Troglitazone ameliorates lipotoxicity in the beta cell line INS-1 expressing PPAR gamma.
To elucidate the mechanisms by which troglitazone, which is a direct ligand for peroxisome proliferator-activated receptor (PPAR) gamma, ameliorates insulin resistance, we have demonstrated that PPAR gamma is expressed in a pancreatic beta cell line, INS-1, using reverse transcription-polymerase chain reaction (RT-PCR). We incubated the cells with 5 micromol/l troglitazone and 1 mmol/l of each major free fatty acid (FFA; palmitic acid, oleic acid, and linoleic acid), alone or in combination, for 48 h. After that, we evaluated glucose-stimulated insulin secretion (GSIS) and 25 mmol/l KCl-induced insulin secretion in the presence of diazoxide, which clamps membrane potential. Our results showed: (1) treatment with troglitazone for 48 h caused enhancement of GSIS, although troglitazone significantly suppressed cell viability assessed by MTT assay. (2) In cells co-treated with troglitazone and FFA, troglitazone ameliorated lipotoxicity due to FFA. (3) In the presence of 300 micromol/l diazoxide and 25 mmol/l KCl, troglitazone did not affect the recovery of GSIS in INS-1 cells. These results suggest that insulin secretion from the rat insulinoma cell line, INS-1, is modulated by troglitazone, acting somewhere in the ATP-sensitive K(+) channel pathway, possibly through PPAR gamma.
Kawai
Toshihide
T
Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Hirose
Hiroshi
H
Seto
Yoshiko
Y
Fujita
Haruhisa
H
Fujita
Hiroshi
H
Ukeda
Kaname
K
Saruta
Takao
T
D000818:Animals; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D002839:Chromans / Q000494:pharmacology*; D017931:DNA Primers; D005230:Fatty Acids, Nonesterified / Q000633:toxicity*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007340:Insulinoma; D007700:Kinetics; D019787:Linoleic Acid / Q000633:toxicity; D019301:Oleic Acid / Q000633:toxicity; D019308:Palmitic Acid / Q000633:toxicity; D010190:Pancreatic Neoplasms; D020675:Peroxisomes / Q000187:drug effects / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000235:genetics*; D000077288:Troglitazone; D014407:Tumor Cells, Cultured
D002839:Chromans; D017931:DNA Primers; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D019301:Oleic Acid; D019308:Palmitic Acid; D019787:Linoleic Acid; D000077288:Troglitazone