共查询到20条相似文献,搜索用时 31 毫秒
1.
Suleiman Al-Sabah Munya Al-Fulaij Ghina Shaaban Hanadi A. Ahmed Rosalind J. Mann Dan Donnelly Moritz Bünemann Cornelius Krasel 《PloS one》2014,9(9)
Background and Objectives
Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are important regulators of insulin secretion, and their functional loss is an early characteristic of type 2 diabetes mellitus (T2DM). Pharmacological levels of GLP-1, but not GIP, can overcome this loss. GLP-1 and GIP exert their insulinotropic effects through their respective receptors expressed on pancreatic β-cells. Both the GLP-1 receptor (GLP-1R) and the GIP receptor (GIPR) are members of the secretin family of G protein-coupled receptors (GPCRs) and couple positively to adenylate cyclase. We compared the signalling properties of these two receptors to gain further insight into why GLP-1, but not GIP, remains insulinotropic in T2DM patients.Methods
GLP-1R and GIPR were transiently expressed in HEK-293 cells, and basal and ligand-induced cAMP production were investigated using a cAMP-responsive luciferase reporter gene assay. Arrestin3 (Arr3) recruitment to the two receptors was investigated using enzyme fragment complementation, confocal microscopy and fluorescence resonance energy transfer (FRET).Results
GIPR displayed significantly higher (P<0.05) ligand-independent activity than GLP-1R. Arr3 displayed a robust translocation to agonist-stimulated GLP-1R but not to GIPR. These observations were confirmed in FRET experiments, in which GLP-1 stimulated the recruitment of both GPCR kinase 2 (GRK2) and Arr3 to GLP-1R. These interactions were not reversed upon agonist washout. In contrast, GIP did not stimulate recruitment of either GRK2 or Arr3 to its receptor. Interestingly, arrestin remained at the plasma membrane even after prolonged (30 min) stimulation with GLP-1. Although the GLP-1R/arrestin interaction could not be reversed by agonist washout, GLP-1R and arrestin did not co-internalise, suggesting that GLP-1R is a class A receptor with regard to arrestin binding.Conclusions
GIPR displays higher basal activity than GLP-1R but does not effectively recruit GRK2 or Arr3. 相似文献2.
Michishige Terasaki Masaharu Nagashima Kyoko Nohtomi Kyoko Kohashi Masako Tomoyasu Kyoko Sinmura Yukinori Nogi Yuki Katayama Kengo Sato Fumiko Itoh Takuya Watanabe Tsutomu Hirano 《PloS one》2013,8(8)
Aim
Several recent reports have revealed that dipeptidyl peptidase (DPP)-4 inhibitors have suppressive effects on atherosclerosis in apolipoprotein E-null (Apoe −/−) mice. It remains to be seen, however, whether this effect stems from increased levels of the two active incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).Methods
Nontreated Apoe −/− mice, streptozotocin-induced diabetic Apoe −/− mice, and db/db diabetic mice were administered the DPP-4 inhibitor vildagliptin in drinking water and co-infused with either saline, the GLP-1 receptor blocker, exendin(9–39), the GIP receptor blocker, (Pro3)GIP, or both via osmotic minipumps for 4 weeks. Aortic atherosclerosis and oxidized low-density lipoprotein-induced foam cell formation in exudate peritoneal macrophages were determined.Results
Vildagliptin increased plasma GLP-1 and GIP levels without affecting food intake, body weight, blood pressure, or plasma lipid profile in any of the animals tested, though it reduced HbA1c in the diabetic mice. Diabetic Apoe −/− mice exhibited further-progressed atherosclerotic lesions and foam cell formation compared with nondiabetic counterparts. Nondiabetic and diabetic Apoe −/− mice showed a comparable response to vildagliptin, namely, remarkable suppression of atherosclerotic lesions with macrophage accumulation and foam cell formation in peritoneal macrophages. Exendin(9–39) or (Pro3)GIP partially attenuated the vildagliptin-induced suppression of atherosclerosis. The two blockers in combination abolished the anti-atherosclerotic effect of vildagliptin in nondiabetic mice but only partly attenuated it in diabetic mice. Vildagliptin suppressed macrophage foam cell formation in nondiabetic and diabetic mice, and this suppressive effect was abolished by infusions with exendin(9–39)+(Pro3)GIP. Incubation of DPP-4 or vildagliptin in vitro had no effect on macrophage foam cell formation.Conclusions
Vildagliptin confers a substantial anti-atherosclerotic effect in both nondiabetic and diabetic mice, mainly via the action of the two incretins. However, the partial attenuation of atherosclerotic lesions by the dual incretin receptor antagonists in diabetic mice implies that vildagliptin confers a partial anti-atherogenic effect beyond that from the incretins. 相似文献3.
