Novel dual incretin agonist peptide with antidiabetic and neuroprotective potential

Research output: Contribution to journalArticle

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Abstract

Glucose-dependent insulinotropic hormone (GIP) and glucagon-like peptide-1 (GLP-1) are incretin hormones that exert an array of beneficial actions on metabolism and cognitive function. GLP-1-based therapeutics have been highly successful in terms of obesity and diabetes management, however GIP therapies have found no clinical utility to date. In the present study we describe, for the first time, the therapeutic effectiveness of a novel GIP/GLP-1 hybrid peptide based on the amino acid sequences of GIP, GLP-1 and the clinically approved GLP-1 mimetic, exendin-4. The hybrid peptide, N-ac(ᴅ-Ala2)GIP/GLP-1-exe, was enzymatically stable for up to 12 h when incubated with DPP-4. N-ac(ᴅ-Ala2)GIP/GLP-1-exe significantly (P<0.001) stimulated insulin secretion from BRIN-BD11 cells and isolated mouse islets, and evoked dose-dependent increases (P<0.001) in cAMP production in both GIP-R and GLP-1-R transfected cells. In mice, injection of the hybrid in combination with glucose significantly (P<0.001) reduced glucose and increased insulin concentrations, with metabolic actions evident (P<0.05) 8 h post-injection. Twice-daily injection of N-ac(ᴅ-Ala2)GIP/GLP-1-exe to high fat fed (HFF) mice for 28 days significantly (P<0.05-P<0.001) reduced body weight, HbA1c, circulating glucose and insulin concentrations. Furthermore, both oral and i.p. glucose tolerance were improved (P<0.001) and insulin sensitivity enhanced. The hybrid peptide also increased (P<0.05-P<0.001) beta cell number, islet area, pancreatic insulin content and islet insulin secretory responsiveness in HFF mice. Finally, N-ac(ᴅ-Ala2)GIP/GLP-1-exe treated mice exhibited improved (P<0.01) recognition memory which was accompanied by enhanced (P<0.05-P<0.001) hippocampal neurogenesis, synapse formation and reduced neuronal oxidative stress. These data demonstrate for the first time the beneficial actions of the novel GIP/GLP-1 hybrid, N-ac(ᴅ-Ala2)GIP/GLP-1-exe, on glucose homeostasis and memory function in diabetes.
LanguageEnglish
Pages264-274
Number of pages11
JournalBIiochemical Pharmacology
Volume155
Early online date19 Jul 2018
DOIs
Publication statusE-pub ahead of print - 19 Jul 2018

Fingerprint

Incretins
Hypoglycemic Agents
Glucagon-Like Peptide 1
Glucose
Peptides
Hormones
Insulin
Medical problems
Injections
Fats
Data storage equipment
Oxidative stress
Neurogenesis
Glucose Tolerance Test

Keywords

  • Glucose dependent insulinotropic hormone (GIP)
  • Glucagon like peptide 1 (GLP-1)
  • insulin secretion
  • Beta cell
  • high fat fed mice
  • Neuroprotection

Cite this

@article{71815718d1154079848dffbd4d41c760,
title = "Novel dual incretin agonist peptide with antidiabetic and neuroprotective potential",
abstract = "Glucose-dependent insulinotropic hormone (GIP) and glucagon-like peptide-1 (GLP-1) are incretin hormones that exert an array of beneficial actions on metabolism and cognitive function. GLP-1-based therapeutics have been highly successful in terms of obesity and diabetes management, however GIP therapies have found no clinical utility to date. In the present study we describe, for the first time, the therapeutic effectiveness of a novel GIP/GLP-1 hybrid peptide based on the amino acid sequences of GIP, GLP-1 and the clinically approved GLP-1 mimetic, exendin-4. The hybrid peptide, N-ac(ᴅ-Ala2)GIP/GLP-1-exe, was enzymatically stable for up to 12 h when incubated with DPP-4. N-ac(ᴅ-Ala2)GIP/GLP-1-exe significantly (P<0.001) stimulated insulin secretion from BRIN-BD11 cells and isolated mouse islets, and evoked dose-dependent increases (P<0.001) in cAMP production in both GIP-R and GLP-1-R transfected cells. In mice, injection of the hybrid in combination with glucose significantly (P<0.001) reduced glucose and increased insulin concentrations, with metabolic actions evident (P<0.05) 8 h post-injection. Twice-daily injection of N-ac(ᴅ-Ala2)GIP/GLP-1-exe to high fat fed (HFF) mice for 28 days significantly (P<0.05-P<0.001) reduced body weight, HbA1c, circulating glucose and insulin concentrations. Furthermore, both oral and i.p. glucose tolerance were improved (P<0.001) and insulin sensitivity enhanced. The hybrid peptide also increased (P<0.05-P<0.001) beta cell number, islet area, pancreatic insulin content and islet insulin secretory responsiveness in HFF mice. Finally, N-ac(ᴅ-Ala2)GIP/GLP-1-exe treated mice exhibited improved (P<0.01) recognition memory which was accompanied by enhanced (P<0.05-P<0.001) hippocampal neurogenesis, synapse formation and reduced neuronal oxidative stress. These data demonstrate for the first time the beneficial actions of the novel GIP/GLP-1 hybrid, N-ac(ᴅ-Ala2)GIP/GLP-1-exe, on glucose homeostasis and memory function in diabetes.",
keywords = "Glucose dependent insulinotropic hormone (GIP) , Glucagon like peptide 1 (GLP-1), insulin secretion, Beta cell, high fat fed mice, Neuroprotection",
author = "NM Pathak and V Pathak and Gault, {Victor A} and S McClean and Nigel Irwin and PR Flatt",
year = "2018",
month = "7",
day = "19",
doi = "10.1016/j.bcp.2018.07.021",
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Novel dual incretin agonist peptide with antidiabetic and neuroprotective potential. / Pathak, NM; Pathak, V; Gault, Victor A; McClean, S; Irwin, Nigel; Flatt, PR.

