Effects of chronic exposure of clonal β-cells to elevated glucose and free fatty acids on incretin receptor gene expression and secretory responses to GIP and GLP-1.

V. Pathak, S. Vasu, P.R. Flatt, N. Irwin

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Abstract

Aim

The incretin effect, mediated by glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), is impaired in type 2 diabetes.

Methods

This study examines the effects of prolonged exposure to elevated glucose and free fatty acids in clonal BRIN BD11 cells on GIP and GLP-1 action.

Results

Glucotoxic conditions (18 h) had no effect on GIP- or GLP-1-mediated insulinotropic responses. In contrast, 48 h glucotoxic culture impaired (p < 0.05 to p < 0.001) insulin release in response to GLP-1, and particularly GIP. Culture under lipotoxic conditions (18 h) impaired (p < 0.05 to p < 0.001) the insulin-releasing effect of GIP, but was without effect on GLP-1. However, 48 h lipotoxic culture compromised both GIP (p < 0.05 to p < 0.001) and GLP-1 (p < 0.05 to p < 0.01) insulin-releasing actions. Glucolipotoxic culture (18 h) completely annulled the insulinotropic action of GIP, whereas GLP-1 effects were similar to control. However, when glucolipotoxic culture was extended to 48 h, both GIP- and GLP-1-mediated effects were (p < 0.05 to p < 0.001) impaired. Assessment of cell viability, number and insulin content revealed detrimental (p < 0.05 to p < 0.001) effects under all culture conditions, barring 18 h glucotoxic and lipotoxic culture. Finally, GIP-R gene and protein expression was increased (p < 0.05 to p < 0.01) under glucotoxic culture, with decreased (p < 0.05 to p < 0.001) expression following glucolipotoxic culture. GLP-1-R gene expression followed a similar trend, but protein levels were generally reduced under all culture conditions.

Conclusion

The results indicate that impaired insulinotropic response to GIP and GLP-1 under diabetic milieu involves mechanisms beyond simple expression of respective receptors.

LanguageEnglish
Pages357-365
JournalDiabetes, Obesity and Metabolism
Volume16
Issue number4
Early online date20 Nov 2013
DOIs
Publication statusPublished - Apr 2014

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Incretins
Glucagon-Like Peptide 1
Nonesterified Fatty Acids
Gene Expression
Glucose
Peptides
Insulin
vpr Genes
Type 2 Diabetes Mellitus
Proteins

Cite this

@article{04b90496b8ab409aa5b10c6714eba3fb,
title = "Effects of chronic exposure of clonal β-cells to elevated glucose and free fatty acids on incretin receptor gene expression and secretory responses to GIP and GLP-1.",
abstract = "Aim The incretin effect, mediated by glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), is impaired in type 2 diabetes. Methods This study examines the effects of prolonged exposure to elevated glucose and free fatty acids in clonal BRIN BD11 cells on GIP and GLP-1 action. Results Glucotoxic conditions (18 h) had no effect on GIP- or GLP-1-mediated insulinotropic responses. In contrast, 48 h glucotoxic culture impaired (p < 0.05 to p < 0.001) insulin release in response to GLP-1, and particularly GIP. Culture under lipotoxic conditions (18 h) impaired (p < 0.05 to p < 0.001) the insulin-releasing effect of GIP, but was without effect on GLP-1. However, 48 h lipotoxic culture compromised both GIP (p < 0.05 to p < 0.001) and GLP-1 (p < 0.05 to p < 0.01) insulin-releasing actions. Glucolipotoxic culture (18 h) completely annulled the insulinotropic action of GIP, whereas GLP-1 effects were similar to control. However, when glucolipotoxic culture was extended to 48 h, both GIP- and GLP-1-mediated effects were (p < 0.05 to p < 0.001) impaired. Assessment of cell viability, number and insulin content revealed detrimental (p < 0.05 to p < 0.001) effects under all culture conditions, barring 18 h glucotoxic and lipotoxic culture. Finally, GIP-R gene and protein expression was increased (p < 0.05 to p < 0.01) under glucotoxic culture, with decreased (p < 0.05 to p < 0.001) expression following glucolipotoxic culture. GLP-1-R gene expression followed a similar trend, but protein levels were generally reduced under all culture conditions. Conclusion The results indicate that impaired insulinotropic response to GIP and GLP-1 under diabetic milieu involves mechanisms beyond simple expression of respective receptors.",
author = "V. Pathak and S. Vasu and P.R. Flatt and N. Irwin",
year = "2014",
month = "4",
doi = "10.1111/dom.12227",
language = "English",
volume = "16",
pages = "357--365",
journal = "Diabetes, Obesity and Metabolism",
issn = "1462-8902",
publisher = "Wiley-Blackwell",
number = "4",

}

TY - JOUR

T1 - Effects of chronic exposure of clonal β-cells to elevated glucose and free fatty acids on incretin receptor gene expression and secretory responses to GIP and GLP-1.

