C-terminal mini-PEGylation of glucose-dependent insulinotropic polypeptide exhibits metabolic stability and improved glucose homeostasis in dietary-induced diabetes

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Abstract

Glucose-dependent insulinotropic polypeptide has been proposed as a Potential therapeutic for type 2 diabetes, however, efforts to bring forward this drug have been hindered due to its short circulating half-life. We have adopted a novel strategy to increase potency and prolong GIP action through C-terminal mini-PEGylation (GIP[mPEG]). In contrast to GIP, GIP[mPEG] was resistant to dipeptidylpeptidase-IV (DPP-IV) up to and including 24 h. Both GIP(mPEG) and GIP concentration-dependently stimulated CAMP production (EC50 6.6 and 0.7 nM, respectively) and insulin secretion (p <0.01 to p <0.001) in pancreatic BRIN-BD11 cells. Acute injection of GIP[mPEG] together with glucose to high fat fed mice significantly lowered plasma glucose (p <0.05) and increased plasma insulin responses (p <0.05). Furthermore, GIP[mPEGJ markedly lowered plasma glucose when administered 4-24 h prior to a glucose load (p <0.05). Daily administration of GIP[mPEG] for 20 days in high fat mice did not alter body weight, food intake or non-fasting plasma insulin, however, non-fasting plasma glucose concentrations were significantly lowered (p <0.05). Moreover, glucose tolerance was significantly improved (p <0.05) together with glucose-mediated plasma insulin responses (p <0.05). Insulin sensitivity, pancreatic insulin content, triglyceride and adiponectin levels were not changed. in summary, these data demonstrate that C-terminal mini-PEGylation of GIP is a useful strategy to prolong metabolic stability and, improve biological action thus representing a novel therapeutic option for type 2 diabetes. (C) 2008 Elsevier Inc. All rights reserved.
LanguageEnglish
Pages2325-2333
JournalBIiochemical Pharmacology
Volume75
Issue number12
DOIs
Publication statusPublished - Jun 2008

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Homeostasis
Glucose
Peptides
Insulin
Type 2 Diabetes Mellitus
Fats
Adiponectin
Half-Life
Insulin Resistance
Triglycerides
Eating
Body Weight
Injections
Therapeutics
Pharmaceutical Preparations

Cite this

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title = "C-terminal mini-PEGylation of glucose-dependent insulinotropic polypeptide exhibits metabolic stability and improved glucose homeostasis in dietary-induced diabetes",
abstract = "Glucose-dependent insulinotropic polypeptide has been proposed as a Potential therapeutic for type 2 diabetes, however, efforts to bring forward this drug have been hindered due to its short circulating half-life. We have adopted a novel strategy to increase potency and prolong GIP action through C-terminal mini-PEGylation (GIP[mPEG]). In contrast to GIP, GIP[mPEG] was resistant to dipeptidylpeptidase-IV (DPP-IV) up to and including 24 h. Both GIP(mPEG) and GIP concentration-dependently stimulated CAMP production (EC50 6.6 and 0.7 nM, respectively) and insulin secretion (p <0.01 to p <0.001) in pancreatic BRIN-BD11 cells. Acute injection of GIP[mPEG] together with glucose to high fat fed mice significantly lowered plasma glucose (p <0.05) and increased plasma insulin responses (p <0.05). Furthermore, GIP[mPEGJ markedly lowered plasma glucose when administered 4-24 h prior to a glucose load (p <0.05). Daily administration of GIP[mPEG] for 20 days in high fat mice did not alter body weight, food intake or non-fasting plasma insulin, however, non-fasting plasma glucose concentrations were significantly lowered (p <0.05). Moreover, glucose tolerance was significantly improved (p <0.05) together with glucose-mediated plasma insulin responses (p <0.05). Insulin sensitivity, pancreatic insulin content, triglyceride and adiponectin levels were not changed. in summary, these data demonstrate that C-terminal mini-PEGylation of GIP is a useful strategy to prolong metabolic stability and, improve biological action thus representing a novel therapeutic option for type 2 diabetes. (C) 2008 Elsevier Inc. All rights reserved.",
author = "Victor Gault and Kerr, {Barry D.} and Nigel Irwin and Peter Flatt",
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T1 - C-terminal mini-PEGylation of glucose-dependent insulinotropic polypeptide exhibits metabolic stability and improved glucose homeostasis in dietary-induced diabetes

AU - Gault, Victor

AU - Kerr, Barry D.

