Glucagon-like peptide 1 in the pathophysiology and pharmacotherapy of clinical obesity

Abstract

Though the pathophysiology of clinical obesity is undoubtedly multifaceted, several lines of clinical evidence implicate an important functional role for glucagon-like peptide 1 (GLP-1) signalling. Clinical studies assessing GLP-1 responses in normal weight and obese subjects suggest that weight gain may induce functional deficits in GLP-1 signalling that facilitates maintenance of the obesity phenotype. In addition, genetic studies implicate a possible role for altered GLP-1 signalling as a risk factor towards the development of obesity. As reductions in functional GLP-1 signalling seem to play a role in clinical obesity, the pharmacological replenishment seems a promising target for the medical management of obesity in clinical practice. GLP-1 analogue liraglutide at a high dose (3 mg/d) has shown promising results in achieving and maintaining greater weight loss in obese individuals compared to placebo control, and currently licensed anti-obesity medications. Generally well tolerated, provided that longer-term data in clinical practice supports the currently available evidence of superior short- and long-term weight loss efficacy, GLP-1 analogues provide promise towards achieving the successful, sustainable medical management of obesity that remains as yet, an unmet clinical need.

Non-responders After Gastric Bypass Surgery for Morbid Obesity: Peptide Hormones and Glucose Homeostasis

“…After RYGBP, GLP-1 increases progressively during the first postoperative year, albeit with considerable delay after improvement in glucose homeostasis and weight loss [5], and therefore, the causative effect of GLP-1 on these changes has been challenged. As reported earlier, the plasma levels of GLP-1 in the short term after RYGBP [34], both our groups present a 30-min peak, with GLP-1 levels increasing tenfold compared with baseline. Similar to GLP-1, RYGBP surgery increases fasting [35] as well as postprandial PYY levels postoperatively compared with lean and obese control subjects [36,37].…”

Current and emerging therapies for managing hyperphagia and obesity in Prader‐Willi syndrome: A narrative review

“…GLP‐1 is a hormone primarily synthesized by the neuroendocrine L‐cells of the ileum and colon and is released in response to food intake . Abnormalities in the postprandial secretion of GLP‐1 have been linked to the pathophysiology of obesity and T2DM . As a potential strategy to enhance GLP‐1 actions, a number of studies have investigated the metabolic effects of GLP‐1 receptor agonists.…”

“…As a potential strategy to enhance GLP‐1 actions, a number of studies have investigated the metabolic effects of GLP‐1 receptor agonists. Intravenously administered GLP‐1 receptor agonists (eg, liraglutide and exenatide) have been shown to delay gastric emptying and suppress appetite, which results in clinically meaningful weight loss, with no apparent cardiovascular or psychiatric adverse effects …”

Liraglutid in der Pharmakotherapie der Adipositas

“…Das Polypeptid GLP-1 besteht aus 31 Aminosäuren und wird aus Proglukagon durch das Enzym Prohormonkonvertase 1 abgespalten. Proglukagon wird peripher in den enteroendokrinen L-Zellen und den pankreatischen α-Zellen, sowie zentral in Neuronen des Hirnstamms synthetisiert (2). GLP-1 entsteht dabei überwiegend in den intestinalen L-Zellen (3).…”

“…2 min, sodass nur 10-15% des freigesetzten GLP-1 biologisch wirksam die Peripherie erreicht (6). Eine parenterale Gabe von modifiziertem GLP-1 verhindert diesen "first-pass-Effekt" in der Leber (2). Die Wirkung des Hormons wird intrazellulär nach Bindung an einen G-Protein gekoppelten GLP-1-Rezeptor (GLP-1R) vermittelt (7).…”