Structurally modified analogues of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypcptide (GIP) as future antidiabetic agents

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Abstract

Glucagon-like pepticle-1(7-36)amide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are gastrointestinal insulin-releasing hormones involved in the regulation of postprandial nutrient homeostasis. These two incretin hormones are glucose-dependent stimulators of pancreatic beta-cell function, exhibiting a spectrum of secondary extrapancreatic activities, which favour the efficient control of blood glucose homeostasis. Such actions of GLP-1 and GIP have generated considerable interest in their possible exploitation as novel agents for the treatment of type 2 diabetes. Despite the many attributes of GLP-1 and GIP as possible future antidiabetic agents, their rapid degradation in the circulation by dipeptidyl peptidase IV (DPI IV) to inactive truncated forms GLP-1(9-36)amide and GIP(3-42), severely limits their therapeutic usefulness. This review will consider recent developments in the design and effectiveness of synthetic DPP IV-resistant analogues of GLP-1 and GIP. Consideration will be given to the effects of N-terminal modification and amino acid Substitution of GLP-1 and GIP either side of the DPP IV cleavage site on (i) susceptibility to (iv) enzymatic degradation, (ii) binding to native hormone receptor, (iii) ability to elevate intracellular cyclic AMP, potency as insulin secretagogues.. and (v) antihyperglycaemic activity in type 2 diabetes. It will be shown that structural modification can produce a varied set of biological activities, ranging from more efficacious analogues to those which antagonise the activity of the native hormone. The antidiabetic properties of the best GLP-1 and GIP analogues indeed promise to provide the basis for novel, effective and long-acting drugs for type 2 diabetes therapy. This approach is currently being pursued actively by the pharmaceutical industry.
LanguageEnglish
Pages3651-3662
JournalCurrent Pharmaceutical Design
Volume10
Issue number29
Publication statusPublished - 2004

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Glucagon-Like Peptide 1
Hypoglycemic Agents
Glucose
Medical problems
Hormones
Insulin
Dipeptidyl Peptidase 4
Incretins
Degradation
Bioactivity
Glucagon
Amides
Pharmaceutical Preparations
Cyclic AMP
Nutrients
Blood Glucose
Substitution reactions
Amino Acids
Peptides

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title = "Structurally modified analogues of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypcptide (GIP) as future antidiabetic agents",
abstract = "Glucagon-like pepticle-1(7-36)amide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are gastrointestinal insulin-releasing hormones involved in the regulation of postprandial nutrient homeostasis. These two incretin hormones are glucose-dependent stimulators of pancreatic beta-cell function, exhibiting a spectrum of secondary extrapancreatic activities, which favour the efficient control of blood glucose homeostasis. Such actions of GLP-1 and GIP have generated considerable interest in their possible exploitation as novel agents for the treatment of type 2 diabetes. Despite the many attributes of GLP-1 and GIP as possible future antidiabetic agents, their rapid degradation in the circulation by dipeptidyl peptidase IV (DPI IV) to inactive truncated forms GLP-1(9-36)amide and GIP(3-42), severely limits their therapeutic usefulness. This review will consider recent developments in the design and effectiveness of synthetic DPP IV-resistant analogues of GLP-1 and GIP. Consideration will be given to the effects of N-terminal modification and amino acid Substitution of GLP-1 and GIP either side of the DPP IV cleavage site on (i) susceptibility to (iv) enzymatic degradation, (ii) binding to native hormone receptor, (iii) ability to elevate intracellular cyclic AMP, potency as insulin secretagogues.. and (v) antihyperglycaemic activity in type 2 diabetes. It will be shown that structural modification can produce a varied set of biological activities, ranging from more efficacious analogues to those which antagonise the activity of the native hormone. The antidiabetic properties of the best GLP-1 and GIP analogues indeed promise to provide the basis for novel, effective and long-acting drugs for type 2 diabetes therapy. This approach is currently being pursued actively by the pharmaceutical industry.",
author = "BD Green and Victor Gault and Finbarr O'Harte and Peter Flatt",
year = "2004",
language = "English",
volume = "10",
pages = "3651--3662",
journal = "Current Pharmaceutical Design",
issn = "1381-6128",
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AU - Green, BD

AU - Gault, Victor

AU - O'Harte, Finbarr

AU - Flatt, Peter

PY - 2004

Y1 - 2004

N2 - Glucagon-like pepticle-1(7-36)amide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are gastrointestinal insulin-releasing hormones involved in the regulation of postprandial nutrient homeostasis. These two incretin hormones are glucose-dependent stimulators of pancreatic beta-cell function, exhibiting a spectrum of secondary extrapancreatic activities, which favour the efficient control of blood glucose homeostasis. Such actions of GLP-1 and GIP have generated considerable interest in their possible exploitation as novel agents for the treatment of type 2 diabetes. Despite the many attributes of GLP-1 and GIP as possible future antidiabetic agents, their rapid degradation in the circulation by dipeptidyl peptidase IV (DPI IV) to inactive truncated forms GLP-1(9-36)amide and GIP(3-42), severely limits their therapeutic usefulness. This review will consider recent developments in the design and effectiveness of synthetic DPP IV-resistant analogues of GLP-1 and GIP. Consideration will be given to the effects of N-terminal modification and amino acid Substitution of GLP-1 and GIP either side of the DPP IV cleavage site on (i) susceptibility to (iv) enzymatic degradation, (ii) binding to native hormone receptor, (iii) ability to elevate intracellular cyclic AMP, potency as insulin secretagogues.. and (v) antihyperglycaemic activity in type 2 diabetes. It will be shown that structural modification can produce a varied set of biological activities, ranging from more efficacious analogues to those which antagonise the activity of the native hormone. The antidiabetic properties of the best GLP-1 and GIP analogues indeed promise to provide the basis for novel, effective and long-acting drugs for type 2 diabetes therapy. This approach is currently being pursued actively by the pharmaceutical industry.

AB - Glucagon-like pepticle-1(7-36)amide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are gastrointestinal insulin-releasing hormones involved in the regulation of postprandial nutrient homeostasis. These two incretin hormones are glucose-dependent stimulators of pancreatic beta-cell function, exhibiting a spectrum of secondary extrapancreatic activities, which favour the efficient control of blood glucose homeostasis. Such actions of GLP-1 and GIP have generated considerable interest in their possible exploitation as novel agents for the treatment of type 2 diabetes. Despite the many attributes of GLP-1 and GIP as possible future antidiabetic agents, their rapid degradation in the circulation by dipeptidyl peptidase IV (DPI IV) to inactive truncated forms GLP-1(9-36)amide and GIP(3-42), severely limits their therapeutic usefulness. This review will consider recent developments in the design and effectiveness of synthetic DPP IV-resistant analogues of GLP-1 and GIP. Consideration will be given to the effects of N-terminal modification and amino acid Substitution of GLP-1 and GIP either side of the DPP IV cleavage site on (i) susceptibility to (iv) enzymatic degradation, (ii) binding to native hormone receptor, (iii) ability to elevate intracellular cyclic AMP, potency as insulin secretagogues.. and (v) antihyperglycaemic activity in type 2 diabetes. It will be shown that structural modification can produce a varied set of biological activities, ranging from more efficacious analogues to those which antagonise the activity of the native hormone. The antidiabetic properties of the best GLP-1 and GIP analogues indeed promise to provide the basis for novel, effective and long-acting drugs for type 2 diabetes therapy. This approach is currently being pursued actively by the pharmaceutical industry.

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