scholarly journals Revisiting the complexity of GLP-1 action-from sites of synthesis to receptor activation

2020 ◽  
Author(s):  
Brent A McLean ◽  
Chi Kin Wong ◽  
Jonathan E Campbell ◽  
David J Hodson ◽  
Stefan Trapp ◽  
...  
Keyword(s):  
Cellular Localization ◽  
Hormone Secretion ◽  
Cell Types ◽  
Receptor Activation ◽  
Neural Pathways ◽  
Cellular Targets ◽  
Multiple Organs ◽  
Islet Hormone ◽  
Glucagon Like Peptide 1 ◽  
Gut Endocrine Cells

Abstract Glucagon-like peptide-1 (GLP-1) is produced in gut endocrine cells and in the brain, and acts through hormonal and neural pathways to regulate islet function, satiety, and gut motility, supporting development of GLP-1 receptor (GLP-1R) agonists for the treatment of diabetes and obesity. Classic notions of GLP-1 acting as a meal-stimulated hormone from the distal gut are challenged by data supporting production of GLP-1 in the endocrine pancreas, and by the importance of brain-derived GLP-1 in the control of neural activity. Moreover, attribution of direct vs. indirect actions of GLP-1 is difficult, as many tissue and cellular targets of GLP-1 action do not exhibit robust or detectable GLP-1R expression. Furthermore, reliable detection of the GLP-1R is technically challenging, highly method-dependent, and subject to misinterpretation. Here we revisit the actions of GLP-1, scrutinizing key concepts supporting gut vs. extra-intestinal GLP-1 synthesis and secretion. We discuss new insights refining cellular localization of GLP-1R expression and integrate recent data to refine our understanding of how and where GLP-1 acts to control inflammation, cardiovascular function, islet hormone secretion, gastric emptying, appetite, and body weight. These findings update our knowledge of cell types and mechanisms linking endogenous vs. pharmacological GLP-1 action to activation of the canonical GLP-1R, and the control of metabolic activity in multiple organs.

Intra-islet regulation of hormone secretion by glucagon-like peptide-1-(7--36) amide

1995 ◽  
Vol 269 (6) ◽  
pp. G852-G860 ◽  
Author(s):  
R. S. Heller ◽  
G. W. Aponte
Keyword(s):  
Monoclonal Antibodies ◽  
Insulin Secretion ◽  
Hormone Secretion ◽  
Glucagon Secretion ◽  
Posttranslational Processing ◽  
Alpha Cells ◽  
Islet Hormone ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Peptide Product

Glucagon-like peptide (GLP)-1-(7--36) amide, a peptide product of the posttranslational processing of pancreatic and intestinal proglucagon, has been shown to regulate insulin secretion. Monoclonal antibodies to glucagon and GLP-1-(7--36) amide were generated to localize GLP-1-(7--36) amide in the pancreatic islets by immunocytochemistry and radioimmunoassay. GLP-1-(7--36) amide immunoreactivity was found in some, but not all, glucagon-containing alpha-cells. Displaceable receptor binding for GLP-1-(7--36) amide and nonamidated GLP-1-(7--37) on hormone secretion were investigated using isolated pancreatic islet preparations. GLP-1-(7--37) and -(7--36) amide significantly increased insulin and somatostatin release in the concentration range of 0.01-100 nM in 11.0 mM glucose. GLP-1-(7--37) and -(7--36) amide had no effect on glucagon secretion in the presence of 11.0 mM glucose. GLP-1-(7--36) amide was released from isolated islets in response to 2.25, 5.5, and 11.0 mM glucose. These results suggest that pancreatic GLP-1 may be important in the regulation of intra-islet hormone secretion.

scholarly journals Upregulated insulin secretion in insulin-resistant mice: evidence of increased islet GLP1 receptor levels and GPR119-activated GLP1 secretion

