287 research outputs found
Rice protein hydrolysates stimulate GLP-1 secretion, reduce GLP-1 degradation, and lower the glycemic response in rats
No full textRice has historically been consumed in Asia as a major source of carbohydrates, however, little is known regarding the functional roles of rice proteins as dietary factors. In the present study, we investigated whether peptides derived from rice proteins could stimulate GLP-1 secretion, which results in reducing glycemia via the incretin effect in normal rats. Hydrolysates were prepared from the protein fraction of rice endosperm or rice bran, and the effects of these hydrolysates on GLP-1 secretion were examined in a murine enteroendocrine cell line GLUTag. Plasma was collected after oral administration of the rice protein hydrolysates, under anesthesia, or during glucose tolerance tests in rats. In anesthetized rats, plasma dipeptidyl peptidase-IV (DPP-IV) activity was measured after ileal administration of the rice protein hydrolysates. GLP-1 secretion from GLUTag cells was potently stimulated by the rice protein hydrolysates, especially by the peptic digest of rice endosperm protein (REPH) and that of rice bran protein (RBPH). Oral administration of REPH or RBPH elevated plasma GLP-1 concentrations, which resulted in the reduction of glycemia under the intraperitoneal glucose tolerance test. In addition, the plasma DPP-IV activity was attenuated after ileal administration of REPH or RBPH, which resulted in a higher ratio of intact (active) GLP-1 to total GLP-1 in the plasma. These results demonstrate that rice proteins exert potent stimulatory effects on GLP-1 secretion, which could contribute to the reduction of postprandial glycemia. The inhibitory effect of these peptides on the plasma DPP-IV activity may potentiate the incretin effect of GLP-1
Evaluation of the hCMEC/D3 cell line, a new "in vitro" model of the human blood-brain barrier for transport and gene regulation studies
No full textBrain endothelial capillary cells form the blood-brain barrier (BBB), a highly selective
membrane between the peripheral blood and the central nervous system. The main
functions of the BBB are to protect the brain tissue by preventing the entry of toxic
compounds and to supply it with nutrients in order to assure proper function. Tight
junctions are the key elements for the establishment of a tight barrier and seal the
intercellular gaps against passive diffusion of hydrophilic compounds. A second important
characteristic of the brain capillary endothelial cells are transport proteins that prevent
brain penetration of their substrates by pumping them back in the blood. These
compounds include a series of clinically used drugs. Important drug efflux transporters
located at the BBB are P-glycoprotein (P-gp), the breast cancer resistance protein
(BCRP) and the family of multidrug resistance proteins (MRP).
During drug development, the question of whether a drug candidate reaches the brain
tissue is of great importance. Therefore, models are needed to predict the BBB
permeability of new compounds. In the past, in vitro models have been developed to
address this question. These models include isolated brain capillaries, isolated primary
brain capillary endothelial cells and BBB cell lines of various origins. A major problem
encountered with these cell lines was an insufficient paracellular resistance.
Recently, the hCMEC/D3 cell line was generated by immortalizing primary human brain
endothelial cells. In culture this cell line shows a morphology that closely resembles to
primary cells, forms tight monolayers and expresses BBB markers such as chemokine
receptors, tight junctional molecules and ATP binding cassette (ABC)-transporters.
The aim of this thesis was to evaluate the hCMEC/D3 cell line as an in vitro model of the
human BBB to study 1) permeability properties including para- and transcellular diffusion
as well as active transport 2) the influence of endo- and exogenous factors on the
paracellular permeability and 3) the regulation of breast cancer resistance protein and Pglycoprotein
by pro-inflammatory cytokines.
The first study describes the characterization of the hCMEC/D3 cells as an in vitro model
of the human BBB for permeability studies (section Error! Reference source not
found.). The ability of the cells to allow discrimination between para- and transcellular
diffusion was investigated by measuring the transport of a series of compounds with
different physicochemical properties. A ratio of 2.8 was observed when comparing the
permeabilities of the compounds with the highest and the lowest diffusion rate. The
passive permeability of sucrose could be reduced significantly by replacing fetal calf
serum with human serum. Furthermore, quantitative mRNA expression of the ABCtransporters
P-gp, BCRP, MRP1, MRP2, MRP3, MRP4, MRP5 as well as the human
transferrin receptor (hTfR) was shown. Protein expression of P-gp, BCRP and the hTfR
was detected and functional activity of P-gp, BCRP and the MRPs was investigated in
efflux experiments. Furthermore, bidirectional P-gp transport activity was observed.
