The role of efferent cholinergic transmission for the insulinotropic and glucagonostatic effects of GLP-1

2015 ◽  
Vol 309 (5) ◽  
pp. R544-R551 ◽  
Author(s):  
Astrid Plamboeck ◽  
Simon Veedfald ◽  
Carolyn F. Deacon ◽  
Bolette Hartmann ◽  
Tina Vilsbøll ◽  
...  
Keyword(s):  
Area Under The Curve ◽  
Glucagon Secretion ◽  
Glucose Turnover ◽  
High Dose ◽  
Cholinergic Transmission ◽  
Blinded Study ◽  
Muscarinic Cholinergic ◽  
Glucagon Like Peptide 1 ◽  
Insulinotropic Effect

The importance of vagal efferent signaling for the insulinotropic and glucagonostatic effects of glucagon-like peptide-1 (GLP-1) was investigated in a randomized single-blinded study. Healthy male participants ( n = 10) received atropine to block vagal cholinergic transmission or saline infusions on separate occasions. At t = 15 min, plasma glucose was clamped at 6 mmol/l. GLP-1 was infused at a low dose (0.3 pmol·kg−1·min−1) from t = 45–95 min and at a higher dose (1 pmol·kg−1·min−1) from t = 95–145 min. Atropine blocked muscarinic, cholinergic transmission, as evidenced by an increase in heart rate [peak: 70 ± 2 (saline) vs. 90 ± 2 (atropine) beats/min, P < 0.002] and suppression of pancreatic polypeptide levels [area under the curve during the GLP-1 infusions (AUC45–145): 492 ± 85 (saline) vs. 247 ± 59 (atropine) pmol/l × min, P < 0.0001]. More glucose was needed to maintain the clamp during the high-dose GLP-1 infusion steady-state period on the atropine day [6.4 ± 0.9 (saline) vs. 8.7 ± 0.8 (atropine) mg·kg−1·min−1, P < 0.0023]. GLP-1 dose-dependently increased insulin secretion on both days. The insulinotropic effect of GLP-1 was not impaired by atropine [C-peptide AUCs45–145: 99 ± 8 (saline) vs. 113 ± 13 (atropine) nmol/l × min, P = 0.19]. Atropine suppressed glucagon levels additively with GLP-1 [AUC45–145: 469 ± 70 (saline) vs. 265 ± 50 (atropine) pmol/l × min, P = 0.018], resulting in hypoglycemia when infusions were suspended [3.6 ± 0.2 (saline) vs. 2.7 ± 0.2 (atropine) mmol/l, P < 0.0001]. To ascertain whether atropine could independently suppress glucagon levels, control experiments ( n = 5) were carried out without GLP-1 infusions [AUC45–145: 558 ± 103 (saline) vs. 382 ± 76 (atropine) pmol/l × min, P = 0.06]. Our results suggest that efferent muscarinic activity is not required for the insulinotropic effect of exogenous GLP-1 but that blocking efferent muscarinic activity independently suppresses glucagon secretion. In combination, GLP-1 and muscarinic blockade strongly affect glucose turnover.

Role of Muscarinic Cholinergic Transmission in Edinger-Westphal Nucleus-induced Choroidal Vasodilation in Pigeon

2000 ◽  
Vol 70 (3) ◽  
pp. 315-327 ◽  
Author(s):  
YURI ZAGVAZDIN ◽  
MALINDA E.C. FITZGERALD ◽  
ANTON REINER
Keyword(s):  
Cholinergic Transmission ◽  
Muscarinic Cholinergic ◽  
Edinger Westphal Nucleus

scholarly journals An Emerging Role of Glucagon-Like Peptide-1 in Preventing Advanced-Glycation-End-Product-Mediated Damages in Diabetes

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Alessandra Puddu ◽  
François Mach ◽  
Alessio Nencioni ◽  
Giorgio Luciano Viviani ◽  
Fabrizio Montecucco
Keyword(s):  
Type 2 Diabetes ◽  
Cell Function ◽  
Glucagon Secretion ◽  
Advanced Glycation ◽  
Chronic Hyperglycemia ◽  
Gut Hormone ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Glucagon-like peptide-1 (GLP-1) is a gut hormone produced in the intestinal epithelial endocrine L cells by differential processing of the proglucagon gene. Released in response to the nutrient ingestion, GLP-1 plays an important role in maintaining glucose homeostasis. GLP-1 has been shown to regulate blood glucose levels by stimulating glucose-dependent insulin secretion and inhibiting glucagon secretion, gastric emptying, and food intake. These antidiabetic activities highlight GLP-1 as a potential therapeutic molecule in the clinical management of type 2 diabetes, (a disease characterized by progressive decline of beta-cell function and mass, increased insulin resistance, and final hyperglycemia). Since chronic hyperglycemia contributed to the acceleration of the formation of Advanced Glycation End-Products (AGEs, a heterogeneous group of compounds derived from the nonenzymatic reaction of reducing sugars with free amino groups of proteins implicated in vascular diabetic complications), the administration of GLP-1 might directly counteract diabetes pathophysiological processes (such as pancreaticβ-cell dysfunction). This paper outlines evidence on the protective role of GLP-1 in preventing the deleterious effects mediated by AGEs in type 2 diabetes.