Niina Matikainen Elias Bj?rnson Sanni S?derlund Christofer Borén Bj?rn Eliasson Kirsi H. Pietil?inen Leonie H. Bogl Antti Hakkarainen Nina Lundbom Angela Rivellese Gabriele Riccardi Jean-Pierre Després Natalie Alméras Jens Juul Holst Carolyn F. Deacon Jan Borén Marja-Riitta Taskinen 《PloS one》2016,11(1)
Context
Glucose and lipids stimulate the gut-hormones glucagon-like peptide (GLP)-1, GLP-2 and glucose-dependent insulinotropic polypeptide (GIP) but the effect of these on human postprandial lipid metabolism is not fully clarified.Objective
To explore the responses of GLP-1, GLP-2 and GIP after a fat-rich meal compared to the same responses after an oral glucose tolerance test (OGTT) and to investigate possible relationships between incretin response and triglyceride-rich lipoprotein (TRL) response to a fat-rich meal.Design
Glucose, insulin, GLP-1, GLP-2 and GIP were measured after an OGTT and after a fat-rich meal in 65 healthy obese (BMI 26.5–40.2 kg/m2) male subjects. Triglycerides (TG), apoB48 and apoB100 in TG-rich lipoproteins (chylomicrons, VLDL1 and VLDL2) were measured after the fat-rich meal.Main Outcome Measures
Postprandial responses (area under the curve, AUC) for glucose, insulin, GLP-1, GLP-2, GIP in plasma, and TG, apoB48 and apoB100 in plasma and TG-rich lipoproteins.Results
The GLP-1, GLP-2 and GIP responses after the fat-rich meal and after the OGTT correlated strongly (r = 0.73, p<0.0001; r = 0.46, p<0.001 and r = 0.69, p<0.001, respectively). Glucose and insulin AUCs were lower, but the AUCs for GLP-1, GLP-2 and GIP were significantly higher after the fat-rich meal than after the OGTT. The peak value for all hormones appeared at 120 minutes after the fat-rich meal, compared to 30 minutes after the OGTT. After the fat-rich meal, the AUCs for GLP-1, GLP-2 and GIP correlated significantly with plasma TG- and apoB48 AUCs but the contribution was very modest.Conclusions
In obese males, GLP-1, GLP-2 and GIP responses to a fat-rich meal are greater than following an OGTT. However, the most important explanatory variable for postprandial TG excursion was fasting triglycerides. The contribution of endogenous GLP-1, GLP-2 and GIP to explaining the variance in postprandial TG excursion was minor. 相似文献4.