In a second project the impact of endo- and exogenous factors on the paracellular
permeability of hCMEC/D3 monolayers was assessed, since it is know that the molecular
assembly of tight junctions depends on the surrounding milieu (section Error! Reference
source not found.). Based on reports in the literature, the cells were incubated with a
variety of compounds that included anti-inflammatory drugs, growth factors and
antioxidants. The effects on the monolayer tightness of hCMEC/D3 were investigated by
measuring the transport of sucrose, a paracellular permeability marker. N-acetylcystein
(NAC), atorvastatin and sodium nitroprusside (SNP) reduced the sucrose permeability
significantly, and slightly increased zonula occludens protein (ZO-1) expression.
Additionally, NAC and SNP reduced the generation of reactive oxygen species (ROS),
which have been reported to disrupt the assembly of tight junctions.
The effect of the pro-inflammatory cytokines IL-1[beta], IL-6 and TNF-[alpha] on the expression and
activity of the ABC-transporters BCRP and P-gp was investigated in the hCMEC/D3 cell
line (section Error! Reference source not found.). IL-1[beta], IL-6 and TNF-[alpha], which are
know to be elevated during various diseases, suppressed significantly BCRP mRNA
expression. In addition, BCRP activity was reduced under the influence of all tested
cytokines, as shown by efflux experiments. P-gp mRNA levels were slightly reduced by
IL-6 but significantly increased after TNF-[alpha] treatment. TNF-[alpha] also increased the protein
expression of P-gp. This in vitro study indicates that expression levels of BCRP and P-gp
at the BBB might be altered during acute or chronic inflammation, resulting in a changed
brain penetration of their substrates.
In an isolated project, the pharmacokinetics and pharmacodynamics of increasing oral
doses of the satiety peptides GLP-1 and PYY3-36 were assessed in healthy male
volunteers. Oral administration of either peptide induced a rapid and dose-dependent
increase in plasma drug concentrations. Oral administration of GLP-1 induced a potent
effect on insulin release and both peptides suppressed ghrelin secretion. In conclusion,
this study showed, for the first time, that satiety peptides such as GLP-1 and PYY3-36
can be orally delivered safely and effectively in humans
GLP-1 metabolite GLP-1(9-36) is a systemic inhibitor of mouse and human pancreatic islet glucagon secretion
No full textDiabetes mellitus is associated with impaired insulin secretion, often aggravated by oversecretion of glucagon. Therapeutic interventions should ideally correct both defects. Glucagon-like peptide 1 (GLP-1) has this capability but exactly how it exerts its glucagonostatic effect remains obscure. Following its release GLP-1 is rapidly degraded from GLP-1(7-36) to GLP-1(9-36). We hypothesised that the metabolite GLP-1(9-36) (previously believed to be biologically inactive) exerts a direct inhibitory effect on glucagon secretion and that this mechanism becomes impaired in diabetes. We used a combination of glucagon secretion measurements in mouse and human islets (including islets from donors with type 2 diabetes), total internal reflection fluorescence microscopy imaging of secretory granule dynamics, recordings of cytoplasmic Ca and measurements of protein kinase A activity, immunocytochemistry, in vivo physiology and GTP-binding protein dissociation studies to explore how GLP-1 exerts its inhibitory effect on glucagon secretion and the role of the metabolite GLP-1(9-36). GLP-1(7-36) inhibited glucagon secretion in isolated islets with an IC of 2.5 pmol/l. The effect was particularly strong at low glucose concentrations. The degradation product GLP-1(9-36) shared this capacity. GLP-1(9-36) retained its glucagonostatic effects after genetic/pharmacological inactivation of the GLP-1 receptor. GLP-1(9-36) also potently inhibited glucagon secretion evoked by β-adrenergic stimulation, amino acids and membrane depolarisation. In islet alpha cells, GLP-1(9-36) led to inhibition of Ca entry via voltage-gated Ca channels sensitive to ω-agatoxin, with consequential pertussis-toxin-sensitive depletion of the docked pool of secretory granules, effects that were prevented by the glucagon receptor antagonists REMD2.59 and L-168049. The capacity of GLP-1(9-36) to inhibit glucagon secretion and reduce the number of docked granules was lost in alpha cells from human donors with type 2 diabetes. In vivo, high exogenous concentrations of GLP-1(9-36) (>100 pmol/l) resulted in a small (30%) lowering of circulating glucagon during insulin-induced hypoglycaemia. This effect was abolished by REMD2.59, which promptly increased circulating glucagon by >225% (adjusted for the change in plasma glucose) without affecting pancreatic glucagon content. We conclude that the GLP-1 metabolite GLP-1(9-36) is a systemic inhibitor of glucagon secretion. We propose that the increase in circulating glucagon observed following genetic/pharmacological inactivation of glucagon signalling in mice and in people with type 2 diabetes reflects the removal of GLP-1(9-36)'s glucagonostatic action. [Abstract copyright: © 2023. The Author(s).