scholarly journals Role of Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists in Hypoglycemia

2021 ◽  
Vol 14 ◽  
pp. 117955142110516
Author(s):  
Daria Ja’arah ◽  
Mazhar Salim Al Zoubi ◽  
Gamal Abdelhady ◽  
Firas Rabi ◽  
Murtaza M Tambuwala
Keyword(s):  
Glucagon Secretion ◽  
Dependent Manner ◽  
Incretin Mimetics ◽  
Receptor Agonists ◽  
Potential Safety ◽  
Recent Addition ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

A relatively recent addition to the arsenal of antidiabetic drugs used for the treatment of type 2 diabetes mellitus (T2DM) has been the “incretin mimetics,” a group of drugs that work on the glucagon-like peptide-1 (GLP-1) receptor and enhance insulin secretion from the pancreatic β-cells in a glucose-dependent manner, more potently in hyperglycemic conditions, while suppressing glucagon secretion at the same time. Therefore, it was assumed that this class of drugs would have a lower risk of hypoglycemia than insulin secretagogues like sulphonylureas. However, GLP-1 receptor agonists have been proposed to cause hypoglycemia in healthy normoglycemic subjects implying that their action is not as glucose-dependent as once thought. Other studies concluded that they might not induce hypoglycemia and the risk is dependent on other individual factors. However, the FDA announced that the 12 GLP-1 receptor agonists currently available on the market had potential safety signs and evaluated the need for regulatory action. This review provides an overview of the studies that investigated the possible hypoglycemic effect of GLP-1 receptor agonists. In addition, the current review describes other adverse effects of GLP-1 receptor agonist treatment.

Pre-emptive Analgesia for Postoperative Pain Relief in Children – Role of Paracetamol

2009 ◽  
pp. 9-16
Author(s):  
Rubina Yasmin ◽  
AKM Akhtaruzzaman ◽  
Paresh Chandra Sarker ◽  
Neaz Ahmed ◽  
Ranadhir Kumar Kundu ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Postoperative Pain ◽  
Diclofenac Sodium ◽  
Total Duration ◽  
Pain Scale ◽  
Prospective Clinical Study ◽  
High Dose ◽  
Induction Of Anaesthesia

This prospective clinical study was carried out in the Dept. of Anaesthesia, Analgesia and Intensive Care Medicine, BSMMU, Dhaka, during the period of May 2003 to July 2003. The study was done to emphasize the importance of giving analgesics preemptively instead of waiting for the child to complain of pain and to produce smooth recovery after surgery by decreasing immediate postoperative pain in children by a simple, safe acceptable drug. The children scheduled for tonsillectomy under general anaesthesia were recruited in this study. The analgesic efficiency of rectal paracetamol in two doses, 25 mg/kg bodywt.(Gr-P25) and 50 mg/kg. bodywt. (Gr-P50) were compared with Diclofenac Sodium suppository 1mg/ kg body weight (Gr-D) given half an hour before induction of anaesthesia. Pain scoring was done by TPPPS (Toddler Pre-schooler postoperative pain scale). Heart rate and blood pressure were stable in Gr-P50 and Gr-D. Time of first demand of analgesic was delayed in Gr-P50 and Gr-D. Total paracetamol consumption in 24 hours was less in Gr-P50(181±14.25) and Gr-D (212±25) than Gr-P25(318± 26.39). Total duration of analgesia in Gr- P50 (657±9.94) mins. and in Gr- D(502±10.63) mins. and in Gr-P25(288±23.17) mins. Pre-emptive high dose rectal paracetamol appears to be more effective than diclofenac sodium suppository for postoperative analgesia in children undergoing tonsillectomy. Journal of BSA, Vol. 18, No. 1 & 2, 2005 p.9-16

The Role of GLP-1 Receptor Expressed in Pancreatic a Cells in Regulating Glucagon Secretion