Aim
We recently reported that glucose-dependent insulinotropic polypeptide (GIP) prevents the development of atherosclerosis in apolipoprotein E-null (Apoe −/−) mice. GIP receptors (GIPRs) are found to be severely down-regulated in diabetic animals. We examined whether GIP can exert anti-atherogenic effects in diabetes.Methods
Nondiabetic Apoe −/− mice, streptozotocin-induced diabetic Apoe −/− mice, and db/db mice were administered GIP (25 nmol/kg/day) or saline (vehicle) through osmotic mini-pumps for 4 weeks. The animals were assessed for aortic atherosclerosis and for oxidized low-density lipoprotein-induced foam cell formation in exudate peritoneal macrophages.Results
Diabetic Apoe −/− mice of 21 weeks of age exhibited more advanced atherosclerosis than nondiabetic Apoe −/− mice of the same age. GIP infusion in diabetic Apoe −/− mice increased plasma total GIP levels by 4-fold without improving plasma insulin, glucose, or lipid profiles. GIP infusion significantly suppressed macrophage-driven atherosclerotic lesions, but this effect was abolished by co-infusions with [Pro3]GIP, a GIPR antagonist. Foam cell formation was stimulated by 3-fold in diabetic Apoe −/− mice compared with their nondiabetic counterparts, but this effect was halved by GIP infusion. GIP infusion also attenuated the foam cell formation in db/db mice. In vitro treatment with GIP (1 nM) reduced foam cell formation by 15% in macrophages from diabetic Apoe −/− mice, and this attenuating effect was weaker than that attained by the same treatment of macrophages from nondiabetic counterparts (35%). While GIPR expression was reduced by only about a half in macrophages from diabetic mice, it was reduced much more dramatically in pancreatic islets from the same animals. Incubation with high glucose (500 mg/dl) for 9–10 days markedly reduced GIPR expression in pancreatic islet cells, but not in macrophages.Conclusions
Long-term infusion of GIP conferred significant anti-atherogenic effects in diabetic mice even though the GIPR expression in macrophages was mildly down-regulated in the diabetic state. 相似文献5.
Background
Glucagon like peptide-1 (GLP-1) stimulates insulin secretion from the pancreas but also has extra-pancreatic effects. GLP-1 may stimulate glucose uptake in cultured muscle cells but the mechanism is not clearly defined. Furthermore, while the pancreatic effects of GLP-1 are glucose-dependent, the glucose-dependency of its extra-pancreatic effects has not been examined.Methods
Skeletal muscle satellite cells isolated from young (22.5±0.97 yr), lean (BMI 22.5±0.6 kg/m2), healthy males were differentiated in media containing either 22.5 mM (high) or 5 mM (normal) glucose for 7 days in the absence or presence of insulin and/or various GLP-1 concentrations. Myocellular effects of GLP-1, insulin and glucose were assessed by western-blot, glucose uptake and glycogen synthesis.Results
We firstly show that the GLP-1 receptor protein is expressed in differentiated human muscle satellite cells (myocytes). Secondly, we show that in 5 mM glucose media, exposure of myocytes to GLP-1 results in a dose dependent increase in glucose uptake, GLUT4 amount and subsequently glycogen synthesis in a PI3K dependent manner, independent of the insulin signaling cascade. Importantly, we provide evidence that differentiation of human satellite cells in hyperglycemic (22.5 mM glucose) conditions increases GLUT1 expression, and renders the cells insulin resistant and interestingly GLP-1 resistant in terms of glucose uptake and glycogen synthesis. Hyperglycemic conditions did not affect the ability of insulin to phosphorylate downstream targets, PKB or GSK3. Interestingly we show that at 5 mM glucose, GLP-1 increases GLUT4 protein levels and that this effect is abolished by hyperglycemia.Conclusions
GLP-1 increases glucose uptake and glycogen synthesis into fully-differentiated human satellite cells in a PI3-K dependent mechanism potentially through increased GLUT4 protein levels. The latter occurs independently of the insulin signaling pathway. Attenuation of both GLP-1 and insulin-induced glucose metabolism by hyperglycemia is likely to occur downstream of PI3K. 相似文献6.