Vol. 155, 19.07.2018, p. 264-274.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Novel dual incretin agonist peptide with antidiabetic and neuroprotective potential

AU - Pathak, NM

AU - Pathak, V

AU - Gault, Victor A

AU - McClean, S

AU - Irwin, Nigel

AU - Flatt, PR

PY - 2018/7/19

Y1 - 2018/7/19

N2 - Glucose-dependent insulinotropic hormone (GIP) and glucagon-like peptide-1 (GLP-1) are incretin hormones that exert an array of beneficial actions on metabolism and cognitive function. GLP-1-based therapeutics have been highly successful in terms of obesity and diabetes management, however GIP therapies have found no clinical utility to date. In the present study we describe, for the first time, the therapeutic effectiveness of a novel GIP/GLP-1 hybrid peptide based on the amino acid sequences of GIP, GLP-1 and the clinically approved GLP-1 mimetic, exendin-4. The hybrid peptide, N-ac(ᴅ-Ala2)GIP/GLP-1-exe, was enzymatically stable for up to 12 h when incubated with DPP-4. N-ac(ᴅ-Ala2)GIP/GLP-1-exe significantly (P<0.001) stimulated insulin secretion from BRIN-BD11 cells and isolated mouse islets, and evoked dose-dependent increases (P<0.001) in cAMP production in both GIP-R and GLP-1-R transfected cells. In mice, injection of the hybrid in combination with glucose significantly (P<0.001) reduced glucose and increased insulin concentrations, with metabolic actions evident (P<0.05) 8 h post-injection. Twice-daily injection of N-ac(ᴅ-Ala2)GIP/GLP-1-exe to high fat fed (HFF) mice for 28 days significantly (P<0.05-P<0.001) reduced body weight, HbA1c, circulating glucose and insulin concentrations. Furthermore, both oral and i.p. glucose tolerance were improved (P<0.001) and insulin sensitivity enhanced. The hybrid peptide also increased (P<0.05-P<0.001) beta cell number, islet area, pancreatic insulin content and islet insulin secretory responsiveness in HFF mice. Finally, N-ac(ᴅ-Ala2)GIP/GLP-1-exe treated mice exhibited improved (P<0.01) recognition memory which was accompanied by enhanced (P<0.05-P<0.001) hippocampal neurogenesis, synapse formation and reduced neuronal oxidative stress. These data demonstrate for the first time the beneficial actions of the novel GIP/GLP-1 hybrid, N-ac(ᴅ-Ala2)GIP/GLP-1-exe, on glucose homeostasis and memory function in diabetes.

AB - Glucose-dependent insulinotropic hormone (GIP) and glucagon-like peptide-1 (GLP-1) are incretin hormones that exert an array of beneficial actions on metabolism and cognitive function. GLP-1-based therapeutics have been highly successful in terms of obesity and diabetes management, however GIP therapies have found no clinical utility to date. In the present study we describe, for the first time, the therapeutic effectiveness of a novel GIP/GLP-1 hybrid peptide based on the amino acid sequences of GIP, GLP-1 and the clinically approved GLP-1 mimetic, exendin-4. The hybrid peptide, N-ac(ᴅ-Ala2)GIP/GLP-1-exe, was enzymatically stable for up to 12 h when incubated with DPP-4. N-ac(ᴅ-Ala2)GIP/GLP-1-exe significantly (P<0.001) stimulated insulin secretion from BRIN-BD11 cells and isolated mouse islets, and evoked dose-dependent increases (P<0.001) in cAMP production in both GIP-R and GLP-1-R transfected cells. In mice, injection of the hybrid in combination with glucose significantly (P<0.001) reduced glucose and increased insulin concentrations, with metabolic actions evident (P<0.05) 8 h post-injection. Twice-daily injection of N-ac(ᴅ-Ala2)GIP/GLP-1-exe to high fat fed (HFF) mice for 28 days significantly (P<0.05-P<0.001) reduced body weight, HbA1c, circulating glucose and insulin concentrations. Furthermore, both oral and i.p. glucose tolerance were improved (P<0.001) and insulin sensitivity enhanced. The hybrid peptide also increased (P<0.05-P<0.001) beta cell number, islet area, pancreatic insulin content and islet insulin secretory responsiveness in HFF mice. Finally, N-ac(ᴅ-Ala2)GIP/GLP-1-exe treated mice exhibited improved (P<0.01) recognition memory which was accompanied by enhanced (P<0.05-P<0.001) hippocampal neurogenesis, synapse formation and reduced neuronal oxidative stress. These data demonstrate for the first time the beneficial actions of the novel GIP/GLP-1 hybrid, N-ac(ᴅ-Ala2)GIP/GLP-1-exe, on glucose homeostasis and memory function in diabetes.

KW - Glucose dependent insulinotropic hormone (GIP)

KW - Glucagon like peptide 1 (GLP-1)

KW - insulin secretion

KW - Beta cell

KW - high fat fed mice

KW - Neuroprotection

U2 - 10.1016/j.bcp.2018.07.021

DO - 10.1016/j.bcp.2018.07.021

M3 - Article

VL - 155

SP - 264

EP - 274

ER -