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 355-OR ◽  
Author(s):  
YANQING ZHANG ◽  
KESHAB R. PARAJULI ◽  
GENEVIEVE E. SMITH ◽  
RAJESH GUPTA ◽  
WEIWEI XU ◽  
...  
Keyword(s):  
Glucagon Secretion ◽  
A Cells

Bioinformatics Analysis and Validation of Differentially Expressed MicroRNAs with Their Target Genes Involved in GLP-1RA Facilitated Osteogenesis

2020 ◽  
Vol 15 ◽  
Author(s):  
Na Wang ◽  
Yukun Li ◽  
Sijing Liu ◽  
Liu Gao ◽  
Chang Liu ◽  
...  
Keyword(s):  
High Throughput Sequencing ◽  
Target Genes ◽  
Bioinformatics Analysis ◽  
Differentially Expressed ◽  
Functional Study ◽  
Regulation Network ◽  
Glucagon Like Peptide 1 ◽  
G Protein Coupled ◽  
Lower Expression

Background: Recent studies revealed that the hypoglycemic hormone, glucagon-like peptide-1 (GLP-1), acted as an important modulator in osteogenesis of bone marrow derived mesenchymal stem cells (BMSCs). Objectives: The aim of this study was to identify the specific microRNA (miRNA) using bioinformatics analysis and validate the presence of differentially expressed microRNAs with their target genes after GLP-1 receptor agonist (GLP-1RA) administration involved in ostogenesis of BMSCs. Methods: MiRNAs were extracted from BMSCs after 5 days’ treatment and sent for high-throughput sequencing for differentially expressed (DE) miRNAs analyses. Then the expression of the DE miRNAs verified by the real-time RT-PCR analyses. Target genes were predicted, and highly enriched GOs and KEGG pathway analysis were conducted using bioinformatics analysis. For the functional study, two of the target genes, SRY (sex determining region Y)-box 5 (SOX5) and G protein-coupled receptor 84 (GPR84), were identified. Results: A total of 5 miRNAs (miRNA-509-5p, miRNA-547-3p, miRNA-201-3p, miRNA-201-5p, and miRNA-novel-272-mature) were identified differentially expressed among groups. The expression of miRNA-novel-272-mature were decreased during the osteogenic differentiation of BMSCs, and GLP-1RA further decreased its expression. MiRNA-novel-272-mature might interact with its target mRNAs to enhance osteogenesis. The lower expression of miRNA-novel-272-mature led to an increase in SOX5 and a decrease in GPR84 mRNA expression, respectively. Conclusions: Taken together, these results provide further insights to the pharmacological properties of GLP-1RA and expand our knowledge on the role of miRNAs-mRNAs regulation network in BMSCs’ differentiation.

Let-7e-5p Regulates GLP-1 Content and Basal Release From Enteroendocrine L Cells From DIO Male Mice

Endocrinology ◽  
2019 ◽  
Vol 161 (2) ◽  
Author(s):  
Sandra Handgraaf ◽  
Rodolphe Dusaulcy ◽  
Florian Visentin ◽  
Jacques Philippe ◽  
Yvan Gosmain
Keyword(s):  
Compensatory Mechanism ◽  
L Cells ◽  
Low Fat Diet ◽  
Obesity And Diabetes ◽  
Basal Release ◽  
Glucagon Like Peptide 1 ◽  
Cell Transcriptome ◽  
Microarray Analyses

Abstract Characterization of enteroendocrine L cells in diabetes is critical for better understanding of the role of glucagon-like peptide-1 (GLP-1) in physiology and diabetes. We studied L-cell transcriptome changes including microRNA (miRNA) dysregulation in obesity and diabetes. We evaluated the regulation of miRNAs through microarray analyses on sorted enteroendocrine L cells from control and obese glucose-intolerant (I-HFD) and hyperglycemic (H-HFD) mice after 16 weeks of respectively low-fat diet (LFD) or high-fat diet (HFD) feeding. The identified altered miRNAs were studied in vitro using the mouse GLUTag cell line to investigate their regulation and potential biological functions. We identified that let-7e-5p, miR-126a-3p, and miR-125a-5p were differentially regulated in L cells of obese HFD mice compared with control LFD mice. While downregulation of let-7e-5p expression was observed in both I-HFD and H-HFD mice, levels of miR-126a-3p increased and of miR-125a-5p decreased significantly only in I-HFD mice compared with controls. Using miRNA inhibitors and mimics we observed that modulation of let-7e-5p expression affected specifically GLP-1 cellular content and basal release, whereas Gcg gene expression and acute GLP-1 secretion and cell proliferation were not affected. In addition, palmitate treatment resulted in a decrease of let-7e-5p expression along with an increase in GLP-1 content and release, suggesting that palmitate acts on GLP-1 through let-7e-5p. By contrast, modulation of miR-125a-5p and miR-126a-3p in the same conditions did not affect content or secretion of GLP-1. We conclude that decrease of let-7e-5p expression in response to palmitate may constitute a compensatory mechanism contributing to maintaining constant glycemia in obese mice.

