Pharmacological inhibition of glucosylceramide synthase enhances insulin sensitivity.

Abstract:

:A growing body of evidence implicates ceramide and/or its glycosphingolipid metabolites in the pathogenesis of insulin resistance. We have developed a highly specific small molecule inhibitor of glucosylceramide synthase, an enzyme that catalyzes a necessary step in the conversion of ceramide to glycosphingolipids. In cultured 3T3-L1 adipocytes, the iminosugar derivative N-(5'-adamantane-1'-yl-methoxy)-pentyl-1-deoxynojirimycin (AMP-DNM) counteracted tumor necrosis factor-alpha-induced abnormalities in glycosphingolipid concentrations and concomitantly reversed abnormalities in insulin signal transduction. When administered to mice and rats, AMP-DNM significantly reduced glycosphingolipid but not ceramide concentrations in various tissues. Treatment of ob/ob mice with AMP-DNM normalized their elevated tissue glucosylceramide levels, markedly lowered circulating glucose levels, improved oral glucose tolerance, reduced A1C, and improved insulin sensitivity in muscle and liver. Similarly beneficial metabolic effects were seen in high fat-fed mice and ZDF rats. These findings provide further evidence that glycosphingolipid metabolites of ceramide may be involved in mediating the link between obesity and insulin resistance and that interference with glycosphingolipid biosynthesis might present a novel approach to the therapy of states of impaired insulin action such as type 2 diabetes.

journal_name

Diabetes

journal_title

Diabetes

authors

Aerts JM,Ottenhoff R,Powlson AS,Grefhorst A,van Eijk M,Dubbelhuis PF,Aten J,Kuipers F,Serlie MJ,Wennekes T,Sethi JK,O'Rahilly S,Overkleeft HS

doi

10.2337/db06-1619

subject

Has Abstract

pub_date

2007-05-01 00:00:00

pages

1341-9

issue

5

eissn

0012-1797

issn

1939-327X

pii

db06-1619

journal_volume

56

pub_type

杂志文章

相关文献

DIABETES文献大全
  • Pancreatic β-cell failure mediated by mTORC1 hyperactivity and autophagic impairment.

    abstract::Hyperactivation of the mammalian target of rapamycin complex 1 (mTORC1) in β-cells is usually found as a consequence of increased metabolic load. Although it plays an essential role in β-cell compensatory mechanisms, mTORC1 negatively regulates autophagy. Using a mouse model with β-cell-specific deletion of Tsc2 (βTsc...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/db13-0970

    authors: Bartolomé A,Kimura-Koyanagi M,Asahara S,Guillén C,Inoue H,Teruyama K,Shimizu S,Kanno A,García-Aguilar A,Koike M,Uchiyama Y,Benito M,Noda T,Kido Y

    更新日期:2014-09-01 00:00:00

  • HIF-1 Mediates Renal Fibrosis in OVE26 Type 1 Diabetic Mice.

    abstract::Hypoxia-inducible factor (HIF)-1 mediates hypoxia- and chronic kidney disease-induced fibrotic events. Here, we assessed whether HIF-1 blockade attenuates the manifestations of diabetic nephropathy in a type 1 diabetic animal model, OVE26. YC-1 [3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole], an HIF-1 inhibitor, red...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/db15-0519

    authors: Nayak BK,Shanmugasundaram K,Friedrichs WE,Cavaglierii RC,Patel M,Barnes J,Block K

    更新日期:2016-05-01 00:00:00

  • Liver-specific loss of lipolysis-stimulated lipoprotein receptor triggers systemic hyperlipidemia in mice.

    abstract:OBJECTIVE:In mammals, proper storage and distribution of lipids in and between tissues is essential for the maintenance of energy homeostasis. In contrast, aberrantly high levels of triglycerides in the blood ("hypertriglyceridemia") represent a hallmark of the metabolic syndrome and type 2 diabetes. As hypertriglyceri...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/db08-1184

    authors: Narvekar P,Berriel Diaz M,Krones-Herzig A,Hardeland U,Strzoda D,Stöhr S,Frohme M,Herzig S

    更新日期:2009-05-01 00:00:00

  • Indinavir induces acute and reversible peripheral insulin resistance in rats.