Salehi A Meidute Abaraviciene S Jimenez-Feltstrom J Ostenson CG Efendic S Lundquist I 《PloS one》2008,3(5):e2165
Background
A distinctive feature of type 2 diabetes is inability of insulin-secreting β-cells to properly respond to elevated glucose eventually leading to β-cell failure. We have hypothesized that an abnormally increased NO production in the pancreatic islets might be an important factor in the pathogenesis of β-cell dysfunction.Principal Findings
We show now that islets of type 2 spontaneous diabetes in GK rats display excessive NO generation associated with abnormal iNOS expression in insulin and glucagon cells, increased ncNOS activity, impaired glucose-stimulated insulin release, glucagon hypersecretion, and impaired glucose-induced glucagon suppression. Pharmacological blockade of islet NO production by the NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME) greatly improved hormone secretion from GK islets suggesting islet NOS activity being an important target to inactivate for amelioration of islet cell function. The incretin hormone GLP-1, which is used in clinical practice suppressed iNOS and ncNOS expression and activity with almost full restoration of insulin release and partial restoration of glucagon release. GLP-1 suppression of iNOS expression was reversed by PKA inhibition but unaffected by the proteasome inhibitor MG132. Injection of glucose plus GLP-1 in the diabetic rats showed that GLP-1 amplified the insulin response but induced a transient increase and then a poor depression of glucagon.Conclusion
The results suggest that abnormally increased NO production within islet cells is a significant player in the pathogenesis of type 2 diabetes being counteracted by GLP-1 through PKA-dependent, nonproteasomal mechanisms. 相似文献7.
Vo Nguyen Trung Hiroshi Yamamoto Akira Furukawa Tsuyoshi Yamaguchi Satoshi Murata Masahiro Yoshimura Yoko Murakami Shigetaka Sato Hideji Otani Satoshi Ugi Katsutaro Morino Hiroshi Maegawa Tohru Tani 《PloS one》2013,8(6)
Background
Enhanced secretion of glucagon-like peptide-1 (GLP-1) has been suggested as a possible mechanism underlying the improvement in type 2 diabetes mellitus (T2DM) after laparoscopic sleeve gastrectomy (LSG). However, the reason for enhanced GLP-1 secretion during glucose challenge after LSG remains unclear because LSG does not include intestinal bypass. In this study, we focused on the effects of LSG on GLP-1 secretion and intestinal motility during the oral glucose tolerance test (OGTT) using cine magnetic resonance imaging (MRI) before and 3 months after LSG.Methods
LSG was performed in 12 obese patients with a body mass index >35 kg/m2. Six patients had T2DM. OGTT was performed before and 3 months after the surgery. Body weight, hemoglobin A1c (HbA1c), and GLP-1 levels during OGTT were examined, and intestinal motility during OGTT was assessed using cine MRI.Results
Body weight was significantly decreased after surgery in all the cases. HbA1c was markedly decreased in all the diabetic subjects. In all cases, GLP-1 secretion during OGTT was enhanced and cine MRI showed markedly increased intestinal motility at 15 and 30 min during OGTT after LSG.Conclusions
LSG leads to accelerated intestinal motility and reduced intestinal transit time, which may be involved in the mechanism underlying enhanced GLP-1 secretion during OGTT after LSG. 相似文献8.
N Martin A Ruddick GK Arthur H Wan L Woodman CE Brightling DJ Jones ID Pavord P Bradding 《PloS one》2012,7(8):e43545
Introduction
Chronic mast cell activation is a characteristic feature of asthma. BEAS-2B human airway epithelial cells (AEC) profoundly inhibit both constitutive and IgE-dependent human lung mast cell (HLMC) histamine release. The aim of this study was to examine the regulation of HLMC degranulation by primary AEC from healthy and asthmatic subjects, and investigate further the inhibitory mechanism.Methods
HLMC were co-cultured with both BEAS-2B and primary AEC grown as monolayers or air-liquid interface (ALI) cultures.Results
Both constitutive and IgE-dependent HLMC histamine release were attenuated by BEAS-2B, primary AEC monolayers and ALI cultures. This occurred in the absence of HLMC-AEC contact indicating the presence of a soluble factor. Unlike healthy ALI AEC, asthmatic ALI-AEC did not significantly reduce constitutive histamine release. AEC inhibitory activity was transferable in primary AEC monolayer supernatant, but less active than with Transwell co-culture, suggesting that the inhibitory factor was labile. The AEC inhibitory effects were attenuated by both AEC wounding and pertussis toxin, indicating the involvement of a G0/Gi receptor coupled mechanism. Solid phase extraction of lipids (<10 kDa) removed the AEC inhibitory activity. The lipid derivatives resolvin D1 and D2 and lipoxin A4 attenuated HLMC histamine release in a dose-dependent fashion but were not detectable in co-culture supernatants.Conclusions
Primary AEC suppress HLMC constitutive and IgE-dependent histamine secretion through the release of a soluble, labile lipid mediator(s) that signals through the G0/Gi receptor coupled mechanism. Manipulation of this interaction may have a significant therapeutic role in asthma. 相似文献9.