scholarly journals Using advanced analysis of multifocal visual-evoked potentials to evaluate the risk of clinical progression in patients with radiologically isolated syndrome

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
J. M. Miguel ◽  
M. Roldán ◽  
C. Pérez-Rico ◽  
M. Ortiz ◽  
L. Boquete ◽  
...  
Keyword(s):  
Evoked Potentials ◽  
Visual Evoked Potentials ◽  
Area Under The Curve ◽  
Multifocal Visual Evoked Potentials ◽  
Radiologically Isolated Syndrome ◽  
Advanced Analysis ◽  
The Time Domain ◽  
Visual Evoked

AbstractThis study aimed to assess the role of multifocal visual-evoked potentials (mfVEPs) as a guiding factor for clinical conversion of radiologically isolated syndrome (RIS). We longitudinally followed a cohort of 15 patients diagnosed with RIS. All subjects underwent thorough ophthalmological, neurological and imaging examinations. The mfVEP signals were analysed to obtain features in the time domain (SNRmin: amplitude, Latmax: monocular latency) and in the continuous wavelet transform (CWT) domain (bmax: instant in which the CWT function maximum appears, Nmax: number of CWT function maximums). The best features were used as inputs to a RUSBoost boosting-based sampling algorithm to improve the mfVEP diagnostic performance. Five of the 15 patients developed an objective clinical symptom consistent with an inflammatory demyelinating central nervous system syndrome during follow-up (mean time: 13.40 months). The (SNRmin) variable decreased significantly in the group that converted (2.74 ± 0.92 vs. 4.07 ± 0.95, p = 0.01). Similarly, the (bmax) feature increased significantly in RIS patients who converted (169.44 ± 24.81 vs. 139.03 ± 11.95 (ms), p = 0.02). The area under the curve analysis produced SNRmin and bmax values of 0.92 and 0.88, respectively. These results provide a set of new mfVEP features that can be potentially useful for predicting prognosis in RIS patients.

Possible Role of High-Dose Barbiturates and Early Administration of Parenteral Ketogenic Diet for Reducing Development of Chronic Epilepsy in Febrile Infection-Related Epilepsy Syndrome: A Case Report

2020 ◽  
Author(s):  
Shimpei Baba ◽  
Tohru Okanishi ◽  
Koichi Ohsugi ◽  
Rika Suzumura ◽  
Keiko Niimi ◽  
...  
Keyword(s):  
Continuous Infusion ◽  
Ketogenic Diet ◽  
Epilepsy Syndrome ◽  
High Dose ◽  
Early Administration ◽  
Chronic Epilepsy ◽  
Time Period ◽  
Irreversible Brain Damage ◽  
Electroencephalogram Eeg

AbstractWe describe the efficacy of high-dose barbiturates and early administration of a parenteral ketogenic diet (KD) as initial treatments for acute status epilepticus (SE) in an 8-year-old girl with febrile infection-related epilepsy syndrome (FIRES). The patient was admitted to our hospital with refractory focal SE. Abundant epileptic discharges over the left frontal region were observed on electroencephalogram (EEG). Treatment with continuous infusion of thiamylal for 4 hours, increased incrementally to 40 mg/kg/h, successfully ended the clinical SE, and induced a burst-suppression coma. The infusion rate was then gradually decreased to 4 mg/kg/h over the next 12 hours. Parenteral KD was administered from days 6 to 21 of illness. Continuous infusion of thiamylal was switched to midazolam on day 10 without causing seizures or EEG exacerbations. The patient has remained seizure free in the 15 months since hospital discharge. The effectiveness of KD for the treatment of FIRES has attracted attention amongst clinicians, but KD treatment may need to last for 2 to 4 days before it can stop SE, a time period that could cause irreversible brain damage. Considering the severity of SE in our patient and the dose of barbiturates needed to treat it, we consider this case to have had a good clinical outcome. The results suggest that rapid termination of seizure using high-dose barbiturates in conjunction with early administration of parenteral KD could reduce the development of chronic epilepsy in patients with FIRES.

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