Investigating the effects of physiological bile acids on GLP-1 secretion and glucose tolerance in normal and GLP-1R-/- mice

2011 ◽  
Vol 392 (6) ◽  
Author(s):  
Eamon P. Rafferty ◽  
Alastair R. Wylie ◽  
Katharine H. Hand ◽  
Chris E. Elliott ◽  
David J. Grieve ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Bile Acids ◽  
Glucagon Secretion ◽  
Peptide Hormone ◽  
Taurocholic Acid ◽  
Oral Glucose ◽  
Glucose Lowering ◽  
Glucose Tolerance Tests

Abstract Physiological secretion of bile acids has previously been linked to the regulation of blood glucose. GLP-1 is an intestinal peptide hormone with important glucose-lowering actions, such as stimulation of insulin secretion and inhibition of glucagon secretion. In this investigation, we assessed the ability of several bile acid compounds to secrete GLP-1 in vitro in STC-1 cells. Bile acids stimulated GLP-1 secretion from 3.3- to 6.2-fold but some were associated with cytolytic effects. Glycocholic and taurocholic acids were selected for in vivo studies in normal and GLP-1R-/- mice. Oral glucose tolerance tests revealed that glycocholic acid did not affect glucose excursions. However, taurocholic acid reduced glucose excursions by 40% in normal mice and by 27% in GLP-1R-/- mice, and plasma GLP-1 concentrations were significantly elevated 30 min post-gavage. Additional studies used incretin receptor antagonists to probe involvement of GLP-1 and GIP in taurocholic acid-induced glucose lowering. The findings suggest that bile acids partially aid glucose regulation by physiologically enhancing nutrient-induced GLP-1 secretion. However, GLP-1 secretion appears to be only part of the glucose-lowering mechanism and our studies indicate that the other major incretin GIP is not involved.

scholarly journals 4-Hydroxyisoleucine: experimental evidence of its insulinotropic and antidiabetic properties

1999 ◽  
Vol 277 (4) ◽  
pp. E617-E623 ◽  
Author(s):  
Christophe Broca ◽  
René Gross ◽  
Pierre Petit ◽  
Yves Sauvaire ◽  
Michèle Manteghetti ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Insulin Response ◽  
Oral Glucose ◽  
Dependent Manner ◽  
Insulin Dependent ◽  
Glucose Tolerance Tests ◽  
Insulin Dependent Diabetic ◽  
Single Intravenous Administration

We have recently shown in vitro that 4-hydroxyisoleucine (4-OH-Ile), an amino acid extracted from fenugreek seeds, potentiates insulin secretion in a glucose-dependent manner. The present study was designed to investigate whether 4-OH-Ile could exert in vivo insulinotropic and antidiabetic properties. For this purpose, intravenous or oral glucose tolerance tests (IVGTTs and OGTTs, respectively) were performed not only in normal animals but also in a type II diabetes rat model. During IVGTT in normal rats or OGTT in normal dogs, 4-OH-Ile (18 mg/kg) improved glucose tolerance. The lactonic form of 4-OH-Ile was ineffective in normal rats. In non-insulin-dependent diabetic (NIDD) rats, a single intravenous administration of 4-OH-Ile (50 mg/kg) partially restored glucose-induced insulin response without affecting glucose tolerance; a 6-day subchronic administration of 4-OH-Ile (50 mg/kg, daily) reduced basal hyperglycemia, decreased basal insulinemia, and slightly, but significantly, improved glucose tolerance. In vitro, 4-OH-Ile (200 μM) potentiated glucose (16.7 mM)-induced insulin release from NIDD rat-isolated islets. So, the antidiabetic effects of 4-OH-Ile on NIDD rats result, at least in part, from a direct pancreatic B cell stimulation.