2013 ◽  
Vol 2 (2) ◽  
pp. 69-78 ◽  
Author(s):  
L Ahlkvist ◽  
K Brown ◽  
B Ahrén
Keyword(s):  
Cell Function ◽  
Hormone Secretion ◽  
Glucagon Secretion ◽  
Β Cell ◽  
Insulin Resistant ◽  
Protein Levels ◽  
Islet Hormone ◽  
Β Cell Function ◽  
Glucagon Like Peptide 1 ◽  
Insulin Responses

We previously demonstrated that the overall incretin effect and the β-cell responsiveness to glucagon-like peptide-1 (GLP1) are increased in insulin-resistant mice and may contribute to the upregulated β-cell function. Now we examined whether this could, first, be explained by increased islet GLP1 receptor (GLP1R) protein levels and, secondly, be leveraged by G-protein-coupled receptor 119 (GPR119) activation, which stimulates GLP1 secretion. Female C57BL/6J mice, fed a control (CD, 10% fat) or high-fat (HFD, 60% fat) diet for 8 weeks, were anesthetized and orally given a GPR119 receptor agonist (GSK706A; 10 mg/kg) or vehicle, followed after 10 min with gavage with a liquid mixed meal (0.285 kcal). Blood was sampled for determination of glucose, insulin, intact GLP1, and glucagon, and islets were isolated for studies on insulin and glucagon secretion and GLP1R protein levels. In HFD vs CD mice, GPR119 activation augmented the meal-induced increase in the release of both GLP1 (AUCGLP1 81±9.6 vs 37±6.9 pM×min, P=0.002) and insulin (AUCINS 253±29 vs 112±19 nM×min, P<0.001). GPR119 activation also significantly increased glucagon levels in both groups (P<0.01) with, however, no difference between the groups. By contrast, GPR119 activation did not affect islet hormone secretion from isolated islets. Glucose elimination after meal ingestion was significantly increased by GPR119 activation in HFD mice (0.57±0.04 vs 0.43±0.03% per min, P=0.014) but not in control mice. Islet GLP1R protein levels was higher in HFD vs CD mice (0.8±0.1 vs 0.5±0.1, P=0.035). In conclusion, insulin-resistant mice display increased islet GLP1R protein levels and augmented meal-induced GLP1 and insulin responses to GPR119 activation, which results in increased glucose elimination. We suggest that the increased islet GLP1R protein levels together with the increased GLP1 release may contribute to the upregulated β-cell function in insulin resistance.

Suppression of glucose production by GLP-1 independent of islet hormones: a novel extrapancreatic effect

2003 ◽  
Vol 285 (4) ◽  
pp. E701-E707 ◽  
Author(s):  
Ronald L. Prigeon ◽  
Shaista Quddusi ◽  
Breay Paty ◽  
David A. D'Alessio
Keyword(s):  
Plasma Glucose ◽  
Hormone Secretion ◽  
Glucose Production ◽  
Preliminary Evidence ◽  
Endogenous Glucose Production ◽  
Glucose Disposal ◽  
Islet Hormones ◽  
Islet Hormone ◽  
Endogenous Glucose ◽  
Glucagon Like Peptide 1

Glucagon-like peptide-1 (GLP-1) is an intestinal hormone that stimulates insulin secretion and decreases glucagon release. It has been hypothesized that GLP-1 also reduces glycemia independent of its effect on islet hormones. Based on preliminary evidence that GLP-1 has independent actions on endogenous glucose production, we undertook a series of experiments that were optimized to address this question. The effect of GLP-1 on glucose appearance (Ra) and glucose disposal (Rd) was measured in eight men during a pancreatic clamp that was performed by infusing octreotide to suppress secretion of islet hormones, while insulin and glucagon were infused at rates adjusted to maintain blood glucose near fasting levels. After stabilization of plasma glucose and equilibration of [3H]glucose tracer, GLP-1 was given intravenously for 60 min. Concentrations of insulin, C-peptide, and glucagon were similar before and during the GLP-1 infusion (115 ± 14 vs. 113 ± 11 pM; 0.153 ± 0.029 vs. 0.156 ± 0.026 nM; and 64.7 ± 11.5 vs. 65.8 ± 13.8 ng/l, respectively). With the initiation of GLP-1, plasma glucose decreased in all eight subjects from steady-state levels of 4.8 ± 0.2 to a nadir of 4.1 ± 0.2 mM. This decrease in plasma glucose was accounted for by a significant 17% decrease in Ra, from 22.6 ± 2.8 to 19.1 ± 2.8 μmol · kg–1 · min–1 ( P < 0.04), with no significant change in Rd. These findings indicate that, under fasting conditions, GLP-1 decreases endogenous glucose production independent of its actions on islet hormone secretion.