    abstract::The use of HIV protease inhibitors (PIs) has been associated with several metabolic changes, including lipodystrophy, hyperlipidemia, and insulin resistance. The etiology of these adverse effects remains unknown. PIs have recently been found to cause acute and reversible inhibition of GLUT4 activity in vitro. To deter...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diabetes.51.4.937

    authors: Hruz PW,Murata H,Qiu H,Mueckler M

    更新日期:2002-04-01 00:00:00

  • The human glucokinase gene beta-cell-type promoter: an essential role of insulin promoter factor 1/PDX-1 in its activation in HIT-T15 cells.

    abstract::The glycolytic enzyme glucokinase plays a primary role in the glucose-responsive secretion of insulin, and defects of this enzyme can cause NIDDM. As a step toward understanding the molecular basis of glucokinase (GK) gene regulation, we assessed the structure and regulation of the human GK gene beta-cell-type promote...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diab.45.11.1478

    authors: Watada H,Kajimoto Y,Umayahara Y,Matsuoka T,Kaneto H,Fujitani Y,Kamada T,Kawamori R,Yamasaki Y

    更新日期:1996-11-01 00:00:00

  • Platelet survival in patients with diabetes mellitus.

    abstract::Platelet survival by 51chromium labeling was determined in six normal control subjects and in twelve patients with diabetes mellitus, before and after improved glucose control (mean HbA1c 10.5 +/- 2.2% and 7.1 +/- 1.8%, respectively). Mean platelet survival was 9.47 +/- 0.85 days for the normal subjects and 9.04 +/- 1...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diab.30.6.486

    authors: Jones RL,Paradise C,Peterson CM

    更新日期:1981-06-01 00:00:00

  • Acute administration of unacylated ghrelin has no effect on Basal or stimulated insulin secretion in healthy humans.

    abstract::Unacylated ghrelin (UAG) is the predominant ghrelin isoform in the circulation. Despite its inability to activate the classical ghrelin receptor, preclinical studies suggest that UAG may promote β-cell function. We hypothesized that UAG would oppose the effects of acylated ghrelin (AG) on insulin secretion and glucose...

    journal_title:Diabetes

    pub_type: 杂志文章,随机对照试验

    doi:10.2337/db13-1598

    authors: Tong J,Davis HW,Summer S,Benoit SC,Haque A,Bidlingmaier M,Tschöp MH,D'Alessio D

    更新日期:2014-07-01 00:00:00

  • Effects of tryptophan on depression and aggression in STZ-D mice.

    abstract::Streptozocin-induced diabetic (STZ-D) mice have reduced brain concentrations of tryptophan, a precursor substance for 5-hydroxytryptamine, and show lengthened immobility in Porsolt's swim test, a putative animal model of depression. This study investigated whether tryptophan affects behavior in Porsolt's swim test in ...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diab.40.12.1598

    authors: Hilakivi-Clarke LA

    更新日期:1991-12-01 00:00:00

  • Genotype by diabetes interaction effects on the detection of linkage of glomerular filtration rate to a region on chromosome 2q in Mexican Americans.

    abstract:OBJECTIVE:Glomerular filtration rate (GFR) is used to assess the progression of renal disease. We performed linkage analysis to localize genes that influence GFR using estimated GFR data from the San Antonio Family Diabetes/Gallbladder Study. We also examined the effect of genotype by diabetes interaction (G x DM) on t...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/db06-0984

    authors: Puppala S,Arya R,Thameem F,Arar NH,Bhandari K,Lehman DM,Schneider J,Fowler S,Farook VS,Diego VP,Almasy L,Blangero J,Stern MP,Duggirala R,Abboud HE

    更新日期:2007-11-01 00:00:00

  • Ameliorating Methylglyoxal-Induced Progenitor Cell Dysfunction for Tissue Repair in Diabetes.

    abstract::Patient-derived progenitor cell (PC) dysfunction is severely impaired in diabetes, but the molecular triggers that contribute to mechanisms of PC dysfunction are not fully understood. Methylglyoxal (MGO) is one of the highly reactive dicarbonyl species formed during hyperglycemia. We hypothesized that the MGO scavenge...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/db18-0933

    authors: Li H,O'Meara M,Zhang X,Zhang K,Seyoum B,Yi Z,Kaufman RJ,Monks TJ,Wang JM

