Abstract
| Language | English |
|---|---|
| Pages | 1-9 |
| Number of pages | 9 |
| Journal | Clinical Medicine Insights: Endocrinology and Diabetes |
| Volume | 12 |
| Issue number | 1-9 |
| DOIs | |
| Publication status | Published - 12 Sep 2019 |
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Keywords
- GIP
- insulin secretion
- glucose homeostasis
- Species Specificity
- Glucose-dependent insulinotropic polypeptide (GIP)
- species specificity
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Characterisation of Glucose-Dependent Insulinotropic Polypeptide Receptor Antagonists in Rodent Pancreatic Beta Cells and Mice. / Perry, Rachele; Craig, Sarah; NG, Tony; Gault, Victor A; Flatt, PR; Irwin, Nigel.
In: Clinical Medicine Insights: Endocrinology and Diabetes , Vol. 12, No. 1-9, 12.09.2019, p. 1-9.Research output: Contribution to journal › Article
TY - JOUR
T1 - Characterisation of Glucose-Dependent Insulinotropic Polypeptide Receptor Antagonists in Rodent Pancreatic Beta Cells and Mice
AU - Perry, Rachele
AU - Craig, Sarah
AU - NG, Tony
AU - Gault, Victor A
AU - Flatt, PR
AU - Irwin, Nigel
PY - 2019/9/12
Y1 - 2019/9/12
N2 - Hypersecretion and alterations in the biological activity of the incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), have been postulated as contributing factors in the development of obesity-related diabetes. However, recent studies also point to weightreducing effects of GIP receptor activation. Therefore, generating precise experimental tools, such as specific and effective GIP receptor (GIPR) antagonists, is of key significance to better understand GIP physiology. Thus, the primary aim of the current study was to uncover improved GIPR antagonists for use in rodent studies, using human and mouse GIP sequences with N- and C-terminal deletions. Initial in vitro studies revealed that the GIPR agonists, human (h) GIP(1-42), hGIP(1-30) and mouse (m) GIP(1-30), stimulated (P < 0.01 to P < 0.001) insulin secretion from rat BRIN-BD11 cells. Analysis of insulin secretory effects of the N- and C-terminally cleaved GIP peptides, including hGIP(3-30), mGIP(3-30), h(Pro3)GIP(3-30), hGIP(5-30), hGIP(3-42) and hGIP(5-42), revealed that these peptides did not modulate insulin secretion. More pertinently, only hGIP(3-30), mGIP(3-30) and h(Pro3)GIP(3-30) were able to significantly (P < 0.01 to P < 0.001) inhibit hGIP(1-42)-stimulated insulin secretion. The human-derived GIPR agonist sequences, hGIP(1-42) and hGIP(1-30), reduced (P < 0.05) glucose levels in mice following conjoint injection with glucose, but mGIP(1-30) was ineffective. None of the N- and C-terminally cleaved GIP peptides affected glucose homeostasis when injected alone with glucose. However, hGIP(5-30) and mGIP(3-30) significantly (P < 0.05 to P < 0.01) impaired the glucose-lowering action of hGIP(1-42). Further evaluation of these most effective sequences demonstrated that mGIP(3-30), but not hGIP(5-30), effectively prevented GIPinduced elevations of plasma insulin concentrations. These data highlight, for the first time, that mGIP(3-30) represents an effective molecule to inhibit GIPR activity in mice
AB - Hypersecretion and alterations in the biological activity of the incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), have been postulated as contributing factors in the development of obesity-related diabetes. However, recent studies also point to weightreducing effects of GIP receptor activation. Therefore, generating precise experimental tools, such as specific and effective GIP receptor (GIPR) antagonists, is of key significance to better understand GIP physiology. Thus, the primary aim of the current study was to uncover improved GIPR antagonists for use in rodent studies, using human and mouse GIP sequences with N- and C-terminal deletions. Initial in vitro studies revealed that the GIPR agonists, human (h) GIP(1-42), hGIP(1-30) and mouse (m) GIP(1-30), stimulated (P < 0.01 to P < 0.001) insulin secretion from rat BRIN-BD11 cells. Analysis of insulin secretory effects of the N- and C-terminally cleaved GIP peptides, including hGIP(3-30), mGIP(3-30), h(Pro3)GIP(3-30), hGIP(5-30), hGIP(3-42) and hGIP(5-42), revealed that these peptides did not modulate insulin secretion. More pertinently, only hGIP(3-30), mGIP(3-30) and h(Pro3)GIP(3-30) were able to significantly (P < 0.01 to P < 0.001) inhibit hGIP(1-42)-stimulated insulin secretion. The human-derived GIPR agonist sequences, hGIP(1-42) and hGIP(1-30), reduced (P < 0.05) glucose levels in mice following conjoint injection with glucose, but mGIP(1-30) was ineffective. None of the N- and C-terminally cleaved GIP peptides affected glucose homeostasis when injected alone with glucose. However, hGIP(5-30) and mGIP(3-30) significantly (P < 0.05 to P < 0.01) impaired the glucose-lowering action of hGIP(1-42). Further evaluation of these most effective sequences demonstrated that mGIP(3-30), but not hGIP(5-30), effectively prevented GIPinduced elevations of plasma insulin concentrations. These data highlight, for the first time, that mGIP(3-30) represents an effective molecule to inhibit GIPR activity in mice
KW - GIP
KW - insulin secretion
KW - glucose homeostasis
KW - Species Specificity
KW - Glucose-dependent insulinotropic polypeptide (GIP)
KW - species specificity
UR - http://www.scopus.com/inward/record.url?scp=85073031642&partnerID=8YFLogxK
U2 - 10.1177/1179551419875453
DO - 10.1177/1179551419875453
M3 - Article
VL - 12
SP - 1
EP - 9
JO - Clinical Medicine Insights: Endocrinology and Diabetes
T2 - Clinical Medicine Insights: Endocrinology and Diabetes
JF - Clinical Medicine Insights: Endocrinology and Diabetes
SN - 1179-5514
IS - 1-9
ER -