High glucose represses β-klotho expression and impairs fibroblast growth factor 21 action in mouse pancreatic islets

Involvement of peroxisome proliferator-activated receptor γ signaling

Wing Yan So, Qianni Cheng, Lihua Chen, Carmella Evans-Molina, Aimin Xu, Karen S L Lam, Po Sing Leung

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

Circulating fibroblast growth factor 21 (FGF21) levels are elevated in diabetic subjects and correlate directly with abnormal glucose metabolism, while pharmacologically administered FGF21 can ameliorate hyperglycemia. The pancreatic islet is an FGF21 target, yet the actions of FGF21 in the islet under normal and diabetic conditions are not fully understood. This study investigated the effects of high glucose on islet FGF21 actions in a diabetic mouse model by investigating db/db mouse islet responses to exogenous FGF21, the direct effects of glucose on FGF21 signaling, and the involvement of peroxisome proliferator-activated receptor γ (PPARγ) in FGF21 pathway activation. Results showed that both adult db/db mouse islets and normal islets treated with high glucose ex vivo displayed reduced β-klotho expression, resistance to FGF21, and decreased PPARγ expression. Rosiglitazone, an antidiabetic PPARγ ligand, ameliorated these effects. Our data indicate that hyperglycemia in type 2 diabetes mellitus may lead to FGF21 resistance in pancreatic islets, probably through reduction of PPARγ expression, which provides a novel mechanism for glucosemediated islet dysfunction.

Original languageEnglish
Pages (from-to)3751-3759
Number of pages9
JournalDiabetes
Volume62
Issue number11
DOIs
StatePublished - Nov 2013

Fingerprint

Peroxisome Proliferator-Activated Receptors
Islets of Langerhans
Glucose
rosiglitazone
Hyperglycemia
fibroblast growth factor 21
Hypoglycemic Agents
Type 2 Diabetes Mellitus
Ligands

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Medicine(all)

Cite this

High glucose represses β-klotho expression and impairs fibroblast growth factor 21 action in mouse pancreatic islets : Involvement of peroxisome proliferator-activated receptor γ signaling. / So, Wing Yan; Cheng, Qianni; Chen, Lihua; Evans-Molina, Carmella; Xu, Aimin; Lam, Karen S L; Leung, Po Sing.

In: Diabetes, Vol. 62, No. 11, 11.2013, p. 3751-3759.

Research output: Contribution to journalArticle

@article{4f0cb889bb8b411a9ca655eb3c262460,
title = "High glucose represses β-klotho expression and impairs fibroblast growth factor 21 action in mouse pancreatic islets: Involvement of peroxisome proliferator-activated receptor γ signaling",
abstract = "Circulating fibroblast growth factor 21 (FGF21) levels are elevated in diabetic subjects and correlate directly with abnormal glucose metabolism, while pharmacologically administered FGF21 can ameliorate hyperglycemia. The pancreatic islet is an FGF21 target, yet the actions of FGF21 in the islet under normal and diabetic conditions are not fully understood. This study investigated the effects of high glucose on islet FGF21 actions in a diabetic mouse model by investigating db/db mouse islet responses to exogenous FGF21, the direct effects of glucose on FGF21 signaling, and the involvement of peroxisome proliferator-activated receptor γ (PPARγ) in FGF21 pathway activation. Results showed that both adult db/db mouse islets and normal islets treated with high glucose ex vivo displayed reduced β-klotho expression, resistance to FGF21, and decreased PPARγ expression. Rosiglitazone, an antidiabetic PPARγ ligand, ameliorated these effects. Our data indicate that hyperglycemia in type 2 diabetes mellitus may lead to FGF21 resistance in pancreatic islets, probably through reduction of PPARγ expression, which provides a novel mechanism for glucosemediated islet dysfunction.",
author = "So, {Wing Yan} and Qianni Cheng and Lihua Chen and Carmella Evans-Molina and Aimin Xu and Lam, {Karen S L} and Leung, {Po Sing}",
year = "2013",
month = "11",
doi = "10.2337/db13-0645",
language = "English",
volume = "62",
pages = "3751--3759",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "11",

}

TY - JOUR

T1 - High glucose represses β-klotho expression and impairs fibroblast growth factor 21 action in mouse pancreatic islets

T2 - Involvement of peroxisome proliferator-activated receptor γ signaling

AU - So, Wing Yan

AU - Cheng, Qianni

AU - Chen, Lihua

AU - Evans-Molina, Carmella

AU - Xu, Aimin

AU - Lam, Karen S L

AU - Leung, Po Sing

PY - 2013/11

Y1 - 2013/11

N2 - Circulating fibroblast growth factor 21 (FGF21) levels are elevated in diabetic subjects and correlate directly with abnormal glucose metabolism, while pharmacologically administered FGF21 can ameliorate hyperglycemia. The pancreatic islet is an FGF21 target, yet the actions of FGF21 in the islet under normal and diabetic conditions are not fully understood. This study investigated the effects of high glucose on islet FGF21 actions in a diabetic mouse model by investigating db/db mouse islet responses to exogenous FGF21, the direct effects of glucose on FGF21 signaling, and the involvement of peroxisome proliferator-activated receptor γ (PPARγ) in FGF21 pathway activation. Results showed that both adult db/db mouse islets and normal islets treated with high glucose ex vivo displayed reduced β-klotho expression, resistance to FGF21, and decreased PPARγ expression. Rosiglitazone, an antidiabetic PPARγ ligand, ameliorated these effects. Our data indicate that hyperglycemia in type 2 diabetes mellitus may lead to FGF21 resistance in pancreatic islets, probably through reduction of PPARγ expression, which provides a novel mechanism for glucosemediated islet dysfunction.

AB - Circulating fibroblast growth factor 21 (FGF21) levels are elevated in diabetic subjects and correlate directly with abnormal glucose metabolism, while pharmacologically administered FGF21 can ameliorate hyperglycemia. The pancreatic islet is an FGF21 target, yet the actions of FGF21 in the islet under normal and diabetic conditions are not fully understood. This study investigated the effects of high glucose on islet FGF21 actions in a diabetic mouse model by investigating db/db mouse islet responses to exogenous FGF21, the direct effects of glucose on FGF21 signaling, and the involvement of peroxisome proliferator-activated receptor γ (PPARγ) in FGF21 pathway activation. Results showed that both adult db/db mouse islets and normal islets treated with high glucose ex vivo displayed reduced β-klotho expression, resistance to FGF21, and decreased PPARγ expression. Rosiglitazone, an antidiabetic PPARγ ligand, ameliorated these effects. Our data indicate that hyperglycemia in type 2 diabetes mellitus may lead to FGF21 resistance in pancreatic islets, probably through reduction of PPARγ expression, which provides a novel mechanism for glucosemediated islet dysfunction.

UR - http://www.scopus.com/inward/record.url?scp=84891684837&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84891684837&partnerID=8YFLogxK

U2 - 10.2337/db13-0645

DO - 10.2337/db13-0645

M3 - Article

VL - 62

SP - 3751

EP - 3759

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 11

ER -