Abstract 1216: The Cardioactive Peptide Apelin Increases Adipocyte Glucose Uptake and is Necessary for the Maintenance of Systemic Insulin Sensitivity

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Patrick Yue ◽  
Tomoko Asagami ◽  
Ramendra K Kundu ◽  
Yin-Gail Yee ◽  
Alexander J Glassford ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Glucose Uptake ◽  
Embryonic Stem ◽  
Peptide Hormone ◽  
Wild Type ◽  
Glucose Levels ◽  
Glucose Tolerance Tests

Background : Apelin, a peptide hormone with unique cardioactive properties, is also an adipokine, secreted by adipocytes in response to insulin. However, the overall effect of apelin on insulin sensitivity remains largely uncharacterized. Methods : For in vitro experiments, 3T3L1 cells were differentiated into adipocytes over 8 days, with apelin (1 microM) added daily to the media. Cells were then treated with insulin (100 nM; n = 5) for 30 minutes and incubated with 2-[ 3 H]-deoxyglucose. Glucose incorporation was then measured by scintillation counting. For in vivo experiments (n = 4 all studies), apelin-deficient (KO) mice were created by homologous recombination in embryonic stem cells. At age 7 weeks, insulin and glucose tolerance tests, as well as an enzyme immunosorbent assay for insulin, were performed after a 6-hour fast. The mice were then scanned by computed tomography using a GE eXplore RS MicroCT system, and visceral adipose content was determined with MicroView software. Upon sacrifice 1 week later, visceral adipocytes were isolated via collagenase digestion, exposed to insulin, and assessed for glucose uptake as above. Results : Because apelin is upregulated by insulin in adipocytes, we measured glucose uptake in differentiated 3T3L1 cells chronically dosed with apelin. Though no differences were observed in basal uptake, insulin-induced uptake was increased versus control (p < 0.05). To further investigate the role of apelin in vivo , we assessed for insulin resistance in apelin KO mice. At 8 weeks of age, apelin KOs were heavier than age-matched wild type controls (25 vs. 22 g; p < 0.05). Though fasting glucose levels were not significantly different between groups, insulin levels were increased in the KOs (895 vs. 477 pg/microL; p < 0.05). In addition, both insulin and glucose tolerance tests were significantly abnormal in the KOs compared to wild type. Moreover, visceral fat volume was greater in the KOs (274 vs. 248 mm 3 /g body weight; p < 0.05). Finally, insulin-stimulated uptake was reduced (p < 0.05). Conclusions : Apelin is necessary for the proper maintenance of glucose homeostasis. Furthermore, apelin potentiates insulin-induced glucose uptake in adipocytes, suggesting a possible mechanism for its insulin sensitizing effects.

Selective amylin inhibition of the glucagon response to arginine is extrinsic to the pancreas

2001 ◽  
Vol 280 (3) ◽  
pp. E443-E449 ◽  
Author(s):  
R. A. Silvestre ◽  
J. Rodrı́guez-Gallardo ◽  
C. Jodka ◽  
D. G. Parkes ◽  
R. A. Pittner ◽  
...  
Keyword(s):  
Glucagon Secretion ◽  
Peptide Hormone ◽  
Β Cells ◽  
Perfused Rat Pancreas ◽  
Anesthetized Rats ◽  
Isolated Pancreas ◽  
Glucagon Suppression ◽  
Insulin Secretion In Vitro

Amylin, a peptide hormone from pancreatic β-cells, is reported to inhibit insulin secretion in vitro and in vivo and to inhibit nutrient-stimulated glucagon secretion in vivo. However, it has been reported not to affect arginine-stimulated glucagon secretion in vitro. To resolve if the latter resulted from inactive peptide (a problem in the early literature), those experiments were repeated here with well-characterized peptide and found to be valid. In isolated perfused rat pancreas preparations, coperfusion with 1 nM amylin had no effect on arginine-, carbachol-, or vasoactive intestinal peptide-stimulated glucagon secretion. Amylin also had no effect on glucagon output stimulated by decreasing glucose concentration from 11 to 3.2 mM or on glucagon suppression caused by increasing glucose from 3.2 to 7 mM. Amylin at 100 nM had no effect in isolated islets in which glucagon secretion was stimulated by exposure to 10 mM arginine, even though glucagon secretion in the same preparation was inhibited by somatostatin. In anesthetized rats, amylin coinfusion had no effect on glucagon secretion stimulated by insulin-induced hypoglycemia. To reconcile reports of glucagon inhibition with the absence of effect in the experiments just described, anesthetized rats coinfused with rat amylin or with saline were exposed sequentially to intravenous l-arginine (during a euglycemic clamp) and then to hypoglycemia. Amylin inhibited arginine-induced, but not hypoglycemia-induced, glucagon secretion in the same animal. In conclusion, we newly identify a selective glucagonostatic effect of amylin that appears to be extrinsic to the isolated pancreas and may be centrally mediated.

