scholarly journals (E)-7-Ethylidene-lithocholic Acid (7-ELCA) Is a Potent Dual Farnesoid X Receptor (FXR) Antagonist and GPBAR1 Agonist Inhibiting FXR-Induced Gene Expression in Hepatocytes and Stimulating Glucagon-like Peptide-1 Secretion From Enteroendocrine Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Alzbeta Stefela ◽  
Miroslav Kaspar ◽  
Martin Drastik ◽  
Thales Kronenberger ◽  
Stanislav Micuda ◽  
...  
Keyword(s):  
Energy Homeostasis ◽  
Lithocholic Acid ◽  
Postprandial Glucose ◽  
Enteroendocrine Cells ◽  
Farnesoid X Receptor ◽  
Synergistic Regulation ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Insulinotropic Effect ◽  
Derivatives Of

Bile acids (BAs) are key signaling steroidal molecules that regulate glucose, lipid, and energy homeostasis via interactions with the farnesoid X receptor (FXR) and G-protein bile acid receptor 1 (GPBAR1). Extensive medicinal chemistry modifications of the BA scaffold led to the discovery of potent selective or dual FXR and GPBAR1 agonists. Herein, we discovered 7-ethylidene-lithocholic acid (7-ELCA) as a novel combined FXR antagonist/GPBAR1 agonist (IC50 = 15 μM/EC50 = 26 nM) with no off-target activation in a library of 7-alkyl substituted derivatives of BAs. 7-ELCA significantly suppressed the effect of the FXR agonist obeticholic acid in BSEP and SHP regulation in human hepatocytes. Importantly, 7-ELCA significantly stimulated the production of glucagon-like peptide-1 (GLP-1), an incretin with insulinotropic effect in postprandial glucose utilization, in intestinal enteroendocrine cells. We can suggest that 7-ELCA may be a prospective approach to the treatment of type II diabetes as the dual modulation of GPBAR1 and FXR has been supposed to be effective in the synergistic regulation of glucose homeostasis in the intestine.

The Physiology of Glucagon-like Peptide 1

2007 ◽  
Vol 87 (4) ◽  
pp. 1409-1439 ◽  
Author(s):  
Jens Juul Holst
Keyword(s):  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Glucagon Secretion ◽  
Peptide Hormone ◽  
Postprandial Glucose ◽  
Cell Secretion ◽  
Amino Acid Peptide ◽  
Reactive Hypoglycemia ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Glucagon-like peptide 1 (GLP-1) is a 30-amino acid peptide hormone produced in the intestinal epithelial endocrine L-cells by differential processing of proglucagon, the gene which is expressed in these cells. The current knowledge regarding regulation of proglucagon gene expression in the gut and in the brain and mechanisms responsible for the posttranslational processing are reviewed. GLP-1 is released in response to meal intake, and the stimuli and molecular mechanisms involved are discussed. GLP-1 is extremely rapidly metabolized and inactivated by the enzyme dipeptidyl peptidase IV even before the hormone has left the gut, raising the possibility that the actions of GLP-1 are transmitted via sensory neurons in the intestine and the liver expressing the GLP-1 receptor. Because of this, it is important to distinguish between measurements of the intact hormone (responsible for endocrine actions) or the sum of the intact hormone and its metabolites, reflecting the total L-cell secretion and therefore also the possible neural actions. The main actions of GLP-1 are to stimulate insulin secretion (i.e., to act as an incretin hormone) and to inhibit glucagon secretion, thereby contributing to limit postprandial glucose excursions. It also inhibits gastrointestinal motility and secretion and thus acts as an enterogastrone and part of the “ileal brake” mechanism. GLP-1 also appears to be a physiological regulator of appetite and food intake. Because of these actions, GLP-1 or GLP-1 receptor agonists are currently being evaluated for the therapy of type 2 diabetes. Decreased secretion of GLP-1 may contribute to the development of obesity, and exaggerated secretion may be responsible for postprandial reactive hypoglycemia.

scholarly journals Postprandial glucose, insulin and glucagon-like peptide 1 responses to sucrose ingested with berries in healthy subjects

2011 ◽  
Vol 107 (10) ◽  
pp. 1445-1451 ◽  
Author(s):  
Riitta Törrönen ◽  
Essi Sarkkinen ◽  
Tarja Niskanen ◽  
Niina Tapola ◽  
Kyllikki Kilpi ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Serum Insulin ◽  
Venous Blood ◽  
Postprandial Glucose ◽  
Carbohydrate Ingestion ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Meal Ingestion ◽  
Single Blind ◽  
Modest Effect

Berries are often consumed with sucrose. They are also rich sources of polyphenols which may modulate glycaemia after carbohydrate ingestion. The present study investigated the postprandial glucose, insulin and glucagon-like peptide 1 (GLP-1) responses to sucrose ingested with berries, in comparison with a similar sucrose load without berries. A total of twelve healthy subjects were recruited to a randomised, single-blind, placebo-controlled crossover study. They participated in two meal tests on separate days. The berry meal was a purée (150 g) made of bilberries, blackcurrants, cranberries and strawberries with 35 g sucrose. The control meal included the same amount of sucrose and available carbohydrates in water. Fingertip capillary and venous blood samples were taken at baseline and at 15, 30, 45, 60, 90 and 120 min after starting to eat the meal. Glucose, insulin and GLP-1 concentrations were determined from the venous samples, and glucose also from the capillary samples. Compared to the control meal, ingestion of the berry meal resulted in lower capillary and venous plasma glucose and serum insulin concentrations at 15 min (P = 0·021,P < 0·007 andP = 0·028, respectively), in higher concentrations at 90 min (P = 0·028,P = 0·021 andP = 0·042, respectively), and in a modest effect on the GLP-1 response (P = 0·05). It also reduced the maximum increases of capillary and venous glucose and insulin concentrations (P = 0·009,P = 0·011 andP = 0·005, respectively), and improved the glycaemic profile (P < 0·001 andP = 0·003 for capillary and venous samples, respectively). These results suggest that the glycaemic control after ingestion of sucrose can be improved by simultaneous consumption of berries.

