Metabolic effects of sustained activation of the GLP-1 receptor alone and in combination with background GIP receptor antagonism in high fat-fed mice

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Abstract

Enzyme-resistant glucagon-like peptide-1 (GLP-1) receptor agonists and GIP receptor antagonists have been proposed to have therapeutic potential for the treatment of type 2 diabetes. Such benefits are based on actions mediated primarily through stimulation of insulin secretion or alleviation of insulin resistance respectively. This study examined the long-term actions of the stable GLP-1 receptor agonist (d-Ala(8))GLP-1 and the GIP receptor antagonist (Pro(3))GIP alone and in combination in high fat-fed mice. Mice on high-fat diet for 155 days were injected once daily with (d-Ala(8))GLP-1 or (Pro(3))GIP (25 nmol/kg body weight) for 24 days. In the following 24-day period, half of the (Pro(3))GIP-treated mice were administered an additional dose of (d-Ala(8))GLP-1 (25 nmol/kg body weight), while the remaining mice continued their original treatment regimes. Daily intraperitoneal injections of (d-Ala(8))GLP-1 or (Pro(3))GIP restored glycaemic control to normal levels and significantly (p <0.05) improved glucose tolerance compared with high-fat controls by day 24. Food intake and body weights were not affected. On day 48, all treatment groups displayed significantly improved glucose tolerance (p <0.05) and insulin sensitivity (p <0.001) compared with high-fat controls on day 48. HDL cholesterol levels were significantly increased in mice treated with (d-Ala(8))GLP-1 alone (p <0.05) or in combination with (Pro(3))GIP (p <0.01) compared with normal chow-fed controls. These results illustrate efficacy of (Pro(3))GIP and (d-Ala(8))GLP-1 for treatment of glucose intolerance and insulin resistance caused by high-fat feeding. Combination therapy appeared to have little benefit over either treatment alone.
LanguageEnglish
Pages603-610
JournalDiabetes Obesity and Metabolism
Volume11
Issue number6
DOIs
Publication statusPublished - Jun 2009

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Glucagon-Like Peptide 1
Fats
Insulin Resistance
Body Weight
Therapeutics
Glucose
Glucose Intolerance
High Fat Diet
gastric inhibitory polypeptide receptor
Glucagon-Like Peptide-1 Receptor
Intraperitoneal Injections
Type 2 Diabetes Mellitus
HDL Cholesterol
Pro(3)-glucose-dependent insulinotropic polypeptide
Eating
Insulin
Enzymes

Cite this

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title = "Metabolic effects of sustained activation of the GLP-1 receptor alone and in combination with background GIP receptor antagonism in high fat-fed mice",
abstract = "Enzyme-resistant glucagon-like peptide-1 (GLP-1) receptor agonists and GIP receptor antagonists have been proposed to have therapeutic potential for the treatment of type 2 diabetes. Such benefits are based on actions mediated primarily through stimulation of insulin secretion or alleviation of insulin resistance respectively. This study examined the long-term actions of the stable GLP-1 receptor agonist (d-Ala(8))GLP-1 and the GIP receptor antagonist (Pro(3))GIP alone and in combination in high fat-fed mice. Mice on high-fat diet for 155 days were injected once daily with (d-Ala(8))GLP-1 or (Pro(3))GIP (25 nmol/kg body weight) for 24 days. In the following 24-day period, half of the (Pro(3))GIP-treated mice were administered an additional dose of (d-Ala(8))GLP-1 (25 nmol/kg body weight), while the remaining mice continued their original treatment regimes. Daily intraperitoneal injections of (d-Ala(8))GLP-1 or (Pro(3))GIP restored glycaemic control to normal levels and significantly (p <0.05) improved glucose tolerance compared with high-fat controls by day 24. Food intake and body weights were not affected. On day 48, all treatment groups displayed significantly improved glucose tolerance (p <0.05) and insulin sensitivity (p <0.001) compared with high-fat controls on day 48. HDL cholesterol levels were significantly increased in mice treated with (d-Ala(8))GLP-1 alone (p <0.05) or in combination with (Pro(3))GIP (p <0.01) compared with normal chow-fed controls. These results illustrate efficacy of (Pro(3))GIP and (d-Ala(8))GLP-1 for treatment of glucose intolerance and insulin resistance caused by high-fat feeding. Combination therapy appeared to have little benefit over either treatment alone.",
author = "Nigel Irwin and Paula McClean and Kerry Hunter and Peter Flatt",
year = "2009",
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doi = "10.1111/j.1463-1326.2009.01036.x",
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T1 - Metabolic effects of sustained activation of the GLP-1 receptor alone and in combination with background GIP receptor antagonism in high fat-fed mice