The Relation Between Glucose Tolerance and Insulin Binding to Circulating Monocytes in Obese Children

PEDIATRICS ◽  
1982 ◽  
Vol 70 (4) ◽  
pp. 633-637
Author(s):  
Kaichi Kida ◽  
Noriyoshi Watanabe ◽  
Yoshiki Fujisawa ◽  
Yoshinori Goto ◽  
Hiroshi Matsuda
Keyword(s):  
Glucose Tolerance ◽  
Insulin Receptors ◽  
Insulin Binding ◽  
Tolerance Test ◽  
Quantitative Relation ◽  
Immunoreactive Insulin ◽  
Oral Glucose ◽  
Obese Children

The quantitative relation between insulin binding to circulating monocytes in vitro and glucose tolerance in obese children in vivo is reported. Sixty-one obese children and 11 healthy control children participated in this study. The oral glucose tolerance test (OGTT) was performed by giving them glucose (1.75 gm/kg of body weight), orally in the morning, and the binding of 125I-labeled insulin to circulating monocytes in vitro was measured prior to OGTT. The glucose tolerance expressed by ΣBS (milligrams/100 ml), the sum of the plasma glucose (blood sugar [BS]) values at OGTT, was significantly correlated with the degree of overweight (r = .316, P &lt; .01) and more highly with ΣIRI (microunits per milliliter), the sum of immunoreactive insulin (IRI) values at OGTT (r = .512, P &lt; .001). Insulin binding to monocytes in vitro (picograms/106 cells) was inversely correlated with the degree of overweight (r = -. 687, P &lt; .001). Furthermore, ΣBS was inversely correlated significantly with insulin binding to monocytes in vitro (r = -.435, P &lt; .002). These data suggest that the decrease of insulin receptors might be one cause for the impairment of the glucose tolerance associated with obesity in children.

The Mechanism of Action of Guar Gum in Improving Glucose Tolerance in Man

1984 ◽  
Vol 66 (3) ◽  
pp. 329-336 ◽  
Author(s):  
N. A. Blackburn ◽  
J. S. Redfern ◽  
H. Jarjis ◽  
A. M. Holgate ◽  
I. Hanning ◽  
...  
Keyword(s):  
Gastric Emptying ◽  
Glucose Tolerance ◽  
Guar Gum ◽  
Glucose Absorption ◽  
Oral Glucose ◽  
Electrical Measurements ◽  
Fluid Convection ◽  
Insulin Responses

1. Experiments were carried out in human volunteers to investigate the mechanism by which guar gum improves glucose tolerance. 2. Guar reduced both plasma glucose and insulin responses to an oral glucose load, and delayed gastric emptying. However, there was no correlation between changes in individual blood glucose responses and changes in gastric emptying rates induced by guar. 3. With a steady-state perfusion technique, glucose absorption was found to be significantly reduced during perfusion of the jejunum with solutions containing guar, but returned to control values during subsequent guar-free perfusions. 4. Preperfusing the intestine with guar did not affect electrical measurements of unstirred layer thickness in the human jejunum in vivo.. 5. Experiments in vitro established that glucose diffusion out of a guar/glucose mixture was delayed under conditions of constant stirring. 6. We conclude that guar improves glucose tolerance predominantly by reducing glucose absorption in the small intestine. It probably does this by inhibiting the effects of intestinal motility on fluid convection.

scholarly journals Peptide-based GIP receptor inhibition exhibits modest metabolic changes in mice when administered either alone or combined with GLP-1 agonism

2019 ◽  
Author(s):  
Jason A. West ◽  
Soumitra S. Ghosh ◽  
David G. Parkes ◽  
Anastasia Tsakmaki ◽  
Rikke V. Grønlund ◽  
...  
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Glucose Tolerance ◽  
Mouse Model ◽  
Metabolic Effects ◽  
Oral Glucose ◽  
Oral Glucose Tolerance ◽  
Gip Receptor

ABSTRACTObjectiveCombinatorial gut hormone therapy is one of the more promising strategies for identifying improved treatments for metabolic disease. Many approaches combine the established benefits of glucagon-like peptide-1 (GLP-1) agonism with one or more additional molecules with the aim of improving metabolic outcomes. Recent attention has been drawn to the glucose-dependent insulinotropic polypeptide (GIP) system due to compelling pre-clinical evidence describing the metabolic benefits of antagonising the GIP receptor (GIPR). We rationalised that benefit might be accrued from combining GIPR antagonism with GLP-1 agonism. To this end we investigated the metabolic effects of co-administration of previously reported peptide-based GIPR antagonists with the GLP-1 agonist liraglutide.MethodsTwo GIPR peptide antagonists, GIPA-1 (mouse GIP(3-30)NH2) and GIPA-2 (NαAc-K10[γEγE-C16]-Arg18-hGIP(5–42)), were pharmacologically characterised in vitro in an assay measuring cAMP production in CHO-K1 cells overexpressing the mouse GIPR. These peptides were then characterised in vivo in lean mice for their effect on oral glucose tolerance, as well as their ability to antagonize exogenous GIP action. Finally, a mouse model of diet-induced obesity (DIO) was used to investigate the potential metabolic benefits of chronic dosing of peptide-based GIPR antagonists, alone or in combination with liraglutide.ResultsIn vitro, both GIPR peptides exhibited potent antagonistic properties, with GIPA-2 being the more potent of the two. Acute in vivo administration of GIPA-1 during an oral glucose tolerance test (OGTT) had negligible effects on glucose tolerance and circulated insulin in lean mice. In contrast, GIPA-2 impaired glucose tolerance and attenuated circulating insulin levels, with offsetting effects on glycemia noted with co-administration with exogenous mouse GIP, suggesting true antagonism via GIPA-2 at the GIP receptor. Chronic administration studies in a DIO mouse model showed expected effects of GLP-1 agonism (via liraglutide), lowering food intake, body weight, fasting blood glucose and plasma insulin concentrations while improving glucose sensitivity, whereas delivery of either GIPR antagonist alone had negligible effects on these parameters. Interestingly, chronic dual therapy with the GIPR antagonists and GLP-1 showed separation from single intervention arms though augmented insulin sensitizing effects (modestly lowering insulin and HOMA-IR) and lowering plasmas triglycerides and free-fatty acids, with more notable effects observed with GIPA-1 compared to GIPA-2.ConclusionWe conclude that, in contrast to the well-documented effects of GLP-1R agonism, systemic administration of peptide-based GIPR antagonists demonstrate minimal benefit on metabolic parameters in DIO mice, exhibiting no major effects on body weight, food intake and glycaemic parameters. However, the co-administration of both a GIPR antagonist together with a GLP1 agonist uncovers interesting synergistic and beneficial effects on measures of insulin sensitivity, circulating lipids and certain adipose stores that seem influenced by the degree or nature of GIP receptor antagonism.