Scott B. Widenmaier Su-Jin Kim Gary K. Yang Thomas De Los Reyes Cuilan Nian Ali Asadi Yutaka Seino Timothy J. Kieffer Yin Nam Kwok Christopher H. S. McIntosh 《PloS one》2010,5(3)
Aims
The gastrointestinal hormone GIP promotes pancreatic islet function and exerts pro-survival actions on cultured β-cells. However, GIP also promotes lipogenesis, thus potentially restricting its therapeutic use. The current studies evaluated the effects of a truncated GIP analog, D-Ala2-GIP1–30 (D-GIP1–30), on glucose homeostasis and β-cell mass in rat models of diabetes.Materials and Methods
The insulinotropic and pro-survival potency of D-GIP1–30 was evaluated in perfused pancreas preparations and cultured INS-1 β-cells, respectively, and receptor selectivity evaluated using wild type and GIP receptor knockout mice. Effects of D-GIP1–30 on β-cell function and glucose homeostasis, in vivo, were determined using Lean Zucker rats, obese Vancouver diabetic fatty rats, streptozotocin treated rats, and obese Zucker diabetic fatty rats, with effects on β-cell mass determined in histological studies of pancreatic tissue. Lipogenic effects of D-GIP1–30 were evaluated on cultured 3T3-L1 adipocytes.Results
Acutely, D-GIP1–30 improved glucose tolerance and insulin secretion. Chronic treatment with D-GIP1–30 reduced levels of islet pro-apoptotic proteins in Vancouver diabetic fatty rats and preserved β-cell mass in streptozotocin treated rats and Zucker diabetic fatty rats, resulting in improved insulin responses and glycemic control in each animal model, with no change in body weight. In in vitro studies, D-GIP1–30 exhibited equivalent potency to GIP1–42 on β-cell function and survival, but greatly reduced action on lipoprotein lipase activity in 3T3-L1 adipocytes.Conclusions
These findings demonstrate that truncated forms of GIP exhibit potent anti-diabetic actions, without pro-obesity effects, and that the C-terminus contributes to the lipogenic actions of GIP. 相似文献10.
Background
Sleeve gastrectomy (SG) has emerged recently as a stand-alone bariatric procedure to treat morbid obesity and enhance glucose homeostasis. The aim of the study was to evaluate its effects in neonatally streptozotocin (STZ)-induced diabetic rats (n-STZ diabetic rats).Methodology and Principal Findings
To induce diabetes, STZ (90 mg/kg) was administered intraperitoneally to 2-day-old male pups. When 12 weeks old, diabetic rats were randomized into sleeve operation group (SLG, n = 6) and sham operation group (SOG, n = 6). Body weights were monitored weekly, and daily consumption of water and food were followed for eight consecutive weeks postoperatively. Serum glucose levels were measured periodically at the 4th and 8th week after surgery. Insulin, ghrelin, glucose-dependent insulinotropic polypeptide (GIP) and Glucagon-like peptide-1 (GLP-1) levels were assayed at the end of the study. Our data showed that SLG rats exhibited significantly lower body weight gain in addition to reduced food and water intakes postoperatively compared to their sham-operation counterparts. However, resolution of diabetes was not observed in our study. Correspondingly, there were no significant differences between SOG rats and SLG rats in glucose metabolism-associated hormones, including insulin, GIP and GLP-1. In contrast, ghrelin level significantly decreased (P<0.01) in SLG group (58.01±3.75 pg/ml) after SG surgery compared to SOG group (76.36±3.51 pg/ml).Conclusions
These observations strongly suggest that SG is effective in controlling body weight. However, SG did not achieve resolution or improvement of diabetes in n-STZ diabetic rats. 相似文献11.
