Rosiglitazone promotes PPARγ-dependent and -independent alterations in gene expression in mouse islets.
The glitazone class of insulin-sensitizing agents act, in part, by the activation of peroxisome proliferator-activated receptor (PPAR)-γ in adipocytes. However, it is unclear whether the expression of PPARγ in the islets is essential for their potential β-cell-sparing properties. To investigate the in vivo effects of rosiglitazone on β-cell biology, we used an inducible, pancreatic and duodenal homeobox-1 enhancer element-driven, Cre recombinase to knockout PPARγ expression specifically in adult β-cells (PPARgKO). Subjecting the PPARgKO mice to a chow diet led to virtually undetectable changes in glucose or insulin sensitivity, which was paralleled by minimal changes in islet gene expression. Similarly, challenging the mutant mice with a high-fat diet and treatment with rosiglitazone did not alter insulin sensitivity, glucose-stimulated insulin secretion, islet size, or proliferation in the knockout mice despite PPARγ-dependent and -independent changes in islet gene expression. These data suggest that PPARγ expression in the β-cells is unlikely to be directly essential for normal β-cell function or the insulin-sensitizing actions of rosiglitazone.
Peninsula College of Medicine and Dentistry, University of Exeter, Exeter EX2 5DW, United Kingdom. hannah.welters@pcmd.ac.uk.
Hannah J
HJ
Welters
Abdelfattah
A
El Ouaamari
Dan
D
Kawamori
John
J
Meyer
Jiang
J
Hu
David M
DM
Smith
Rohit N
RN
Kulkarni
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002096:C-Peptide / Q000097:blood; D059305:Diet, High-Fat; D005786:Gene Expression Regulation / Q000187:drug effects*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D047495:PPAR gamma / Q000378:metabolism*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*
D001786:Blood Glucose; D002096:C-Peptide; D007004:Hypoglycemic Agents; D007328:Insulin; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone