Sulfonylurea Compounds Uncouple the Glucose Dependence of the Insulinotropic Effect of Glucagon-Like Peptide 1

Diabetes ◽  
2007 ◽  
Vol 56 (2) ◽  
pp. 438-443 ◽  
Author(s):  
Jocelyn de Heer ◽  
Jens J. Holst
Keyword(s):  
Sulfonylurea Compounds ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Insulinotropic Effect ◽  
Glucose Dependence

GLP-1-(9–36) amide reduces blood glucose in anesthetized pigs by a mechanism that does not involve insulin secretion

2002 ◽  
Vol 282 (4) ◽  
pp. E873-E879 ◽  
Author(s):  
Carolyn F. Deacon ◽  
Astrid Plamboeck ◽  
Søren Møller ◽  
Jens J. Holst
Keyword(s):  
Insulin Secretion ◽  
Therapeutic Potential ◽  
Intravenous Glucose ◽  
Dpp Iv ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Independent Effects ◽  
Insulinotropic Effect ◽  
Insulin Responses

Glucagon-like peptide 1 (GLP-1) is a potent anti-hyperglycemic hormone currently under investigation for its therapeutic potential. However, due to rapid degradation by dipeptidyl peptidase IV (DPP IV), which limits its metabolic stability and eliminates its insulinotropic activity, it has been impossible to assess its true efficacy in vivo. In chloralose-anesthetized pigs given valine-pyrrolidide (to block endogenous DPP IV activity), the independent effects of GLP-1-(7–36) amide on glucose and insulin responses to intravenous glucose were assessed, and the metabolite generated by DPP IV, GLP-1-(9–36) amide, was investigated for any ability to influence these responses. GLP-1-(7–36) amide enhanced insulin secretion ( P < 0.03 vs. vehicle), but GLP-1-(9–36) amide was without effect, either alone or when coinfused with GLP-1-(7–36) amide. In contrast, GLP-1-(9–36) amide did affect glucose responses ( P < 0.03). Glucose excursions were greater after saline (121 ± 17 mmol · l−1 · min) than after GLP-1-(9–36) amide (73 ± 19 mmol · l−1 · min; P < 0.05), GLP-1-(7–36) amide (62 ± 13 mmol · l−1 · min; P < 0.02) or GLP-1-(7–36) amide + GLP-1-(9–36) amide (50 ± 13 mmol · l−1 · min; P < 0.005). Glucose elimination rates were faster after GLP-1-(7–36) amide + (9–36) amide (10.3 ± 1.2%/min) than after GLP-1-(7–36) amide (7.0 ± 0.9%/min; P < 0.04), GLP-1-(9–36) amide (6.8 ± 1.0%/min; P < 0.03), or saline (5.4 ± 1.2%/min; P < 0.005). Glucagon concentrations were unaffected. These results demonstrate that GLP-1-(9–36) amide neither stimulates insulin secretion nor antagonizes the insulinotropic effect of GLP-1-(7–36) amide in vivo. Moreover, the metabolite itself possesses anti-hyperglycemic effects, supporting the hypothesis that selective DPP IV action is important in glucose homeostasis.

scholarly journals The insulinotropic effect of exogenous glucagon-like peptide-1 is not affected by acute vagotomy in anaesthetized pigs

2016 ◽  
Vol 101 (7) ◽  
pp. 895-912 ◽  
Author(s):  
Simon Veedfald ◽  
Marie Hansen ◽  
Louise Wulff Christensen ◽  
Sara Agnete Hjort Larsen ◽  
Karina Rahr Hjøllund ◽  
...  
Keyword(s):  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Insulinotropic Effect

Small Molecule Allosteric Modulation of the Glucagon-Like Peptide-1 Receptor Enhances the Insulinotropic Effect of Oxyntomodulin

2012 ◽  
Vol 82 (6) ◽  
pp. 1066-1073 ◽  
Author(s):  
Francis S. Willard ◽  
Denise Wootten ◽  
Aaron D. Showalter ◽  
Emilia E. Savage ◽  
James Ficorilli ◽  
...  
Keyword(s):  
Small Molecule ◽  
Allosteric Modulation ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Insulinotropic Effect

Intraportal GLP-1 stimulates insulin secretion predominantly through the hepatoportal-pancreatic vagal reflex pathways