AU - Irwin, Nigel

AU - Flatt, Peter

PY - 2008/6

Y1 - 2008/6

N2 - Glucose-dependent insulinotropic polypeptide has been proposed as a Potential therapeutic for type 2 diabetes, however, efforts to bring forward this drug have been hindered due to its short circulating half-life. We have adopted a novel strategy to increase potency and prolong GIP action through C-terminal mini-PEGylation (GIP[mPEG]). In contrast to GIP, GIP[mPEG] was resistant to dipeptidylpeptidase-IV (DPP-IV) up to and including 24 h. Both GIP(mPEG) and GIP concentration-dependently stimulated CAMP production (EC50 6.6 and 0.7 nM, respectively) and insulin secretion (p <0.01 to p <0.001) in pancreatic BRIN-BD11 cells. Acute injection of GIP[mPEG] together with glucose to high fat fed mice significantly lowered plasma glucose (p <0.05) and increased plasma insulin responses (p <0.05). Furthermore, GIP[mPEGJ markedly lowered plasma glucose when administered 4-24 h prior to a glucose load (p <0.05). Daily administration of GIP[mPEG] for 20 days in high fat mice did not alter body weight, food intake or non-fasting plasma insulin, however, non-fasting plasma glucose concentrations were significantly lowered (p <0.05). Moreover, glucose tolerance was significantly improved (p <0.05) together with glucose-mediated plasma insulin responses (p <0.05). Insulin sensitivity, pancreatic insulin content, triglyceride and adiponectin levels were not changed. in summary, these data demonstrate that C-terminal mini-PEGylation of GIP is a useful strategy to prolong metabolic stability and, improve biological action thus representing a novel therapeutic option for type 2 diabetes. (C) 2008 Elsevier Inc. All rights reserved.

AB - Glucose-dependent insulinotropic polypeptide has been proposed as a Potential therapeutic for type 2 diabetes, however, efforts to bring forward this drug have been hindered due to its short circulating half-life. We have adopted a novel strategy to increase potency and prolong GIP action through C-terminal mini-PEGylation (GIP[mPEG]). In contrast to GIP, GIP[mPEG] was resistant to dipeptidylpeptidase-IV (DPP-IV) up to and including 24 h. Both GIP(mPEG) and GIP concentration-dependently stimulated CAMP production (EC50 6.6 and 0.7 nM, respectively) and insulin secretion (p <0.01 to p <0.001) in pancreatic BRIN-BD11 cells. Acute injection of GIP[mPEG] together with glucose to high fat fed mice significantly lowered plasma glucose (p <0.05) and increased plasma insulin responses (p <0.05). Furthermore, GIP[mPEGJ markedly lowered plasma glucose when administered 4-24 h prior to a glucose load (p <0.05). Daily administration of GIP[mPEG] for 20 days in high fat mice did not alter body weight, food intake or non-fasting plasma insulin, however, non-fasting plasma glucose concentrations were significantly lowered (p <0.05). Moreover, glucose tolerance was significantly improved (p <0.05) together with glucose-mediated plasma insulin responses (p <0.05). Insulin sensitivity, pancreatic insulin content, triglyceride and adiponectin levels were not changed. in summary, these data demonstrate that C-terminal mini-PEGylation of GIP is a useful strategy to prolong metabolic stability and, improve biological action thus representing a novel therapeutic option for type 2 diabetes. (C) 2008 Elsevier Inc. All rights reserved.

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