Christine Bernsmeier Anne C. Meyer-Gerspach Lea S. Blaser Lia Jeker Robert E. Steinert Markus H. Heim Christoph Beglinger 《PloS one》2014,9(1)
Background & Aims
The incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are gastrointestinal peptide hormones regulating postprandial insulin release from pancreatic β-cells. GLP-1 agonism is a treatment strategy in Type 2 diabetes and is evaluated in Non-alcoholic fatty liver disease (NAFLD). However, the role of incretins in its pathophysiology is insufficiently understood. Studies in mice suggest improvement of hepatic steatosis by GLP-1 agonism. We determined the secretion of incretins after oral glucose administration in non-diabetic NAFLD patients.Methods
N = 52 patients (n = 16 NAFLD and n = 36 Non-alcoholic steatohepatitis (NASH) patients) and n = 50 matched healthy controls were included. Standardized oral glucose tolerance test was performed. Glucose, insulin, glucagon, GLP-1 and GIP plasma levels were measured sequentially for 120 minutes after glucose administration.Results
Glucose induced GLP-1 secretion was significantly decreased in patients compared to controls (p<0.001). In contrast, GIP secretion was unchanged. There was no difference in GLP-1 and GIP secretion between NAFLD and NASH subgroups. All patients were insulin resistant, however HOMA2-IR was highest in the NASH subgroup. Fasting and glucose-induced insulin secretion was higher in NAFLD and NASH compared to controls, while the glucose lowering effect was diminished. Concomitantly, fasting glucagon secretion was significantly elevated in NAFLD and NASH.Conclusions
Glucose-induced GLP-1 secretion is deficient in patients with NAFLD and NASH. GIP secretion is contrarily preserved. Insulin resistance, with hyperinsulinemia and hyperglucagonemia, is present in all patients, and is more severe in NASH compared to NAFLD. These pathophysiologic findings endorse the current evaluation of GLP-1 agonism for the treatment of NAFLD. 相似文献12.
Marie-Line Peyot Joshua P. Gray Julien Lamontagne Peter J. S. Smith George G. Holz S. R. Murthy Madiraju Marc Prentki Emma Heart 《PloS one》2009,4(7)
Background
Glucagon like peptide-1 (GLP-1) and its analogue exendin-4 (Ex-4) enhance glucose stimulated insulin secretion (GSIS) and activate various signaling pathways in pancreatic β-cells, in particular cAMP, Ca2+ and protein kinase-B (PKB/Akt). In many cells these signals activate intermediary metabolism. However, it is not clear whether the acute amplification of GSIS by GLP-1 involves in part metabolic alterations and the production of metabolic coupling factors.Methodology/Prinicipal Findings
GLP-1 or Ex-4 at high glucose caused release (∼20%) of the total rat islet insulin content over 1 h. While both GLP-1 and Ex-4 markedly potentiated GSIS in isolated rat and mouse islets, neither had an effect on β-cell fuel and energy metabolism over a 5 min to 3 h time period. GLP-1 activated PKB without changing glucose usage and oxidation, fatty acid oxidation, lipolysis or esterification into various lipids in rat islets. Ex-4 caused a rise in [Ca2+]i and cAMP but did not enhance energy utilization, as neither oxygen consumption nor mitochondrial ATP levels were altered.Conclusions/Significance
The results indicate that GLP-1 barely affects β-cell intermediary metabolism and that metabolic signaling does not significantly contribute to GLP-1 potentiation of GSIS. The data also indicate that insulin secretion is a minor energy consuming process in the β-cell, and that the β-cell is different from most cell types in that its metabolic activation appears to be primarily governed by a “push” (fuel substrate driven) process, rather than a “pull” mechanism secondary to enhanced insulin release as well as to Ca2+, cAMP and PKB signaling. 相似文献13.