Insulin Secretion and Glucose Tolerance after Islet Transplantation in Rats with Noninsulin-Dependent Diabetes Induced by Neonatal Streptozotocin

1997 ◽  
Vol 6 (1) ◽  
pp. 23-32 ◽  
Author(s):  
Maria-Angeles Tormo ◽  
Trinidad Leon-Quinto ◽  
Catherine Saulnier ◽  
Danielle Bailbe ◽  
Patricia Serradas ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Insulin Release ◽  
Insulin Response ◽  
Tolerance Test ◽  
Oral Glucose ◽  
Β Cells ◽  
Basal Plasma

The present study was designed to identify in a model of noninsulin-dependent diabetes induced by neonatal streptozotocin (n0-STZ), the long-term consequences of an islet graft upon 1) glucose handling of the recipient and, 2) glucose response of the residual β cells in the recipient pancreas. We have examined, 4 and 8 wk after islet implantation under the kidney capsule of syngeneic diabetic n0-STZ rats, their tolerance to glucose administered in vivo, together with their insulin release in response to glucose in vivo (oral glucose tolerance test) as well as in vitro (perfused pancreas). The results in the islet-grafted n0-STZ rats, were compared to those obtained in nongrafted nondiabetic rats and nongrafted n0-STZ rats. Our study shows that transplanting a limited number (900) of adult islets under the kidney capsule reverses to normal, many parameters of the noninsulin-dependent diabetic state in the n0-STZ rat model: these include body weight, basal plasma glucose in both the nonfasted and postabsorptive states, and basal plasma insulin in the postabsorptive state. Furthermore, tolerance to oral glucose administration was greatly improved in the transplanted rats and it was correlated with restoration of a manifest glucose-induced insulin secretion in vivo as evaluated (ΔI) during an oral glucose tolerance test. Our data clearly show that the insulin response to glucose from the endogenous pancreas of n0-STZ diabetic rat was not really improved by long-term (8 wk) basal normoglycemia. More precisely, we were able to detect a slight but significant improvement of the early phase of insulin release in vitro in response to glucose; however, the overall insulin response remained 15 times lower than the normal one with no reapparance of the late phase of insulin release. After cessation of glucose stimulation in vivo, off-response of insulin, which is also a landmark of the impaired insulin release by the β cells of n0-STZ rats, was still detectable in the perfused pancreas of the transplanted n0-STZ rats. Finally, because the reactivity to glucose of the endogenous residual β cells was not regained, the insulin released in vivo during the oral glucose test in the graft-bearing n0-STZ rats can be attributed mainly to functioning of the grafted islets population. Copyright © 1997 Elsevier Science Inc.

scholarly journals Antihyperglycemic Effect of Lavandula pedunculata: In Vivo, In Vitro and Ex Vivo Approaches

Pharmaceutics ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2019
Author(s):  
Salima Boutahiri ◽  
Mohamed Bouhrim ◽  
Chayma Abidi ◽  
Hamza Mechchate ◽  
Ali S. Alqahtani ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Aqueous Extract ◽  
Digestive Enzymes ◽  
Ex Vivo ◽  
Glucose Absorption ◽  
Oral Glucose ◽  
Oral Glucose Tolerance ◽  
Antihyperglycemic Effect

Lavandula pedunculata (Mill.) Cav. (LP) is one of lavender species traditionally used in Morocco to prevent or cure diabetes, alone or in the form of polyherbal preparations (PHP). Therefore, the primary objective of this study was to test the antihyperglycemic effect of the aqueous extract of LP, alone and in combination with Punica granatum L. (PG) and Trigonella foenum-graecum L. (FGK). The secondary objective was to explore some mechanisms of action on the digestive functions. The antihyperglycemic effect of the aqueous extract of LP, alone and in combination with PG and FGK, was studied in vivo using an oral glucose tolerance test (OGTT). In addition, LP extract was tested on the activities of some digestive enzymes (pancreatic α-amylase and intestinal α-glucosidase) in vitro and on the intestinal absorption of glucose ex vivo using a short-circuit current (Isc) technique. Acute and chronic oral administration of LP aqueous extract reduced the peak of the glucose concentration (30 min, p < 0.01) and the area under the curve (AUC, p < 0.01). The effect of LP + PG was at the same amplitude to that of the positive control Metformin (MET). LP aqueous extract inhibited the pancreatic α-amylase with an IC50 almost identical to acarbose (0.44 ± 0.05 mg/mL and 0.36 ± 0.02 mg/mL, respectively), as well as the intestinal α-glucosidase, (IC50 = 131 ± 20 µg/mL) and the intestinal glucose absorption (IC50 = 81.28 ± 4.01 µg/mL) in concentration-dependent manners. LP aqueous extract exhibited potent actions on hyperglycemia, with an inhibition on digestive enzymes and glucose absorption. In addition, the combination with PG and FGK enhanced oral glucose tolerance in rats. These findings back up the traditional use of LP in type 2 diabetes treatment and the effectiveness of the alternative and combinative poly-phytotherapy (ACPP).