GLP-1 and estrogen conjugate acts in the supramammillary nucleus to reduce food-reward and body weight
No full textAbstractThe obesity epidemic continues unabated and currently available pharmacological treatments are not sufficiently effective. Combining gut/brain peptide, GLP-1, with estrogen into a conjugate may represent a novel, safe and potent, strategy to treat diabesity. Here we demonstrate that the central administration of GLP-1-estrogen conjugate reduced food reward, food intake, and body weight in rats. In order to determine the brain location of the interaction of GLP-1 with estrogen, we avail of single-photon emission computed tomography imaging of regional cerebral blood flow and pinpoint a brain site unexplored for its role in feeding and reward, the supramammillary nucleus (SUM) as a potential target of the conjugated GLP-1-estrogen. We confirm that conjugated GLP-1 and estrogen directly target the SUM with site-specific microinjections. Additional microinjections of GLP-1-estrogen into classic energy balance controlling nuclei, the lateral hypothalamus (LH) and the nucleus of the solitary tract (NTS) revealed that the metabolic benefits resulting from GLP-1-estrogen injections are mediated through the LH and to some extent by the NTS. In contrast, no additional benefit of the conjugate was noted on food reward when the compound was microinjected into the LH or the NTS, identifying the SUM as the only neural substrate identified here to underlie the reward reducing benefits of GLP-1 and estrogen conjugate. Collectively we discover a surprising neural substrate underlying food intake and reward effects of GLP-1 and estrogen and uncover a new brain area capable of regulating energy balance and reward
Trp-Tyr is a dipeptide structure that potently stimulates GLP-1 secretion in a murine enteroendocrine cell model, identified by comprehensive analysis
No full textDietary peptides potently stimulate glucagon-like peptide-1 (GLP-1) secretion, however, the underlying molecular mechanisms, such as structure-activity relationships and sensing mechanisms are only partly elucidated. In this study, we used a dipeptide library to identify dipeptides that potently stimulate GLP-1 release and to clarify the underlying structure-activity relationship. Murine enteroendocrine GLUTag cells were exposed to 339 dipeptides for 60 min, and the concen-tration of GLP-1 released into the supernatant was measured. Subsequently, selected dipeptides were examined for their reproducibility and dose responsiveness. In addition, we investigated the role of constituent amino acids in the secretion of GLP-1, and whether tripeptides containing the active dipeptide structures maintained their activity. In a concentration range of 1-5 mg/mL, twelve dipeptides had reproducible and concentration-dependent GLP-1-releasing activity. Among them, nine dipeptides (FY, KF, NI, PM, QL, QY, WF, WN, WY) were novel, with WY exhibiting the most potent activity. The reverse sequences and most free amino acids did not induce GLP-1 secretion, indicating that GLP-1-producing cells recognize the struc-ture of each peptide to induce GLP-1 secretion. However, no apparent similarities were found between the active peptides. A comparison between the six tripeptides composed of F, W, and Y revealed the further potent tripeptides FWY and WYF, than WY. In the present study, a comprehensive analysis revealed nine novel dipeptides with high potential to stimulate GLP-1 secretion. Furthermore, the results indicate that 'WY' is a specific dipeptide sequence that potently stimulates GLP-1 secretion. & COPY; 2023 Elsevier Inc. All rights reserved
GLP-1 RA Treatment Patterns Among Type 2 Diabetes Patients in Five European Countries
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GLP-1 Receptor Agonists for Type 2 Diabetes and Their Role in Primary Care: An Australian Perspective
No full textProvide enhanced digital features for this article
If you are an author of this publication and would like to provide additional
enhanced digital features for your article then please contact [email protected].
The journal offers a range of additional features designed to increase
visibility and readership. All features will be thoroughly peer reviewed to
ensure the content is of the highest scientific standard and all features are
marked as ‘peer reviewed’ to ensure readers are aware that the content has been
reviewed to the same level as the articles they are being presented alongside.
Moreover, all sponsorship and disclosure information is included to provide
complete transparency and adherence to good publication practices. This ensures
that however the content is reached the reader has a full understanding of its
origin. No fees are charged for hosting additional open access content.