Background
According to the WHO, more than 1 billion people worldwide are overweight and at risk of developing chronic illnesses, including cardiovascular disease, type 2 diabetes, hypertension and stroke. Current therapies show limited efficacy and are often associated with unpleasant side-effect profiles, hence there is a medical need for new therapeutic interventions in the field of obesity. Gastric inhibitory peptide (GIP, also known as glucose-dependent insulinotropic polypeptide) has recently been postulated to link over-nutrition with obesity. In fact GIP receptor-deficient mice (GIPR−/−) were shown to be completely protected from diet-induced obesity. Thus, disrupting GIP signaling represents a promising novel therapeutic strategy for the treatment of obesity.Methodology/Principal Findings
In order to block GIP signaling we chose an active vaccination approach using GIP peptides covalently attached to virus-like particles (VLP-GIP). Vaccination of mice with VLP-GIP induced high titers of specific antibodies and efficiently reduced body weight gain in animals fed a high fat diet. The reduction in body weight gain could be attributed to reduced accumulation of fat. Moreover, increased weight loss was observed in obese mice vaccinated with VLP-GIP. Importantly, despite the incretin action of GIP, VLP-GIP-treated mice did not show signs of glucose intolerance.Conclusions/Significance
This study shows that vaccination against GIP was safe and effective. Thus active vaccination may represent a novel, long-lasting treatment for obesity. However further preclinical safety/toxicology studies will be required before the therapeutic concept can be addressed in humans. 相似文献14.
15.
Edwin T. Parlevliet Yanan Wang Janine J. Geerling Janny P. Schr?der-Van der Elst Kristen Picha Karyn O'Neil Vedrana Stojanovic-Susulic Tatiana Ort Louis M. Havekes Johannes A. Romijn Hanno Pijl Patrick C. N. Rensen 《PloS one》2012,7(11)
Objective
In addition to improve glucose intolerance, recent studies suggest that glucagon-like peptide-1 (GLP-1) receptor agonism also decreases triglyceride (TG) levels. The aim of this study was to evaluate the effect of GLP-1 receptor agonism on very-low-density lipoprotein (VLDL)-TG production and liver TG metabolism.Experimental Approach
The GLP-1 peptide analogues CNTO3649 and exendin-4 were continuously administered subcutaneously to high fat diet-fed APOE*3-Leiden transgenic mice. After 4 weeks, hepatic VLDL production, lipid content, and expression profiles of selected genes involved in lipid metabolism were determined.Results
CNTO3649 and exendin-4 reduced fasting plasma glucose (up to −30% and −28% respectively) and insulin (−43% and −65% respectively). In addition, these agents reduced VLDL-TG production (−36% and −54% respectively) and VLDL-apoB production (−36% and −43% respectively), indicating reduced production of VLDL particles rather than reduced lipidation of apoB. Moreover, they markedly decreased hepatic content of TG (−39% and −55% respectively), cholesterol (−30% and −55% respectively), and phospholipids (−23% and −36% respectively), accompanied by down-regulation of expression of genes involved in hepatic lipogenesis (Srebp-1c, Fasn, Dgat1) and apoB synthesis (Apob).Conclusion
GLP-1 receptor agonism reduces VLDL production and hepatic steatosis in addition to an improvement of glycemic control. These data suggest that GLP-receptor agonists could reduce hepatic steatosis and ameliorate dyslipidemia in patients with type 2 diabetes mellitus. 相似文献16.
17.
Background
Autosomal dominant non-autoimmune hyperthyroidism (ADNAH) is a rare genetic disorder of the endocrine system. Molecular genetic studies in ADNAH have revealed heterozygous germline mutations in the TSHR. To data, mutations leading to an increase in the constitutive activation of the TSHR have been described in the transmembrane segments, exoloops and cytoplasmic loop of TSHR. These mutations result in constitutive activation of the Gαs/cAMP or Gαq/11/inositol phosphate (IP) pathways, which stimulate thyroid hormone production and thyroid proliferation.Methodology/Principal Findings
In a previous study, we reported a new TSHR mutation located in the C-terminal domain of TSHR, which results in a substitution of the conserved Ile691 for Phe. In this study, to address the question of whether the I691F mutated receptor could be responsible for Gαs/cAMP or Gαq/11/IP constitutive activity, wild-type and TSHR mutants were expressed in COS-7 cells to determine cAMP constitutive activity and IP formation. Compared to the cell surface with expression of the A623V mutated receptor as positive control, the I691F mutated receptor showed a slight increase of cAMP accumulation. Furthermore, I691F resulted in constitutive activation of the Gαq/11/IP signaling pathway.Conclusions/Significance
Our results indicate that Ile691 not only contributes to keeping TSHR inactive in the Gαs/cAMP pathways but also in the Gαq/11/IP cascade. 相似文献18.