    更新日期:2019-06-01 00:00:00

  • Insulin sensitivity, binding, and kinetics in pancreatogenic and type I diabetes.

    abstract::Pancreatogenic diabetes (PD), secondary either to chronic calcific pancreatitis or to pancreatectomy, is characterized by higher frequency of hypoglycemic events during insulin therapy in comparison with type I insulin-dependent diabetes (IDD). Not only glucagon deficiency, but an enhanced peripheral tissue sensitivit...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diab.31.4.346

    authors: Nosadini R,del Prato S,Tiengo A,Duner E,Toffolo G,Cobelli C,Faronato PP,Moghetti P,Muggeo M

    更新日期:1982-04-01 00:00:00

  • Diabetes in pregnancy. Skeletal malformations in the offspring of diabetic rats after intermittent withdrawal of insulin in early gestation.

    abstract::Precise timing of the teratogenic period in diabetic pregnancy is of clinical importance since correction of the glucose intolerance during this period may protect the offspring from malformations. An experimental approach to elucidate this problem with regard to skeletal development was made in groups of pregnant str...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diab.32.12.1141

    authors: Eriksson UJ,Dahlström E,Hellerström C

    更新日期:1983-12-01 00:00:00

  • HLA Class II Antigen Processing and Presentation Pathway Components Demonstrated by Transcriptome and Protein Analyses of Islet β-Cells From Donors With Type 1 Diabetes.

    abstract::Type 1 diabetes studies consistently generate data showing islet β-cell dysfunction and T cell-mediated anti-β-cell-specific autoimmunity. To explore the pathogenesis, we interrogated the β-cell transcriptomes from donors with and without type 1 diabetes using both bulk-sorted and single β-cells. Consistent with immun...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/db18-0686

    authors: Russell MA,Redick SD,Blodgett DM,Richardson SJ,Leete P,Krogvold L,Dahl-Jørgensen K,Bottino R,Brissova M,Spaeth JM,Babon JAB,Haliyur R,Powers AC,Yang C,Kent SC,Derr AG,Kucukural A,Garber MG,Morgan NG,Harlan DM

    更新日期:2019-05-01 00:00:00

  • The role of enteroviral infections in the development of IDDM: limitations of current approaches.

    abstract::Enteroviruses have been examined for their possible role in the etiology of IDDM for nearly 40 years, yet the evidence remains inconclusive. The mechanism of acute cytolytic infection of beta-cells, proposed by earlier studies, appears to be incompatible with the long preclinical period of autoimmunity preceding IDDM....

    journal_title:Diabetes

    pub_type: 杂志文章,评审

    doi:10.2337/diab.46.2.161

    authors: Graves PM,Norris JM,Pallansch MA,Gerling IC,Rewers M

    更新日期:1997-02-01 00:00:00

  • One in Ten CD8+ Cells in the Pancreas of Living Individuals With Recent Onset Type 1 Diabetes Recognizes the Preproinsulin Epitope PPI15-24.

    abstract::In type 1 diabetes, a lifelong autoimmune disease, T cells infiltrate the islets and the exocrine pancreas in high numbers. CD8+ T cells are the main cell type found in the insulitic lesion, and CD8+ T cells reactive against beta cell antigens have been detected in the periphery and in the pancreas of subjects with sh...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/db20-0908

    authors: Rodriguez-Calvo T,Krogvold L,Amirian N,Dahl-Jørgensen K,von Herrath M

    更新日期:2021-01-07 00:00:00

  • Helper-inducer T-lymphocytes mediate diabetes in EMC-infected BALB/c ByJ mice.

    abstract::Diabetes mellitus developing in BALB/c ByJ mice infected with the M variant of encephalomyocarditis (EMC) virus is dependent on thymic immune mechanisms. We treated mice with the anti-T-lymphocyte monoclonal anti-L3T4 and anti-Lyt2.2 antibodies before virus inoculation and monitored the infection and occurrence of dia...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diab.36.7.877

    authors: Haynes MK,Huber SA,Craighead JE

    更新日期:1987-07-01 00:00:00

  • Genetics of NIDDM in France: studies with 19 candidate genes in affected sib pairs.