AU - Pathak, V.

AU - Vasu, S.

AU - Flatt, P.R.

AU - Irwin, N.

PY - 2014/4

Y1 - 2014/4

N2 - Aim The incretin effect, mediated by glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), is impaired in type 2 diabetes. Methods This study examines the effects of prolonged exposure to elevated glucose and free fatty acids in clonal BRIN BD11 cells on GIP and GLP-1 action. Results Glucotoxic conditions (18 h) had no effect on GIP- or GLP-1-mediated insulinotropic responses. In contrast, 48 h glucotoxic culture impaired (p < 0.05 to p < 0.001) insulin release in response to GLP-1, and particularly GIP. Culture under lipotoxic conditions (18 h) impaired (p < 0.05 to p < 0.001) the insulin-releasing effect of GIP, but was without effect on GLP-1. However, 48 h lipotoxic culture compromised both GIP (p < 0.05 to p < 0.001) and GLP-1 (p < 0.05 to p < 0.01) insulin-releasing actions. Glucolipotoxic culture (18 h) completely annulled the insulinotropic action of GIP, whereas GLP-1 effects were similar to control. However, when glucolipotoxic culture was extended to 48 h, both GIP- and GLP-1-mediated effects were (p < 0.05 to p < 0.001) impaired. Assessment of cell viability, number and insulin content revealed detrimental (p < 0.05 to p < 0.001) effects under all culture conditions, barring 18 h glucotoxic and lipotoxic culture. Finally, GIP-R gene and protein expression was increased (p < 0.05 to p < 0.01) under glucotoxic culture, with decreased (p < 0.05 to p < 0.001) expression following glucolipotoxic culture. GLP-1-R gene expression followed a similar trend, but protein levels were generally reduced under all culture conditions. Conclusion The results indicate that impaired insulinotropic response to GIP and GLP-1 under diabetic milieu involves mechanisms beyond simple expression of respective receptors.

AB - Aim The incretin effect, mediated by glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), is impaired in type 2 diabetes. Methods This study examines the effects of prolonged exposure to elevated glucose and free fatty acids in clonal BRIN BD11 cells on GIP and GLP-1 action. Results Glucotoxic conditions (18 h) had no effect on GIP- or GLP-1-mediated insulinotropic responses. In contrast, 48 h glucotoxic culture impaired (p < 0.05 to p < 0.001) insulin release in response to GLP-1, and particularly GIP. Culture under lipotoxic conditions (18 h) impaired (p < 0.05 to p < 0.001) the insulin-releasing effect of GIP, but was without effect on GLP-1. However, 48 h lipotoxic culture compromised both GIP (p < 0.05 to p < 0.001) and GLP-1 (p < 0.05 to p < 0.01) insulin-releasing actions. Glucolipotoxic culture (18 h) completely annulled the insulinotropic action of GIP, whereas GLP-1 effects were similar to control. However, when glucolipotoxic culture was extended to 48 h, both GIP- and GLP-1-mediated effects were (p < 0.05 to p < 0.001) impaired. Assessment of cell viability, number and insulin content revealed detrimental (p < 0.05 to p < 0.001) effects under all culture conditions, barring 18 h glucotoxic and lipotoxic culture. Finally, GIP-R gene and protein expression was increased (p < 0.05 to p < 0.01) under glucotoxic culture, with decreased (p < 0.05 to p < 0.001) expression following glucolipotoxic culture. GLP-1-R gene expression followed a similar trend, but protein levels were generally reduced under all culture conditions. Conclusion The results indicate that impaired insulinotropic response to GIP and GLP-1 under diabetic milieu involves mechanisms beyond simple expression of respective receptors.

U2 - 10.1111/dom.12227

DO - 10.1111/dom.12227

M3 - Article

VL - 16

SP - 357

EP - 365

JO - Diabetes, Obesity and Metabolism

T2 - Diabetes, Obesity and Metabolism

JF - Diabetes, Obesity and Metabolism

SN - 1462-8902

IS - 4

ER -