AU - Irwin, Nigel

AU - McClean, Paula

AU - Hunter, Kerry

AU - Flatt, Peter

PY - 2009/6

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N2 - Enzyme-resistant glucagon-like peptide-1 (GLP-1) receptor agonists and GIP receptor antagonists have been proposed to have therapeutic potential for the treatment of type 2 diabetes. Such benefits are based on actions mediated primarily through stimulation of insulin secretion or alleviation of insulin resistance respectively. This study examined the long-term actions of the stable GLP-1 receptor agonist (d-Ala(8))GLP-1 and the GIP receptor antagonist (Pro(3))GIP alone and in combination in high fat-fed mice. Mice on high-fat diet for 155 days were injected once daily with (d-Ala(8))GLP-1 or (Pro(3))GIP (25 nmol/kg body weight) for 24 days. In the following 24-day period, half of the (Pro(3))GIP-treated mice were administered an additional dose of (d-Ala(8))GLP-1 (25 nmol/kg body weight), while the remaining mice continued their original treatment regimes. Daily intraperitoneal injections of (d-Ala(8))GLP-1 or (Pro(3))GIP restored glycaemic control to normal levels and significantly (p <0.05) improved glucose tolerance compared with high-fat controls by day 24. Food intake and body weights were not affected. On day 48, all treatment groups displayed significantly improved glucose tolerance (p <0.05) and insulin sensitivity (p <0.001) compared with high-fat controls on day 48. HDL cholesterol levels were significantly increased in mice treated with (d-Ala(8))GLP-1 alone (p <0.05) or in combination with (Pro(3))GIP (p <0.01) compared with normal chow-fed controls. These results illustrate efficacy of (Pro(3))GIP and (d-Ala(8))GLP-1 for treatment of glucose intolerance and insulin resistance caused by high-fat feeding. Combination therapy appeared to have little benefit over either treatment alone.

AB - Enzyme-resistant glucagon-like peptide-1 (GLP-1) receptor agonists and GIP receptor antagonists have been proposed to have therapeutic potential for the treatment of type 2 diabetes. Such benefits are based on actions mediated primarily through stimulation of insulin secretion or alleviation of insulin resistance respectively. This study examined the long-term actions of the stable GLP-1 receptor agonist (d-Ala(8))GLP-1 and the GIP receptor antagonist (Pro(3))GIP alone and in combination in high fat-fed mice. Mice on high-fat diet for 155 days were injected once daily with (d-Ala(8))GLP-1 or (Pro(3))GIP (25 nmol/kg body weight) for 24 days. In the following 24-day period, half of the (Pro(3))GIP-treated mice were administered an additional dose of (d-Ala(8))GLP-1 (25 nmol/kg body weight), while the remaining mice continued their original treatment regimes. Daily intraperitoneal injections of (d-Ala(8))GLP-1 or (Pro(3))GIP restored glycaemic control to normal levels and significantly (p <0.05) improved glucose tolerance compared with high-fat controls by day 24. Food intake and body weights were not affected. On day 48, all treatment groups displayed significantly improved glucose tolerance (p <0.05) and insulin sensitivity (p <0.001) compared with high-fat controls on day 48. HDL cholesterol levels were significantly increased in mice treated with (d-Ala(8))GLP-1 alone (p <0.05) or in combination with (Pro(3))GIP (p <0.01) compared with normal chow-fed controls. These results illustrate efficacy of (Pro(3))GIP and (d-Ala(8))GLP-1 for treatment of glucose intolerance and insulin resistance caused by high-fat feeding. Combination therapy appeared to have little benefit over either treatment alone.

U2 - 10.1111/j.1463-1326.2009.01036.x

DO - 10.1111/j.1463-1326.2009.01036.x

M3 - Article

VL - 11

SP - 603

EP - 610

JO - Diabetes, Obesity and Metabolism

T2 - Diabetes, Obesity and Metabolism

JF - Diabetes, Obesity and Metabolism

SN - 1463-1326

IS - 6

ER -