    abstract::As part of an ongoing search for susceptibility loci for NIDDM, we tested 19 genes whose products are implicated in insulin secretion or action for linkage with NIDDM. Loci included the G-protein-coupled inwardly rectifying potassium channels expressed in beta-cells (KCNJ3 and KCNJ7), glucagon (GCG), glucokinase regul...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diab.46.6.1062

    authors: Vionnet N,Hani EH,Lesage S,Philippi A,Hager J,Varret M,Stoffel M,Tanizawa Y,Chiu KC,Glaser B,Permutt MA,Passa P,Demenais F,Froguel P

    更新日期:1997-06-01 00:00:00

  • Increased serum IGF-I during pregnancy is associated with progression of diabetic retinopathy.

    abstract::The IGF system has been associated with development and progression of diabetic retinopathy. We examined whether a simple measurement of the IGF system (serum total IGF-I) correlated with progression of diabetic retinopathy in pregnancy in type 1 diabetes. A prospective observational study was performed in 103 pregnan...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diabetes.52.3.852

    authors: Lauszus FF,Klebe JG,Bek T,Flyvbjerg A

    更新日期:2003-03-01 00:00:00

  • Fatty acid synthase inhibitors modulate energy balance via mammalian target of rapamycin complex 1 signaling in the central nervous system.

    abstract:OBJECTIVE:Evidence links the hypothalamic fatty acid synthase (FAS) pathway to the regulation of food intake and body weight. This includes pharmacological inhibitors that potently reduce feeding and body weight. The mammalian target of rapamycin (mTOR) is an intracellular fuel sensor whose activity in the hypothalamus...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/db07-1690

    authors: Proulx K,Cota D,Woods SC,Seeley RJ

    更新日期:2008-12-01 00:00:00

  • Increase in simultaneous coexpression of naive and memory lymphocyte markers at diagnosis of IDDM.

    abstract::The monoclonal antibodies 2H4 (anti-CD45RA) and UCHL1 (anti-CD45RO) were used to subdivide the CD4 and CD8 T-cell subsets into naive and memory cells. The peripheral blood lymphocytes of 34 patients with recent-onset IDDM, 21 patients with long-standing IDDM, and healthy control subjects of similar age and sex were an...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diab.42.1.127

    authors: Smerdon RA,Peakman M,Hussain MJ,Alviggi L,Watkins PJ,Leslie RD,Vergani D

    更新日期:1993-01-01 00:00:00

  • Insulin resistance by uncleaved insulin proreceptor. Emergence of binding site by trypsin.

    abstract::Two sisters presented with severe insulin resistance and markedly decreased insulin binding to erythrocytes, cultured fibroblasts, and transformed lymphocytes. The dose-response curve of insulin-stimulated amino acid uptake in the fibroblasts was shifted to the right. The molecular weight of the insulin receptor on th...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diab.37.5.653

    authors: Kobayashi M,Sasaoka T,Takata Y,Hisatomi A,Shigeta Y

    更新日期:1988-05-01 00:00:00

  • Effects of pioglitazone on adipose tissue remodeling within the setting of obesity and insulin resistance.

    abstract::Obesity and dysfunctional energy partitioning can lead to the development of insulin resistance and type 2 diabetes. The antidiabetic thiazolidinediones shift the energy balance toward storage, leading to an increase in whole-body adiposity. These studies examine the effects of pioglitazone (Pio) on adipose tissue phy...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diabetes.50.8.1863

    authors: de Souza CJ,Eckhardt M,Gagen K,Dong M,Chen W,Laurent D,Burkey BF

    更新日期:2001-08-01 00:00:00

  • Plasma protein changes, blood viscosity, and diabetic microangiopathy.

    abstract::Diabetic microangiopathy is a slowly progressive condition that usually manifests itself years after the onset of the carbohydrate-metabolism disturbance. It is a far more striking problem in some diabetics than in others. Differences in the pattern of its effect in several body systems suggest that the local vascular...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:

    authors: McMillan DE

    更新日期:1976-01-01 00:00:00

  • Evidence that two naturally occurring human insulin receptor alpha-subunit variants are immunologically distinct.