2013 ◽  
Vol 305 (3) ◽  
pp. E376-E387 ◽  
Author(s):  
Makoto Nishizawa ◽  
Hajime Nakabayashi ◽  
Keigo Uehara ◽  
Atsushi Nakagawa ◽  
Kenzo Uchida ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Portal Vein ◽  
Sham Operation ◽  
Insulin Levels ◽  
Reflex Pathways ◽  
Vagal Reflex ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Insulinotropic Effect ◽  
Vagal Efferents

We previously reported that glucagon-like peptide-1 (GLP-1) appearance in the portal vein facilitates hepatic vagal afferent activity, and this further augments reflexively the pancreatic vagal efferents in anesthetized rats, suggesting a neuroincretin effect of GLP-1. To determine whether the GLP-1-induced vagal pathways lead to a neuronal-mediated component (NMC) of insulin secretion, we infused GLP-1 at a physiological or pharmacological dose (1 or 3 pmol·kg−1·min−1, respectively) into the portal vein in conscious rats with selective hepatic vagotomy (Vagox) or sham operation (Sham). The experiments consisted of two sequential 10-min intraportal infusions (P1 and P2): glucose at a physiological rate (56 μmol·kg−1·min−1) in P1 and the glucose plus GLP-1 or vehicle in P2. Under arterial isoglycemia across the groups, the physiological GLP-1 infusion in Sham augmented promptly and markedly arterial insulin levels, approximately twofold the levels in glucose alone infusion ( P < 0.005), and insulin levels in Vagox diminished apparently ( P < 0.05). Almost 60% of the GLP-1-induced insulin secretion (AUC) in Sham met the NMC, i.e., difference between insulin secretion in Sham and Vagox, (AUC 976 ± 65 vs. 393 ± 94 pmol·min/l, respectively, P < 0.005). Intraportal pharmacological GLP-1 infusion further augmented insulin secretion in both groups, but the NMC remained in 46% (NS; Sham vs. Vagox). In contrast, “isoglycemic” intravenous GLP-1 infusion (3 pmol·kg−1·min−1) evoked an equal insulin secretion in both groups. Thus, the present results indicate that GLP-1 appearing in the portal vein evokes a powerful neuronal-mediated insulinotropic effect, suggesting the neuroincretin effect.

Inhibition of carbohydrate-mediated glucagon-like peptide-I (7–36)amide secretion by circulating non-esterified fatty acids

1999 ◽  
Vol 96 (4) ◽  
pp. 335-342
Author(s):  
L. RANGANATH ◽  
F. NORRIS ◽  
L. MORGAN ◽  
J. WRIGHT ◽  
V. MARKS
Keyword(s):  
Fatty Acids ◽  
Intrinsic Defect ◽  
Complete Suppression ◽  
Esterified Fatty Acids ◽  
Simple Obesity ◽  
Obese Subjects ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Pancreatic Hormone ◽  
Insulinotropic Effect

Two studies were performed to assess the entero-insular axis in simple obesity and the possible effect of variations in the level of circulating non-esterified fatty acids (NEFA) on one of the components of the entero-insular axis, glucagon-like peptide-1 [(7–36) amide]. In the first study, we compared the entero-pancreatic hormone response to oral carbohydrate in obese and lean women. Obese subjects demonstrated hyperinsulinaemia and impaired glucose tolerance but this was not associated with an increased secretion of either glucose-dependent insulinotropic polypeptide or glucagon-like peptide-1 (GLP-1). These findings therefore provide no support for the hypothesis that overactivity of the entero-insular axis contributes to the hyperinsulinaemia seen in obesity. Indeed, the plasma GLP-1 response to carbohydrate was markedly attenuated in obese subjects, confirming previous observations. In the second study, in which carbohydrate-stimulated GLP-1 responses were again evaluated in obese and lean women, circulating NEFA levels were modulated using either heparin (to increase serum NEFA) or acipimox (to reduce serum NEFA). Treatment with acipimox resulted in complete suppression of NEFA levels and in a markedly higher GLP-1 response than the response to carbohydrate alone or to carbohydrate plus heparin. We suggest that higher fasting and postprandial NEFA levels in obesity may tonically inhibit nutrient-mediated GLP-1 secretion, and that this results in attenuation of the GLP-1 response to carbohydrate. However, although serum NEFA levels post-acipimox were similarly suppressed in both lean and obese subjects, the GLP-1 response was again significantly lower in obese subjects, suggesting the possibility of an intrinsic defect of GLP-1 secretion in obesity. The reduction of GLP-1 levels in obesity may be important both in relation to its insulinotropic effect and to its postulated role as a satiety factor.