Objective
This study explores a new, non-invasive imaging method for the specific diagnosis of insulinoma by providing an initial investigation of the use of 125I-labelled molecules of the glucagon-like peptide-1 (GLP-1) analogue liraglutide for in vivo and in vitro small-animal SPECT/CT (single-photon emission computed tomography/computed tomography) imaging of insulinomas.Methods
Liraglutide was labelled with 125I by the Iodogen method. The labelled 125I-liraglutide compound and insulinoma cells from the INS-1 cell line were then used for in vitro saturation and competitive binding experiments. In addition, in a nude mouse model, the use of 125I-liraglutide for the in vivo small-animal SPECT/CT imaging of insulinomas and the resulting distribution of radioactivity across various organs were examined.Results
The labelling of liraglutide with 125I was successful, yielding a labelling rate of approximately 95% and a radiochemical purity of greater than 95%. For the binding between 125I-liraglutide and the GLP-1 receptor on the surface of INS-1 cells, the equilibrium dissociation constant (Kd) was 128.8±30.4 nmol/L(N = 3), and the half-inhibition concentration (IC50) was 542.4±187.5 nmol/L(N = 3). Small-animal SPECT/CT imaging with 125I-liraglutide indicated that the tumour imaging was clearest at 90 min after the 125I-liraglutide treatment. An examination of the in vivo distribution of radioactivity revealed that at 90 min after the 125I-liraglutide treatment, the target/non-target (T/NT) ratio for tumour and muscle tissue was 4.83±1.30(N = 3). Our study suggested that 125I-liraglutide was predominantly metabolised and cleared by the liver and kidneys.Conclusion
The radionuclide 125I-liraglutide can be utilised for the specific imaging of insulinomas, representing a new non-invasive approach for the in vivo diagnosis of insulinomas. 相似文献19.
Jobin Mathew Savitha Balakrishnan Sherin Antony Pretty Mary Abraham CS Paulose 《Journal of biomedical science》2012,19(1):25
Abstact
Background
Gamma amino butyric acid (GABA), the principal inhibitory neurotransmitter in the cerebral cortex, maintains the inhibitory tones that counter balances neuronal excitation. When this balance is perturbed, seizures may ensue.Methods
In the present study, alterations of the general GABA, GABAA and GABAB receptors in the cerebral cortex of the epileptic rat and the therapeutic application of Bacopa monnieri were investigated.Results
Scatchard analysis of [3H]GABA, [3H]bicuculline and [3H]baclofen in the cerebral cortex of the epileptic rat showed significant decrease in Bmax (P < 0.001) compared to control. Real Time PCR amplification of GABA receptor subunits such as GABAAά1, GABAAγ, GABAAδ, GABAB and GAD where down regulated (P < 0.001) in epileptic rats. GABAAά5 subunit and Cyclic AMP responsible element binding protein were up regulated. Confocal imaging study confirmed the decreased GABA receptors in epileptic rats. Epileptic rats have deficit in radial arm and Y maze performance.Conclusions
Bacopa monnieri and Bacoside-A treatment reverses epilepsy associated changes to near control suggesting that decreased GABA receptors in the cerebral cortex have an important role in epileptic occurrence; Bacopa monnieri and Bacoside-A have therapeutic application in epilepsy management. 相似文献20.
éva Borbély Zsófia Hajna Katalin Sándor László Kereskai István Tóth Erika Pintér Péter Nagy János Szolcsányi John Quinn Andreas Zimmer James Stewart Christopher Paige Alexandra Berger Zsuzsanna Helyes 《PloS one》2013,8(4)