    abstract::The IgG from a patient (Italy 2 [I2]) with hypoglycemia, due to autoantibodies to the insulin receptor, was purified on protein A Sepharose into two fractions that were tested in various human tissues and cells. The IgG fraction that bound protein A (absorbed IgG [IgGa]) nearly completely inhibited the binding of 125I...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diab.41.1.6

    authors: Sesti G,Marini MA,Montemurro A,Condorelli L,Borboni P,Haring HU,Ullrich A,Goldfine ID,De Pirro R,Lauro R

    更新日期:1992-01-01 00:00:00

  • Partial Disruption of Lipolysis Increases Postexercise Insulin Sensitivity in Skeletal Muscle Despite Accumulation of DAG.

    abstract::Type 2 diabetes and skeletal muscle insulin resistance have been linked to accumulation of the intramyocellular lipid-intermediate diacylglycerol (DAG). However, recent animal and human studies have questioned such an association. Given that DAG appears in different stereoisomers and has different reactivity in vitro,...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/db16-0655

    authors: Serup AK,Alsted TJ,Jordy AB,Schjerling P,Holm C,Kiens B

    更新日期:2016-10-01 00:00:00

  • Human pancreatic β-cell G1/S molecule cell cycle atlas.

    abstract::Expansion of pancreatic β-cells is a key goal of diabetes research, yet induction of adult human β-cell replication has proven frustratingly difficult. In part, this reflects a lack of understanding of cell cycle control in the human β-cell. Here, we provide a comprehensive immunocytochemical "atlas" of G1/S control m...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/db12-0777

    authors: Fiaschi-Taesch NM,Kleinberger JW,Salim FG,Troxell R,Wills R,Tanwir M,Casinelli G,Cox AE,Takane KK,Scott DK,Stewart AF

    更新日期:2013-07-01 00:00:00

  • Expression and role of Bcl-2 in rat blastocysts exposed to high D-glucose.

    abstract::Bcl-2 mRNA expression was detected in rat blastocysts by in situ hybridization. The distribution of mRNA expression was rather heterogenous, with approximately 2% of high-expressing cells. In vitro exposure to 28 mmol/l D-glucose for 24 h resulted in a significant increase in the proportion of these cells compared wit...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diabetes.50.1.143

    authors: Pampfer S,Cordi S,Vanderheyden I,Van Der Smissen P,Courtoy PJ,Van Cauwenberge A,Alexandre H,Donnay I,De Hertogh R

    更新日期:2001-01-01 00:00:00

  • Hyperglycemia and beta-cell adaptation during prolonged somatostatin infusion with glucagon replacement in man.

    abstract::To assess the relationship between beta-cell function and the level and duration of hyperglycemia during generalized beta-cell impairment, we studied the effects of acute and prolonged infusion of somatostatin in seven normal men. Twenty minutes after beginning an acute infusion of somatostatin (200 microgram/h) plus ...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diab.32.10.943

    authors: Ward WK,Halter JB,Best JD,Beard JC,Porte D Jr

    更新日期:1983-10-01 00:00:00

  • Developmental-stage-dependent teratogenic effects of maternal spontaneous diabetes in the chinese hamster.

    abstract::The effect of maternal diabetes on teratogenesis was examined utilizing female Chinese hamsters with typical diabetic symptoms from our closed colony (CHA) and F13-F19 of the brother-sister mating generations of a diabetic strain (CHAD). Both groups were mated with nondiabetic males from CHA. Embryologic studies on da...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/diab.32.7.637

    authors: Funaki K,Mikamo K

    更新日期:1983-07-01 00:00:00

  • Resistin impairs insulin-evoked vasodilation.

    abstract:OBJECTIVE:Since vascular dysfunction is a main trait of obese subjects, in the present study we evaluated the vascular impact of resistin, a recently discovered hormone markedly increased in obesity. RESEARCH DESIGN AND METHODS:We performed our analysis on aortic and mesenteric segments from young and old C57BL/6 mice...

    journal_title:Diabetes

    pub_type: 杂志文章

    doi:10.2337/db07-0557

    authors: Gentile MT,Vecchione C,Marino G,Aretini A,Di Pardo A,Antenucci G,Maffei A,Cifelli G,Iorio L,Landolfi A,Frati G,Lembo G

    更新日期:2008-03-01 00:00:00