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Laboratory Articles

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Ryan G

on 14 April 2010

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Transcript of Laboratory Articles

doi: 10.2337/db05-0996
Diabetes January 2007 vol. 56 no. 1 143-151 Exendin-4 Potently Decreases Ghrelin Levels in Fasting Rats
Diego Pérez-Tilve1, Lucas González-Matías1, Mayte Alvarez-Crespo1, Roberto Leiras1, Sulay Tovar2, Carlos Diéguez2 and Federico Mallo SUMMARY
Recombinant (genetically-altered or recombined?) glucagon-like peptide-1 (7-36)amide (rGLP-1) was recently shown to cause significant weight loss in type 2 diabetics when administered for 6 weeks as a continuous subcutaneous infusion. The mechanisms responsible for the weight loss are not clarified. In the present study, rGLP-1 was given for 5 d by prandial subcutaneous injections (PSI) (76 nmol 30 min before meals, four times daily; a total of 302.4 nmol/24 h) or by continuous subcutaneous infusion (CSI) (12.7 nmol/h; a total of 304.8 nmol/24 h). This was performed in nineteen healthy obese subjects (mean age 44.2 (sem 2.5) years; BMI 39.0 (sem 1.2) kg/m(2)) in a prospective randomised, double-blind, placebo-controlled, cross-over study. Compared with the placebo, rGLP-1 administered as PSI and by CSI generated a 15 % reduction in mean food intake per meal (P=0.02) after 5 d treatment. A weight loss of 0.55 (sem 0.2) kg (P<0.05) was registered after 5 d with PSI of rGLP-1. Gastric emptying rate was reduced during both PSI (P<0.001) and CSI (P<0.05) treatment, but more rapidly and to a greater extent with PSI of rGLP-1. To conclude, a 5 d treatment of rGLP-1 at high doses by PSI, but not CSI, promptly slowed gastric emptying as a probable mechanism of action of increased satiety, decreased hunger and, hence, reduced food intake with an ensuing weight loss. •Ghrelin is a potent orexigenic and adipogenic hormone that strongly influences fat deposition and the generation of hunger in obesity.

•Exendin (Ex)-4 is an agonist of the glucagon-like peptide (GLP)-1 receptor (GLP-1r) that has anorexigenic and fat-reducing properties.

•Here, we report that Ex-4 reduces the levels of ghrelin by up to 74% in fasted rats.

•These effects are dose dependent and long lasting (up to 8 h), and they can be detected after both central and peripheral administration of Ex-4.

•Suppression of ghrelin was neither mimicked by GLP-1(7–36)-NH2 nor blocked by the GLP-1r antagonist Ex-(9–39).

•Moreover, it was independent of the levels of leptin and insulin. (relevant to any connections to diabetes we might want to talk about).

•The decrease in ghrelin levels induced by Ex-4 may explain the reduced food intake in fasted rats, justifying the more potent anorexigenic effects of Ex-4 when compared with GLP-1.

•As well as the potential benefits of Ex-4 in type 2 diabetes, the potent effects of Ex-4 on ghrelin make it tempting to speculate that Ex-4 could offer a therapeutic option for PWS and other syndromes characterized by substantial amounts of circulating ghrelin.
Prandial subcutaneous injections of glucagon-like peptide-1 causes weight loss in obese human subjects.
The British Journal of Nutrition [0007-1145]
yr:2004 vol:91 iss:3 pg:439 -46 Glucagon-like peptide-1: a potent regulator of
food intake in humans.
Gut [0017-5749] J.P. GUTZWILLER ET AL.
yr:1999 vol:44 iss:1 pg:81-86 SUMMARY
Background/Aims—Studies in animals suggest a physiological role for glucagon-like peptide-1-(7-36)-amide (GLP-1) in regulating satiety. The role of GLP-1 in regulating food intake in man has, however, not been investigated.
Subjects—Sixteen healthy male subjects were examined in a double blind placebo controlled fashion.
Methods—The effect of graded intravenous doses (0,0.375, 0.75, and 1.5 pmol/kg/min) of synthetic human GLP-1 on food intake and feelings of hunger and satiety was tested in healthy volunteers.
Results—Graded GLP-1 infusions resulted in a dose dependent reduction in food intake (maximal inhibition 35%, p<0.001 v control) and a similar reduction in calorie intake (32%; p<0.001). Fluid ingestion was also reduced by GLP-1 (18% reduction, p<0.01). No overt side effects were produced by GLP-1, but subjects experienced less hunger and early fullness in the period before a meal during GLP-1 infusion at the highest dose (p<0.05).
Conclusions—Intravenous infusions of GLP-1 decrease spontaneous food intake even at physiological plasma concentrations, implying an important role for GLP-1 in the regulation of the early satiety response in humans.
Keywords: glucagon-like peptide-1; satiety; food intake; hunger and fullness score. HIGHLIGHTS
GLP-1 suppresses glucagon secretion, stimulates B-cell neogenesis as well as proinsulin biosynthesis and inhibits gastric emptying and acid secretion.
Recently, GLP-1 could be shown to reduce caloric intake and to enhance satiety, most likely via specific receptors within the central nervous system, resulting in reduced weight gain in experimental animals.
In nondiabetic and Type 2 diabetic human subjects, exogenous GLP-1 reduces hunger, caloric intake and body weight.
Therefore, in addition to its well-characterized antidiabetogenic effect, the anorectic effect may offer GLP-1 a potential in the pharmacotherapy of obesity. It is still unknown whether the GLP-1 effect on caloric intake is sustained after long-term treatment.
Furthermore, the exact mechanisms by which the peptide exerts its biological effects have not yet been clarified.
Due to the rapid degradation of native GLP-1, its therapeutic application is limited by the short half-life.
Therefore, suitable modes of administration are needed in order to reach stable plasma concentrations.
Future research the role of GLP-1 in the central regulation of feeding and to discuss its possible application in the pharmacotherapy of obesity. Glucagon-like peptide 1 as a regulator of food intake and body weight: therapeutic perspectives.
European Journal of Pharmacology [0014-2999]
J.J. MEIER ET AL. yr:2002 vol:440 iss:2-3 pg:269 -79

"additional gastrointestinal hormones involved in feeding, including cholecystokinin, glucagon-like peptide 1, and ghrelin, transmit satiety or hunger signals to the brain via the vagal afferent nerve and/or the blood stream." The role of the vagal nerve in peripheral PYY3-36-induced feeding reduction in rats.
Endocrinology [0013-7227] S. KODA
yr:2005 vol:146 iss:5 pg:2369-2375
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