Other enhanced features include, but are not limited to:
• Slide decks
• Videos and animations
• Audio abstracts
• Audio slides</p
Oral Administration of Corn Zein Hydrolysate Stimulates GLP-1 and GIP Secretion and Improves Glucose Tolerance in Male Normal Rats and Goto-Kakizaki Rats
No full textWe have previously demonstrated that ileal administration of the dietary protein hydrolysate prepared from corn zein (ZeinH) stimulated glucagon-like peptide-1 (GLP-1) secretion and attenuated hyperglycemia in rats. In this study, to examine whether oral administration of ZeinH improves glucose tolerance by stimulating GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) secretion, glucose tolerance tests were performed in normal Sprague-Dawley male rats and diabetic Goto-Kakizaki (GK) male rats. The test solution was gavaged before ip glucose injection in normal rats or gavaged together with glucose in GK rats. Blood samples were collected from the tail vein or by using the jugular catheter to measure glucose, insulin, GLP-1, and GIP levels. In the ip glucose tolerance test, oral administration of ZeinH (2 g/kg) significantly suppressed the glycemic response accompanied by an immediate increase in plasma GLP-1 and GIP levels in normal rats. In contrast, oral administration of another dietary peptide, meat hydrolysate, did not elicit a similar effect. The glucose-lowering effect of ZeinH was attenuated by a GLP-1 receptor antagonist or by a GIP receptor antagonist. Furthermore, oral ZeinH induced GLP-1 secretion and reduced glycemic response in GK rats under the oral glucose tolerance test. These results indicate that the oral administration of the dietary peptide ZeinH improves glucose tolerance in normal and diabetic rats by its incretin-releasing activity, namely, the incretinotropic effect
GLP-1 receptor stimulation depresses heart rate variability and inhibits neurotransmission to cardiac vagal neurons
No full textAims Glucagon-like peptide 1 (GLP-1) is an incretin hormone released from the gut in response to food intake. Whereas GLP-1 acts in the periphery to inhibit glucagon secretion and stimulate insulin release, it also acts in the central nervous system to mediate autonomic control of feeding, body temperature, and cardiovascular function. Because of its role as an incretin hormone, GLP-1 receptor analogs are used as a treatment for type 2 diabetes. Central or peripheral administration of GLP-1 increases blood pressure and heart rate, possibly by activating brainstem autonomic nuclei and increasing vagus nerve activity. However, the mechanism(s) by which GLP-1 receptor stimulation affects cardiovascular function are unknown. We used the long-lasting GLP-1 receptor agonist Exendin-4 (Ex-4) to test the hypothesis that GLP-1 signalling modulates central parasympathetic control of heart rate.Methods and results Using a telemetry system, we assessed heart rate in mice during central Ex-4 administration. Heart rate was increased by both acute and chronic central Ex-4 administration. Spectral analysis indicated that the high frequency and low frequency powers of heart rate variability were diminished by Ex-4 treatment. Finally, Ex-4 decreased both excitatory glutamatergic and inhibitory glycinergic neurotransmission to preganglionic parasympathetic cardiac vagal neurons. Conclusion These data suggest that central GLP-1 receptor stimulation diminishes parasympathetic modulation of the heart thereby increasing heart rate. © 2010 The Author
GLP-1 receptor agonists—another promising therapy for Alport syndrome?
No full text\ua9 The Author(s) 2025. Alport syndrome (AS) is a progressive monogenic glomerular kidney disease characterised by kidney function decline, hearing loss, and ocular abnormalities, often leading to early-onset kidney failure (KF). While current therapies, such as renin-angiotensin system inhibitors (RASi), offer some benefits, many patients still experience KF at a young age, highlighting the need for additional treatment options. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as promising agents with demonstrated cardiovascular and nephroprotective effects in type 2 diabetes (T2D) and chronic kidney disease (CKD) patients. Evidence from several major clinical trials has shown that GLP-1 RAs can reduce cardiovascular events and slow CKD progression by reducing albuminuria. Their potential mechanisms of action include anti-inflammatory, anti-fibrotic, and antioxidative effects, making them particularly relevant for the treatment of AS, where inflammation and fibrosis play crucial roles in disease progression. This review explores the therapeutic potential of GLP-1 RAs in AS, summarising pre-clinical and clinical data and elucidating the pathways through which GLP-1 RAs might offer renoprotective benefits. We advocate for further research into their application in AS and recommend the inclusion of AS patients in future clinical trials to better understand their impact on disease progression and patient outcomes
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