Improved insulin sensitivity and islet function after PPARdelta activation in diabetic db/db mice.
(2010) In European Journal of Pharmacology 626(2-3). p.297-305- Abstract
- The peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the nuclear receptor superfamily. Several reports have shown that PPARdelta is involved in lipid metabolism, increasing fat oxidation and depleting lipid accumulation. Whether PPARdelta is involved in the regulation of glucose metabolism is not completely understood. In this study, we examined effects of long-term PPARdelta activation on glycemic control, islet function and insulin sensitivity in diabetic db/db mice. Male db/db mice were administered orally once daily with a selective and partial PPARdelta agonist (NNC 61-5920, 30mg/kg) for eight weeks; control mice received vehicle. Fasting and non-fasting plasma glucose were reduced, reflected... (More)
- The peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the nuclear receptor superfamily. Several reports have shown that PPARdelta is involved in lipid metabolism, increasing fat oxidation and depleting lipid accumulation. Whether PPARdelta is involved in the regulation of glucose metabolism is not completely understood. In this study, we examined effects of long-term PPARdelta activation on glycemic control, islet function and insulin sensitivity in diabetic db/db mice. Male db/db mice were administered orally once daily with a selective and partial PPARdelta agonist (NNC 61-5920, 30mg/kg) for eight weeks; control mice received vehicle. Fasting and non-fasting plasma glucose were reduced, reflected in reduced hemoglobinA(1c) (3.6+/-1.6% vs. 5.4+/-1.8 in db/db controls, P<0.05) and furthermore, the AUC(glucose) after oral glucose (3g/kg) was reduced by 67% (P<0.05) after long-term PPARdelta activation. Following intravenous glucose (1g/kg), glucose tolerance was improved after PPARdelta activation (K(G) 1.3+/-0.6 vs. -0.05+/-0.7 %/min, P=0.048). Insulin sensitivity, measured as the glucose clearance after intravenous injection of glucose (1g/kg) and insulin (0.75 or 1.0U/kg), during inhibition of endogenous insulin secretion by diazoxide (25mg/kg), was improved (K(G) 2.9+/-0.6 vs. 1.3+/-0.3 %/min in controls, P<0.05) despite lower insulin levels. Furthermore, islets isolated from PPARdelta agonist treated mice demonstrated improved glucose responsiveness as well as improved cellular topography. In conclusion, PPARdelta agonism alleviates insulin resistance and improves islet function and topography, resulting in improved glycemia in diabetic db/db mice. This suggests that activation of PPARdelta improves glucose metabolism and may therefore potentially be target for treatment of type 2 diabetes. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1500443
- author
- Sörhede Winzell, Maria LU ; Wulff, Erik Max ; Olsen, Grith Skytte ; Sauerberg, Per ; Gotfredsen, Carsten F and Ahrén, Bo LU
- organization
- publishing date
- 2010
- type
- Contribution to journal
- publication status
- published
- subject
- in
- European Journal of Pharmacology
- volume
- 626
- issue
- 2-3
- pages
- 297 - 305
- publisher
- Elsevier
- external identifiers
-
- wos:000274090800029
- pmid:19818749
- scopus:70649114413
- pmid:19818749
- ISSN
- 1879-0712
- DOI
- 10.1016/j.ejphar.2009.09.053
- language
- English
- LU publication?
- yes
- id
- e015374a-7055-43ab-8070-94d69e4d7912 (old id 1500443)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/19818749?dopt=Abstract
- date added to LUP
- 2016-04-01 11:02:41
- date last changed
- 2024-10-07 19:31:41
@article{e015374a-7055-43ab-8070-94d69e4d7912,
abstract = {{The peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the nuclear receptor superfamily. Several reports have shown that PPARdelta is involved in lipid metabolism, increasing fat oxidation and depleting lipid accumulation. Whether PPARdelta is involved in the regulation of glucose metabolism is not completely understood. In this study, we examined effects of long-term PPARdelta activation on glycemic control, islet function and insulin sensitivity in diabetic db/db mice. Male db/db mice were administered orally once daily with a selective and partial PPARdelta agonist (NNC 61-5920, 30mg/kg) for eight weeks; control mice received vehicle. Fasting and non-fasting plasma glucose were reduced, reflected in reduced hemoglobinA(1c) (3.6+/-1.6% vs. 5.4+/-1.8 in db/db controls, P<0.05) and furthermore, the AUC(glucose) after oral glucose (3g/kg) was reduced by 67% (P<0.05) after long-term PPARdelta activation. Following intravenous glucose (1g/kg), glucose tolerance was improved after PPARdelta activation (K(G) 1.3+/-0.6 vs. -0.05+/-0.7 %/min, P=0.048). Insulin sensitivity, measured as the glucose clearance after intravenous injection of glucose (1g/kg) and insulin (0.75 or 1.0U/kg), during inhibition of endogenous insulin secretion by diazoxide (25mg/kg), was improved (K(G) 2.9+/-0.6 vs. 1.3+/-0.3 %/min in controls, P<0.05) despite lower insulin levels. Furthermore, islets isolated from PPARdelta agonist treated mice demonstrated improved glucose responsiveness as well as improved cellular topography. In conclusion, PPARdelta agonism alleviates insulin resistance and improves islet function and topography, resulting in improved glycemia in diabetic db/db mice. This suggests that activation of PPARdelta improves glucose metabolism and may therefore potentially be target for treatment of type 2 diabetes.}},
author = {{Sörhede Winzell, Maria and Wulff, Erik Max and Olsen, Grith Skytte and Sauerberg, Per and Gotfredsen, Carsten F and Ahrén, Bo}},
issn = {{1879-0712}},
language = {{eng}},
number = {{2-3}},
pages = {{297--305}},
publisher = {{Elsevier}},
series = {{European Journal of Pharmacology}},
title = {{Improved insulin sensitivity and islet function after PPARdelta activation in diabetic db/db mice.}},
url = {{https://lup.lub.lu.se/search/files/2332993/1508700.pdf}},
doi = {{10.1016/j.ejphar.2009.09.053}},
volume = {{626}},
year = {{2010}},
}