Abstract:
AIMS/HYPOTHESIS:Activation of the G protein-coupled receptor (GPR)40 by long-chain fatty acids potentiates glucose-stimulated insulin secretion (GSIS) from pancreatic beta cells, and GPR40 agonists are in clinical development for type 2 diabetes therapy. GPR40 couples to the G protein subunit Gα(q/11) but the signalling cascade activated downstream is unknown. This study aimed to determine the mechanisms of GPR40-dependent potentiation of GSIS by fatty acids. METHODS:Insulin secretion in response to glucose, oleate or diacylglycerol (DAG) was assessed in dynamic perifusions and static incubations in islets from wild-type (WT) and Gpr40 (-/-) mice. Depolymerisation of filamentous actin (F-actin) was visualised by phalloidin staining and epifluorescence. Pharmacological and molecular approaches were used to ascertain the roles of protein kinase D (PKD) and protein kinase C delta in GPR40-mediated potentiation of GSIS. RESULTS:Oleate potentiates the second phase of GSIS, and this effect is largely dependent upon GPR40. Accordingly, oleate induces rapid F-actin remodelling in WT but not in Gpr40 (-/-) islets. Exogenous DAG potentiates GSIS in both WT and Gpr40 (-/-) islets. Oleate induces PKD phosphorylation at residues Ser-744/748 and Ser-916 in WT but not Gpr40 (-/-) islets. Importantly, oleate-induced F-actin depolymerisation and potentiation of GSIS are lost upon pharmacological inhibition of PKD1 or deletion of Prkd1. CONCLUSIONS/INTERPRETATION:We conclude that the signalling cascade downstream of GPR40 activation by fatty acids involves activation of PKD1, F-actin depolymerisation and potentiation of second-phase insulin secretion. These results provide important information on the mechanisms of action of GPR40, a novel drug target for type 2 diabetes.
journal_name
Diabetologiajournal_title
Diabetologiaauthors
Ferdaoussi M,Bergeron V,Zarrouki B,Kolic J,Cantley J,Fielitz J,Olson EN,Prentki M,Biden T,MacDonald PE,Poitout Vdoi
10.1007/s00125-012-2650-xsubject
Has Abstractpub_date
2012-10-01 00:00:00pages
2682-2692issue
10eissn
0012-186Xissn
1432-0428pii
10.1007/s00125-012-2650-xjournal_volume
55pub_type
杂志文章相关文献
DIABETOLOGIA文献大全abstract:AIMS/HYPOTHESIS:The aim of this study was to compare glycaemic control and maternal-fetal outcomes in women with type 1 diabetes managed on insulin pumps compared with multiple daily injections of insulin (MDI). METHODS:In a retrospective study, glycaemic control and outcomes of 387 consecutive pregnancies in women wi...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s00125-014-3163-6
更新日期:2014-04-01 00:00:00
abstract:AIMS/HYPOTHESIS:Activin receptor-like kinase 7 (ALK7), a member of the type I receptor serine/threonine kinases of the TGF-beta superfamily, was recently reported to regulate cell proliferation and apoptosis. We hypothesised that ALK7 may play a role in modulating pancreatic beta cell proliferation and/or apoptosis. M...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s00125-005-0095-1
更新日期:2006-03-01 00:00:00
abstract::Analysis of the plasma from a totally pancreatectomized patient, with antiserum 30 K, has demonstrated basal glucagon immunoreactivity (GIR) levels in the normal range (80-110 pg/ml). Neither i. v. arginine nor oral glucose affected these GIR values, thus indicating the absence of functioning pancreatic or gastrointes...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/BF01220639
更新日期:1976-12-01 00:00:00
abstract::Neurotrophin-3 (NT-3) acts as a target-derived neurotrophic factor for large calibre sensory neurones and plays a role in the maintenance of the adult phenotype of proprioceptive and mechanoreceptive fibres. Large fibre sensory neuropathy is common in diabetes mellitus and the aim of this study was to determine whethe...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s001250050907
更新日期:1998-03-01 00:00:00
abstract:AIMS/HYPOTHESIS:The aim of this study was to investigate the action of the glucose-lowering compound sodium tungstate on glucose transport in muscle myotubes and to unravel the molecular events underlying the effects observed. METHODS:We studied the effects of tungstate on 2-deoxy-D: -glucose uptake, levels and transl...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s00125-008-1003-2
更新日期:2008-07-01 00:00:00
abstract:AIMS/HYPOTHESIS:In patients with type 1 diabetes, there has been concern about the effects of recurrent hypoglycaemia and chronic hyperglycaemia on cognitive function. Because other biomedical factors may also increase the risk of cognitive decline, this study examined whether macrovascular risk factors (hypertension, ...
