Physiology and Therapeutic Potential of Glucagon-Like Peptide-1

1998 ◽  
Vol 94 (s38) ◽  
pp. 1P-1P
Author(s):  
CMB Edwards ◽  
JF Todd ◽  
MA Ghatei ◽  
SR Bloom
Keyword(s):  
Therapeutic Potential ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Subcutaneous glucagon-like peptide-1 (7-36) amide is insulinotropic and can cause hypoglycaemia in fasted healthy subjects

1998 ◽  
Vol 95 (6) ◽  
pp. 719-724 ◽  
Author(s):  
C. Mark B. EDWARDS ◽  
Jeannie F. TODD ◽  
Mohammad A. GHATEI ◽  
Stephen R. BLOOM
Keyword(s):  
Blood Pressure ◽  
Type 2 Diabetes ◽  
Plasma Glucose ◽  
Healthy Subjects ◽  
Therapeutic Potential ◽  
Double Blind ◽  
Gut Hormone ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

1. Glucagon-like peptide-1 (7-36) amide (GLP-1) is a gut hormone released postprandially that stimulates insulin secretion, suppresses glucagon secretion and delays gastric emptying. The insulinotropic action of GLP-1 is more potent under hyperglycaemic conditions. Several published studies have indicated the therapeutic potential of subcutaneous GLP-1 in non-insulin-dependent (Type 2) diabetes mellitus. 2. We investigated whether subcutaneous GLP-1, at a dose shown to improve glycaemic control in early Type 2 diabetes, is insulinotropic at normal fasting glucose concentrations. A double-blind, randomized, crossover study of 10 healthy subjects injected with GLP-1 or saline subcutaneously after a 16 h fast was performed. The effect on cardiovascular parameters was also examined. 3. GLP-1 caused a near 5-fold rise in plasma insulin concentration. After treatment with GLP-1, circulating plasma glucose concentrations fell below the normal range in all subjects. One subject had symptoms of hypoglycaemia after GLP-1. A rise in pulse rate was found which correlated with the fall in plasma glucose concentration. An increase in blood pressure occurred with GLP-1 injection which was seen at the same time as the rise in plasma GLP-1 concentrations. 4. This study indicates that subcutaneous GLP-1 can override the normal homoeostatic mechanism maintaining fasting plasma glucose in man, and is also associated with an increase in blood pressure.

scholarly journals How glucagon-like peptide 1 receptor agonists work

2021 ◽  
Author(s):  
Christine Rode Andreasen ◽  
Andreas Andersen ◽  
Filip Krag Knop ◽  
Tina Vilsbøll
Keyword(s):  
Body Weight ◽  
Therapeutic Potential ◽  
Clinical Effects ◽  
Glucose Lowering ◽  
Receptor Agonists ◽  
Reduce Body Weight ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Clinical Utilisation

Recent years, glucagon-like peptide 1 receptor agonists (GLP-1RAs) have become central in the treatment of type 2 diabetes (T2D). In addition to their glucose-lowering properties with low risk of hypoglycaemia, GLP-1RAs reduce body weight and show promising results in reducing cardiovascular risk and renal complications in high-risk individuals with T2D. These findings have changed guidelines on T2D management over the last years, and GLP-1RAs are now widely used in overweight patients with T2D as well as in patients with T2D and cardiovascular disease regardless of glycaemic control. The currently available GLP-1RAs have different pharmacokinetic profiles and differ in their ability to improve glycaemia, reduce body weight and in their cardio- and renal protective potentials. Understanding how these agents work, including insights into their pleiotropic effects on T2D pathophysiology, may improve their clinical utilisation and be useful for exploring other indications such as non-alcoholic steatohepatitis and neurodegenerative disorders. In this review, we provide an overview of approved GLP-1RAs, their clinical effects and mode of actions, and we offer insights into the potential of GLP-1RAs for other indications than T2D. Finally, we will discuss the emerging data and therapeutic potential of using GLP-1RAs in combinations with other receptor agonists.

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 Disconnect between signalling potency and in vivo efficacy of pharmacokinetically optimised biased glucagon-like peptide-1 receptor agonists

2019 ◽  
Author(s):  
Maria Lucey ◽  
Philip Pickford ◽  
James Minnion ◽  
Jan Ungewiss ◽  
Katja Schoeneberg ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Receptor Trafficking ◽  
Appetite Suppression ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
And Diffusion

AbstractObjectiveTo determine how pharmacokinetically advantageous acylation impacts on glucagon-like peptide-1 receptor (GLP-1R) signal bias, trafficking, anti-hyperglycaemic efficacy and appetite suppression.MethodsIn vitro signalling responses were measured using biochemical and biosensor assays. GLP-1 receptor trafficking was determined by confocal microscopy and diffusion-enhanced resonance energy transfer. Pharmacokinetics, glucoregulatory effects and appetite suppression were measured in acute, sub-chronic and chronic settings in mice.ResultsA C-terminally acylated ligand, exendin-phe1-C16, was identified with undetectable β-arrestin recruitment and GLP-1R internalisation. Depending on the cellular system used, this molecule was up to 1000-fold less potent than the comparator exendin-asp-3-C16 for cyclic AMP signalling, yet was considerably more effective in vivo, particularly for glucose regulation.ConclusionsC-terminal acylation of biased GLP-1R agonists increases their degree of signal bias in favour of cAMP production and improves their therapeutic potential.

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