scholarly journals Dipeptidyl Peptidase-4 at the Interface Between Inflammation and Metabolism

2020 ◽  
Vol 13 ◽  
pp. 117955142091297 ◽  
Author(s):  
Natasha A Trzaskalski ◽  
Evgenia Fadzeyeva ◽  
Erin E Mulvihill
Keyword(s):  
Protein Interactions ◽  
Hormone Secretion ◽  
Dipeptidyl Peptidase ◽  
Protein Protein Interactions ◽  
Nonalcoholic Fatty Liver ◽  
Dipeptidyl Peptidase 4 ◽  
Metabolic Dysregulation ◽  
Islet Hormone ◽  
Glucagon Like Peptide 1

Dipeptidyl peptidase-4 (DPP4) is a serine protease that rapidly inactivates the incretin peptides, glucagon-like peptide-1, and glucose-dependent insulinotropic polypeptide to modulate postprandial islet hormone secretion and glycemia. Dipeptidyl peptidase-4 also has nonglycemic effects by controlling the progression of inflammation, which may be mediated more through direct protein-protein interactions than catalytic activity in the context of nonalcoholic fatty liver disease (NAFLD), obesity, and type 2 diabetes (T2D). Failure to resolve inflammation resulting in chronic subclinical activation of the immune system may influence the development of metabolic dysregulation. Thus, through both its cleavage and regulation of the bioactivity of peptide hormones and its influence on inflammation, DPP4 exhibits a diverse array of effects that can influence the progression of metabolic disease. Here, we highlight our current understanding of the complex biology of DPP4 at the intersection of inflammation, obesity, T2D, and NAFLD. We compare and review new mechanisms identified in basic laboratory and clinical studies, which may have therapeutic application and relevance to the pathogenesis of obesity and T2D.

scholarly journals Glyoxal Does Not Preserve Cellular Proteins as Accurately as PFA: A Microscopical Survey of Epitopes

2019 ◽  
Author(s):  
Ferda Topal Celikkan ◽  
Ceren Mungan ◽  
Merve Sucu ◽  
Fatma Uysal ◽  
Selda Kahveci ◽  
...  
Keyword(s):  
Cellular Localization ◽  
Super Resolution ◽  
Cell Types ◽  
Cellular Proteins ◽  
Human Stem Cells ◽  
Cellular Targets ◽  
Molecular Alterations ◽  
Recent Developments ◽  
Spatio Temporal ◽  
Fixed Cell

AbstractChemical fixation is one of the most critical steps to retaining cellular targets as naturally as possible. Recent developments in microscopy allow sophisticated detection and measuring techniques with which spatio-temporal molecular alterations is conceivable. Here, we document the fixation competence of glyoxal (Gly), a less-toxic dialdehyde molecule, and paraformaldehyde (PFA) side-by-side (with or without Triton-X 100 permealization) in live- and fixed-cell preparations including human stem cells, spermatozoa, mouse oocytes/embryos using super-resolution microscopy. Although Gly seemed to act faster than PFA, catastrophic consequences were found not acceptable, especially in oocytes and embryos. Due to cell lysate and immunocytochemistry surveys, it was obvious that PFA is superior to Gly in retaining cellular proteins in situ with little/no background staining. In many samples, PFA revealed more reliable and consistent results regarding the protein quantity and cellular localization corresponding to previously defined patterns in the literature. Although the use of Gly is beneficial as indicated by previous reports, we concluded that it does not meet the requirement for proper fixation, at least for the tested cell types and proteins.