journal_title:Diabetologia
pub_type: 临床试验,杂志文章
doi:10.1007/s00125-010-1883-9
更新日期:2011-02-01 00:00:00
abstract:AIMS/HYPOTHESIS:Reduced oxidative capacity of the mitochondria in skeletal muscle has been suggested to contribute to insulin resistance and type 2 diabetes. Moreover, a set of genes influencing oxidative phosphorylation (OXPHOS) is downregulated in diabetic muscle. Here we studied whether genetic, epigenetic and non-g...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s00125-008-1018-8
更新日期:2008-07-01 00:00:00
abstract:AIMS/HYPOTHESIS:Type 2 diabetes is an established risk factor for cardiovascular disease (CVD). This increased risk may be due in part to the increased levels of inflammatory factors associated with diabetes. Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is a risk marker for CVD and has pro-inflammatory effects...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s00125-010-1969-4
更新日期:2011-02-01 00:00:00
abstract:AIMS/HYPOTHESIS:Diabetes promotes cerebral neovascularisation via increased vascular endothelial growth factor (VEGF) angiogenic signalling. Roundabout-4 (ROBO4) protein is an endogenous inhibitor of VEGF signalling that stabilises the vasculature. Yet, how diabetes affects ROBO4 function remains unknown. We hypothesis...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s00125-017-4214-6
更新日期:2017-04-01 00:00:00
abstract:AIMS/HYPOTHESIS:Insulin resistance is frequently associated with hypertension and type 2 diabetes. The cytochrome P450 (CYP) arachidonic acid epoxygenases (CYP2C, CYP2J) and their epoxyeicosatrienoic acid (EET) products lower blood pressure and may also improve glucose homeostasis. However, the direct contribution of e...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s00125-017-4260-0
更新日期:2017-06-01 00:00:00
abstract::We have studied the presence of GAD65 autoantibodies in women with insulin-dependent diabetes mellitus (IDDM) (n = 28) or gestational diabetes (GDM) (n = 139) diagnosed during pregnancy and investigated the temporal relationship between these autoantibodies and the subsequent recurrence or development of IDDM. Among t...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s001250050578
更新日期:1996-11-01 00:00:00
abstract::This study estimates the direct health care costs of the incidence of insulin-dependent diabetes mellitus (IDDM) in Spain. A discrete event simulation model was developed to approximate the natural history of a cohort of newly diagnosed patients in a given year and used to calculate the average costs which would accum...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s001250050680
更新日期:1997-03-01 00:00:00
abstract:AIMS/HYPOTHESIS:Augmented oxidative stress induced by hyperglycaemia possibly contributes to the pathogenesis of diabetic complications. Oxidative stress is known to increase the conversion of deoxyguanosine to 8-oxo, 2'-deoxyguanosine in DNA. To investigate the possible contribution of oxidative DNA damage to the path...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s001250051258
更新日期:1999-08-01 00:00:00
abstract::The aim of the present study was to measure whole body glucose uptake (M) and oxidation rate by euglycaemic hyperinsulinaemic clamp and indirect calorimetry in 7 morbidly obese subjects (BMI > 40 kg/m2) at three time points: before bilio-pancreatic diversion (BPD) surgery (Ob); 3 months after surgery POI; and after re...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s001250050721
更新日期:1997-05-01 00:00:00
abstract::Demographic and biological data were collected from all Caucasian Type 1 diabetic patients (n = 279) who were recruited at clinical onset by the Belgian Diabetes Registry over 34 months. The male/female ratio was significantly higher for onset between age 20 and 40 years (2.4) than before age 20 years (1.0); no age-or...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/BF00401060
更新日期:1993-11-01 00:00:00
abstract::Thiazolidinediones are potent antidiabetic compounds, which act by enhancing peripheral insulin sensitivity. They are also activators of the peroxisome proliferator activated receptor gamma in adipose tissue. Pioglitazone induces in vivo adipocyte differentiation in the obese Zucker fa/fa rat and hence the capacity of...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s001250051014
更新日期:1998-08-01 00:00:00
abstract:AIMS/HYPOTHESIS:Elevated plasma levels of NEFA impair insulin action. Given the positive linear correlation between NEFA released by adipocytes and plasma NEFA levels, identification of mechanisms controlling adipocyte lipolysis and NEFA release could provide a guide to new therapies for insulin resistance and type 2 d...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s00125-008-1036-6
更新日期:2008-08-01 00:00:00
abstract::The past decade has resulted in multiple new findings of potential proteomic biomarkers of diabetic kidney disease (DKD). Many of these biomarkers reflect an important role in the (patho)physiology and biological processes of DKD. Situations in which proteomics could be applied in clinical practice include the identif...