Adipose tissue hypoxia and low-grade inflammation: a possible mechanism for ethanol-related glucose intolerance?

2015 ◽  
Vol 113 (9) ◽  
pp. 1355-1364 ◽  
Author(s):  
Zhen He ◽  
Min Li ◽  
Dongmei Zheng ◽  
Qing Chen ◽  
Wenwen Liu ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Glucose Tolerance ◽  
Hypoxia Inducible Factor ◽  
Ethanol Consumption ◽  
Oral Glucose ◽  
Low Grade ◽  
Tnf Α ◽  
Low Grade Inflammation

The exact mechanism of ethanol's effects on glucose tolerance has not been well determined. The present study focuses for the first time on hypoxia and low-grade inflammation in adipose tissue (AT). In the in vivo experiments, twenty-four male Wistar rats were randomly allocated into control and ethanol feeding groups. Ethanol-treated rats received edible ethanol once a day at a total dosage of 5 g/kg per d, and the controls received distilled water. Ethanol volumes were adjusted every week. At the end of 8 weeks, we carried out an oral glucose tolerance test. Blood and AT were collected for measuring hypoxia-inducible factor-1α (HIF-1α), GLUT1, TNF-α, IL-6, leptin and vascular endothelial growth factor (VEGF). In the in vitro experiments, differentiated OP9 adipocytes were incubated with 100 mm of ethanol for 48 h; the media and cells were then collected for measuring HIF-1α, GLUT1, TNF-α and IL-6. The results showed that long-term ethanol consumption impaired glucose tolerance in rats. Ethanol consumption had little influence on body weight, but both epididymal and perirenal AT were markedly enlarged in the ethanol-treated rats as compared to the controls. Visceral adipose tissue (VAT) had accumulated, and the protein levels of HIF-1α and GLUT1, the indicators of hypoxia in rat epididymal AT and OP9 adipocytes, were elevated. Secondary to the AT hypoxia, the levels of inflammation-related adipokines, such as TNF-α, IL-6, leptin and VEGF, were increased. Based on these findings, we conclude that VAT hypoxia and low-grade inflammation might be a new mechanism in the treatment of ethanol-related diabetes.

Traceable Peptidic Ligands that Target Ghrelin Receptors

2020 ◽  
Vol 21 (10) ◽  
pp. 955-964 ◽  
Author(s):  
Mengjie Liu ◽  
John Wade ◽  
Mohammed Akhter Hossain
Keyword(s):  
In Vivo Imaging ◽  
Peptide Hormone ◽  
Structural Features ◽  
Pharmacological Properties ◽  
Imaging Studies ◽  
Cognate Receptor ◽  
Ghrelin Receptors ◽  
Biochemical Research

: Ghrelin is a 28-amino acid octanoylated peptide hormone that is implicated in many physiological and pathophysiological processes. Specific visualization of ghrelin and its cognate receptor using traceable ligands is crucial in elucidating the localization, functions, and expression pattern of the peptide’s signaling pathway. Here 12 representative radio- and fluorescently-labeled peptide-based ligands are reviewed for in vitro and in vivo imaging studies. In particular, the focus is on their structural features, pharmacological properties, and applications in further biochemical research.

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