230 Monosodium Glutamate Reduces Postprandial Glucose With Altered Secretion of Insulin and Glucagon Like Peptide-1

2012 ◽  
Vol 142 (5) ◽  
pp. S-56-S-57
Author(s):  
Hiroko Hosaka ◽  
Motoyasu Kusano ◽  
Hiroaki Zai ◽  
Yasuyuki Shimoyama ◽  
Akiyo Kawada ◽  
...  
Keyword(s):  
Monosodium Glutamate ◽  
Postprandial Glucose ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Physiology of Proglucagon Peptides: Role of Glucagon and GLP-1 in Health and Disease

2015 ◽  
Vol 95 (2) ◽  
pp. 513-548 ◽  
Author(s):  
Darleen A. Sandoval ◽  
David A. D'Alessio
Keyword(s):  
Glucose Homeostasis ◽  
Energy Homeostasis ◽  
Glucose Production ◽  
Glucagon Secretion ◽  
The Body ◽  
Pharmacological Interaction ◽  
Glucose Levels ◽  
Health And Disease ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

The preproglucagon gene ( Gcg) is expressed by specific enteroendocrine cells (L-cells) of the intestinal mucosa, pancreatic islet α-cells, and a discrete set of neurons within the nucleus of the solitary tract. Gcg encodes multiple peptides including glucagon, glucagon-like peptide-1, glucagon-like peptide-2, oxyntomodulin, and glicentin. Of these, glucagon and GLP-1 have received the most attention because of important roles in glucose metabolism, involvement in diabetes and other disorders, and application to therapeutics. The generally accepted model is that GLP-1 improves glucose homeostasis indirectly via stimulation of nutrient-induced insulin release and by reducing glucagon secretion. Yet the body of literature surrounding GLP-1 physiology reveals an incompletely understood and complex system that includes peripheral and central GLP-1 actions to regulate energy and glucose homeostasis. On the other hand, glucagon is established principally as a counterregulatory hormone, increasing in response to physiological challenges that threaten adequate blood glucose levels and driving glucose production to restore euglycemia. However, there also exists a potential role for glucagon in regulating energy expenditure that has recently been suggested in pharmacological studies. It is also becoming apparent that there is cross-talk between the proglucagon derived-peptides, e.g., GLP-1 inhibits glucagon secretion, and some additive or synergistic pharmacological interaction between GLP-1 and glucagon, e.g., dual glucagon/GLP-1 agonists cause more weight loss than single agonists. In this review, we discuss the physiological functions of both glucagon and GLP-1 by comparing and contrasting how these peptides function, variably in concert and opposition, to regulate glucose and energy homeostasis.

Pharmacokinetic and pharmacodynamic evaluation of site-specific PEGylated glucagon-like peptide-1 analogs as flexible postprandial-glucose controllers

2009 ◽  
Vol 98 (4) ◽  
pp. 1556-1567 ◽  
Author(s):  
Su Young Chae ◽  
Young Goo Chun ◽  
Seulki Lee ◽  
Cheng-Hao Jin ◽  
Eun Seong Lee ◽  
...  
Keyword(s):  
Postprandial Glucose ◽  
Site Specific ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

scholarly journals Glucagon-like peptide 1 and peptide YY are in separate storage organelles in enteroendocrine cells

2014 ◽  
Vol 357 (1) ◽  
pp. 63-69 ◽  
Author(s):  
Hyun-Jung Cho ◽  
Eliza S. Robinson ◽  
Leni R. Rivera ◽  
Paul J. McMillan ◽  
Adam Testro ◽  
...  
Keyword(s):  
Peptide Yy ◽  
Enteroendocrine Cells ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

scholarly journals Influence of gastric emptying on the control of postprandial glycemia: physiology and therapeutic implications

2014 ◽  
Vol 12 (2) ◽  
pp. 251-253 ◽  
Author(s):  
Marcos Antonio Tambascia ◽  
Domingos Augusto Cherino Malerbi ◽  
Freddy Goldberg Eliaschewitz
Keyword(s):  
Gastric Emptying ◽  
Glucose Homeostasis ◽  
Neural Mechanism ◽  
Postprandial Glucose ◽  
Therapeutic Implications ◽  
Intrinsic Factors ◽  
Postprandial Glycemia ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Extrinsic And Intrinsic Factors

The maintenance of glucose homeostasis is complex and involves, besides the secretion and action of insulin and glucagon, a hormonal and neural mechanism, regulating the rate of gastric emptying. This mechanism depends on extrinsic and intrinsic factors. Glucagon-like peptide-1 secretion regulates the speed of gastric emptying, contributing to the control of postprandial glycemia. The pharmacodynamic characteristics of various agents of this class can explain the effects more relevant in fasting or postprandial glucose, and can thus guide the individualized treatment, according to the clinical and pathophysiological features of each patient.

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