Glucagon-Like Peptide 1 Shows Glucose Dependence in Regulating Islet Hormone Secretion

Metabolism ◽  
2020 ◽  
Vol 104 ◽  
pp. 154069
Author(s):  
Naveena R. Daram ◽  
Kelli L. Jordan ◽  
Prasanna K. Dadi ◽  
Lawrence Berry ◽  
David A. Jacobson
Keyword(s):  
Hormone Secretion ◽  
Islet Hormone ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Glucose Dependence

scholarly journals Contribution of Ionotropic Glutamatergic Receptors to Excitability and Attentional Signals in Macaque Frontal Eye Field

2021 ◽  
Author(s):  
Miguel Dasilva ◽  
Christian Brandt ◽  
Marc Alwin Gieselmann ◽  
Claudia Distler ◽  
Alexander Thiele
Keyword(s):  
Attentional Control ◽  
Large Scale ◽  
Neuronal Excitability ◽  
Cell Types ◽  
Receptor Activation ◽  
Frontal Eye Field ◽  
Control Signals ◽  
Cognitive Operations ◽  
Eye Field ◽  
Large Scale Networks

Abstract Top-down attention, controlled by frontal cortical areas, is a key component of cognitive operations. How different neurotransmitters and neuromodulators flexibly change the cellular and network interactions with attention demands remains poorly understood. While acetylcholine and dopamine are critically involved, glutamatergic receptors have been proposed to play important roles. To understand their contribution to attentional signals, we investigated how ionotropic glutamatergic receptors in the frontal eye field (FEF) of male macaques contribute to neuronal excitability and attentional control signals in different cell types. Broad-spiking and narrow-spiking cells both required N-methyl-D-aspartic acid and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor activation for normal excitability, thereby affecting ongoing or stimulus-driven activity. However, attentional control signals were not dependent on either glutamatergic receptor type in broad- or narrow-spiking cells. A further subdivision of cell types into different functional types using cluster-analysis based on spike waveforms and spiking characteristics did not change the conclusions. This can be explained by a model where local blockade of specific ionotropic receptors is compensated by cell embedding in large-scale networks. It sets the glutamatergic system apart from the cholinergic system in FEF and demonstrates that a reduction in excitability is not sufficient to induce a reduction in attentional control signals.

scholarly journals Targeting the GPR119/incretin axis: a promising new therapy for metabolic-associated fatty liver disease

2021 ◽  
Vol 26 (1) ◽  
Author(s):  
Jianan Zhao ◽  
Yu Zhao ◽  
Yiyang Hu ◽  
Jinghua Peng
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Drug Targets ◽  
Metabolic Dysfunction ◽  
Multiple Organs ◽  
Glucose And Lipid Metabolism ◽  
Potential Therapeutic Role ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

AbstractIn the past decade, G protein-coupled receptors have emerged as drug targets, and their physiological and pathological effects have been extensively studied. Among these receptors, GPR119 is expressed in multiple organs, including the liver. It can be activated by a variety of endogenous and exogenous ligands. After GPR119 is activated, the cell secretes a variety of incretins, including glucagon-like peptide-1 and glucagon-like peptide-2, which may attenuate the metabolic dysfunction associated with fatty liver disease, including improving glucose and lipid metabolism, inhibiting inflammation, reducing appetite, and regulating the intestinal microbial system. GPR119 has been a potential therapeutic target for diabetes mellitus type 2 for many years, but its role in metabolic dysfunction associated fatty liver disease deserves further attention. In this review, we discuss relevant research and current progress in the physiology and pharmacology of the GPR119/incretin axis and speculate on the potential therapeutic role of this axis in metabolic dysfunction associated with fatty liver disease, which provides guidance for transforming experimental research into clinical applications.

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