tyrosine phosphatase 2(256-760) construct as a new, sensitive marker for the detection of islet autoimmunity in type 2 diabetic patients: the non-insulin requiring autoimmune diabetes (NIRAD) study 2.

    abstract:OBJECTIVE:The presence of autoantibodies to islet antigens GAD and/or tyrosine phosphatase 2 (IA-2) in type 2 diabetic patients (latent autoimmune diabetes in adults [LADA]) identifies subjects at high risk to develop insulin dependency. The aim of this study was to dissect humoral anti-IA-2 immune response in Caucasia...


    pub_type: 杂志文章,多中心研究


    authors: Tiberti C,Giordano C,Locatelli M,Bosi E,Bottazzo GF,Buzzetti R,Cucinotta D,Galluzzo A,Falorni A,Dotta F

    更新日期:2008-05-01 00:00:00

  • New concept for long-acting insulin: spontaneous conversion of an inactive modified insulin to the active hormone in circulation: 9-fluorenylmethoxycarbonyl derivative of insulin.

    abstract::Insulin is a short-lived species in the circulatory system. After binding to its receptor sites and transmission of its biological signals, bound insulin undergoes receptor-mediated endocytosis and consequent degradation. An inactive insulin derivative that is not recognized by the receptor has a longer circulation li...


    pub_type: 杂志文章


    authors: Gershonov E,Shechter Y,Fridkin M

    更新日期:1999-07-01 00:00:00

  • Macrophage scavenger receptor-a-deficient mice are resistant against diabetic nephropathy through amelioration of microinflammation.

    abstract::Microinflammation is a common major mechanism in the pathogenesis of diabetic vascular complications, including diabetic nephropathy. Macrophage scavenger receptor-A (SR-A) is a multifunctional receptor expressed on macrophages. This study aimed to determine the role of SR-A in diabetic nephropathy using SR-A-deficien...


    pub_type: 杂志文章


    authors: Usui HK,Shikata K,Sasaki M,Okada S,Matsuda M,Shikata Y,Ogawa D,Kido Y,Nagase R,Yozai K,Ohga S,Tone A,Wada J,Takeya M,Horiuchi S,Kodama T,Makino H

    更新日期:2007-02-01 00:00:00

  • Artifactual insulin release from differentiated embryonic stem cells.

    abstract::Several recent reports claim the generation of insulin-producing cells from embryonic stem cells via the differentiation of progenitors that express nestin. Here, we investigate further the properties of these insulin-containing cells. We find that although differentiated cells contain immunoreactive insulin, they do ...


    pub_type: 杂志文章


    authors: Hansson M,Tonning A,Frandsen U,Petri A,Rajagopal J,Englund MC,Heller RS,Håkansson J,Fleckner J,Sköld HN,Melton D,Semb H,Serup P

    更新日期:2004-10-01 00:00:00

  • Mechanism by Which Caloric Restriction Improves Insulin Sensitivity in Sedentary Obese Adults.

    abstract::Caloric restriction (CR) improves insulin sensitivity and reduces the incidence of diabetes in obese individuals. The underlying mechanisms whereby CR improves insulin sensitivity are not clear. We evaluated the effect of 16 weeks of CR on whole-body insulin sensitivity by pancreatic clamp before and after CR in 11 ob...


    pub_type: 杂志文章,随机对照试验


    authors: Johnson ML,Distelmaier K,Lanza IR,Irving BA,Robinson MM,Konopka AR,Shulman GI,Nair KS

    更新日期:2016-01-01 00:00:00

  • HLA and insulin-dependent diabetes. A protective perspective.

    abstract::This article presents a model for the HLA effect in insulin-dependent diabetes mellitus (IDDM) that is almost the mirror image of a model suggested by Nepom. In the Nepom model, the products of certain HLA alleles are associated with IDDM because they bind and present a specific peptide or peptides so as to induce an ...


    pub_type: 杂志文章,评审


    authors: Sheehy MJ

    更新日期:1992-02-01 00:00:00

  • Function and Mechanism of Long Noncoding RNAs in Adipocyte Biology.

    abstract::The last two decades have witnessed an explosion of interest in adipocyte biology, coinciding with the upsurge of obesity and metabolic syndrome. Now we have new perspectives on the distinct developmental origins of white, brown, and beige adipocytes and their role in metabolic physiology and disease. Beyond fuel meta...


    pub_type: 杂志文章,评审


    authors: Sun L,Lin JD

    更新日期:2019-05-01 00:00:00

  • Altered natural killer cells in type 1 diabetic patients.

    abstract::Evidence from animal models suggests that natural killer (NK) cells can be important players in the development of type 1 diabetes, although data in humans are still sparse. We studied the frequency and activation state of blood NK cells at different stages of human type 1 diabetes, and whether genetic or phenotypic N...


    pub_type: 杂志文章


    authors: Rodacki M,Svoren B,Butty V,Besse W,Laffel L,Benoist C,Mathis D

    更新日期:2007-01-01 00:00:00

  • Insulin-stimulated glucose uptake does not require p38 mitogen-activated protein kinase in adipose tissue or skeletal muscle.

    abstract::It has been proposed that p38 mitogen-activated protein kinase (MAPK) isoforms sensitive to the pyridinylimidazole compounds SB 203580 and SB 202190 may participate in the acute insulin-dependent activation of glucose transporters recruited to the plasma membrane of adipocytes and skeletal muscle. Here, we explore whe...


    pub_type: 杂志文章


    authors: Turban S,Beardmore VA,Carr JM,Sakamoto K,Hajduch E,Arthur JS,Hundal HS

    更新日期:2005-11-01 00:00:00

  • Gene expression profiles of nondiabetic and diabetic obese mice suggest a role of hepatic lipogenic capacity in diabetes susceptibility.

    abstract::Obesity is a strong risk factor for the development of type 2 diabetes. We have previously reported that in adipose tissue of obese (ob/ob) mice, the expression of adipogenic genes is decreased. When made genetically obese, the BTBR mouse strain is diabetes susceptible and the C57BL/6J (B6) strain is diabetes resistan...


    pub_type: 杂志文章


    authors: Lan H,Rabaglia ME,Stoehr JP,Nadler ST,Schueler KL,Zou F,Yandell BS,Attie AD

    更新日期:2003-03-01 00:00:00