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 Polymer-Based Delivery of Glucagon-Like Peptide-1 for the Treatment of Diabetes

2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
Pyung-Hwan Kim ◽  
Sung Wan Kim
Keyword(s):  
Half Life ◽  
Renal Elimination ◽  
Chemical Conjugation ◽  
Dpp Iv ◽  
Polymeric Delivery ◽  
Treatment Of Diabetes ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Insulinotropic Effect

The incretin hormones, glucagon-like peptide-1 (GLP-1) and its receptor agonist (exendin-4), are well known for glucose homeostasis, insulinotropic effect, and effects on weight loss and food intake. However, due to the rapid degradation of GLP-1 by dipeptidylpeptidase-IV (DPP-IV) enzyme and renal elimination of exendin-4, their clinical applications have been restricted. Although exendin-4 has longer half-life than GLP-1, it still requires frequent injections to maintain efficacy for the treatment of diabetes. In recent decades, various polymeric delivery systems have been developed for the delivery of GLP-1 and exendin-4 genes or peptides for their long-term action and the extra production in ectopic tissues. Herein, we discuss the modification of the expression cassettes and peptides for long-term production and secretion of the native peptides. In addition, the characteristics of nonviral or viral system used for a delivery of a modified GLP-1 or exendin-4 are described. Furthermore, recent efforts to improve the biological half-life of GLP-1 or exendin-4 peptide via chemical conjugation with various smart polymers via chemical conjugation compared with native peptide are discussed.

scholarly journals Testosterone enhances GLP-1 efficacy at the plasma membrane and endosomes to augment insulin secretion in male pancreatic β cells

2020 ◽  
Author(s):  
Weiwei Xu ◽  
Fiona B. Ashford ◽  
Stavroula Bitsi ◽  
Lina Schiffer ◽  
M.M. Fahd Qadir ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Insulin Secretion ◽  
Androgen Receptor ◽  
Large Population ◽  
Β Cells ◽  
Β Cell ◽  
Increased Risk ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Insulinotropic Effect

AbstractMale mice with elimination of the androgen receptor (AR) in islet β cells (βARKO) exhibit blunted glucose-stimulated insulin secretion (GSIS), leading to hypoinsulinemia and hyperglycemia when challenged with a Western diet. Testosterone activation of an extranuclear AR in β cells potentiates GSIS by amplifying the insulinotropic action of glucagon-like peptide-1 (GLP-1). Here, using a combination of βARKO and β cell-selective GLP-1 receptor knockout mice and their islets, we show that AR activation in β cells amplifies the insulinotropic effect of islet-derived GLP-1. In β cell models expressing cAMP sensors, testosterone enhances the ability of GLP-1, but not that of glucose-dependent insulinotropic polypeptide or glucagon, to produce cAMP. Accordingly, testosterone selectively enhances the ability of GLP-1 to potentiate GSIS. Notably, testosterone enhances GLP-1 production of cAMP at the plasma membrane and endosomes. In male mouse and human islets, the insulinotropic effect of testosterone is abolished following inhibition of the membrane and endosomal cAMP-dependent protein kinase A and exchange protein activated by cAMP islet 2 pathways. Thus, membrane localization of AR enhances the ability of the GLP-1 receptor to produce cAMP, thus increasing glucose-stimulated insulin exocytosis.Significance StatementThis study reveals that testosterone, acting on the androgen receptor (AR) in insulin-producing β cells amplifies the insulinotropic action of glucagon-like peptide-1 (GLP-1) by increasing GLP-1-mediated production of cAMP at the plasma membrane and endosomal compartments, to promote insulin vesicles exocytosis in human β cells. This study establishes a novel biological paradigm in which membrane location of a steroid nuclear receptor enhances the ability of a G protein-coupled receptor to produce cAMP. It has exceptional clinical significance for targeted delivery of testosterone to β cells in the large population of aging and androgen-deficient men who are at increased risk of diabetes.

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