journal_title:Diabetologia
pub_type: 杂志文章,评审
doi:10.1007/s00125-016-4001-9
更新日期:2016-09-01 00:00:00
abstract::Gender and biological sex impact the pathogenesis of numerous diseases, including metabolic disorders such as diabetes. In most parts of the world, diabetes is more prevalent in men than in women, especially in middle-aged populations. In line with this, considering almost all animal models, males are more likely to d...
journal_title:Diabetologia
pub_type: 杂志文章,评审
doi:10.1007/s00125-019-05040-3
更新日期:2020-03-01 00:00:00
abstract::Among monosaccharides, fructose has a small hyperglycaemic effect. In order to better explain the mechanisms which cause this metabolic property, we used tracers labelled with stable isotopes (deuterated glucose and naturally 13C labelled fructose) to quantify the overall glucose appearance, the rate of appearance in ...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/BF00400238
更新日期:1993-04-01 00:00:00
abstract:AIMS/HYPOTHESIS:Peroxisome proliferator-activated receptor-gamma coactivator-1 (PPARGC1) acts as a cofactor for several nuclear hormone receptors in many tissues and organs implicated in blood pressure regulation. Here, we assessed the association between the Gly482Ser variant of PPARGC1 and the arterial hypertension f...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s00125-004-1567-4
更新日期:2004-11-01 00:00:00
abstract::We examined glomerular basement membrane anionic site distribution identified by cationic gold in seven patients with insulin-dependent and four patients with non-insulin-dependent diabetes mellitus, presenting a spectrum of clinical and glomerular changes. Anionic sites were investigated by pretreatment of tissue wit...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/BF00400607
更新日期:1995-12-01 00:00:00
abstract::Following prolonged administration of tolbutamide the DNA- and protein content per islet was enhanced but the IRI content per islet was diminished. Glucose-induced (2.0, 8.0 or 16.6 mM) and leucine-induced (12.5 or 25.0 mM) IRI release from isolated islets, as well as 14C02-production from U-14C glucose, were decrease...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/BF00422395
更新日期:1975-08-01 00:00:00
abstract::Isolated pancreatic islets of normoglycemic sand rats do not respond to 2.5 mM glucose with an enhanced glucagon secretion, which could be observed in normal Wistar rats. Arginine stimulates glucagon release in the presence of 2.5 mM glucose in Wistar rats as well as in sand rats. The secretion pattern is not caused b...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/BF00422820
更新日期:1975-02-01 00:00:00
abstract::The adrenergic regulation of adipose tissue lipolysis in response to insulin-induced hypoglycaemia (intravenous infusion of soluble insulin 0.10 IU.kg body weight-1.h-1 until the arterial plasma glucose fell below 2.8 mmol/l) was investigated directly in vivo in 11 insulin-dependent diabetic (IDDM) patients and 12 con...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s001250050519
更新日期:1996-07-01 00:00:00
abstract::The incidence, prevalence, and ages and dates of onset of diabetes, were studied in 184 families with 2 or more affected children. Results suggested that the siblings of children who developed diabetes before the age of 16 years were 26 times more likely to develop diabetes than other children. Of all siblings surveye...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/BF00280517
更新日期:1980-10-01 00:00:00
abstract:AIMS/HYPOTHESIS:The aim of this study was to assess the predictive role of autonomic reactivity in body weight loss induced by gastric bypass. METHODS:A group of 22 morbidly obese subjects, who were due to undergo a gastric bypass, were submitted, before surgery, to a euglycaemic-hyperinsulinaemic clamp, during which ...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/s00125-005-1792-5
更新日期:2005-07-01 00:00:00
abstract::Short- and long-term regulation of hepatic carbohydrate metabolism by insulin-like growth factor II was studied in primary cultures of adult rat hepatocytes and compared to the metabolic potency of insulin. Insulin-like growth factor II stimulated glycogen synthesis from [14C]glucose, uptake of [3H]aminoisobutyric aci...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/BF00400920
更新日期:1992-03-01 00:00:00
abstract:AIMS/HYPOTHESIS:We investigated the potential effects of the Continuous Glucose Monitoring System (CGMS), as compared with self-monitoring of blood glucose, on glycaemic control in children with type 1 diabetes. METHODS:The following electronic databases were searched throughout June 2007: MEDLINE, EMBASE and The Coch...
journal_title:Diabetologia
pub_type: 杂志文章,meta分析,评审
doi:10.1007/s00125-007-0884-9
更新日期:2008-02-01 00:00:00
abstract::Using an antiserum raised to a recombinant coxsackie virus B 3 capsid protein, VP1, an immunocytochemical technique was developed which was capable of detecting the presence of all coxsackie B viruses in formalin fixed paraffin embedded infected tissue culture cells. This technique was tested on autopsy heart and panc...
journal_title:Diabetologia
pub_type: 杂志文章
doi:10.1007/BF00403323
更新日期:1990-05-01 00:00:00