Role and mechanism of rosiglitazone on the impairment of insulin secretion induced by free fatty acids on isolated rat islets.
BACKGROUND
Prolonged exposure of pancreatic beta-cells to fatty acids increases basal insulin secretion but inhibits glucose-stimulated insulin secretion. Rosiglitazone is a new antidiabetic agent of the thiazolidinediones. However, the relationship between thiazolidinediones and insulin secretion is highly controversial. The aim of this study is to explore the effect and mechanism of rosiglitazone on insulin secretion of islets under chronic exposure to free fatty acids (FFA).


METHODS
Pancreatic islets were isolated from the pancreata of male Sprague-Dawley rats by the collagenase digestion and by the dextran gradient centrifugation method. The purified islets were cultured in the presence or absence of rosiglitazone and palmitate for 48 hours. The insulin secretion was measured by radioimmunoassay. The mRNA level of peroxisome proliferator-activated receptor gamma, uncoupling protein 2 (UCP-2) and insulin were determined by real-time polymerase chain reaction (PCR). The cell cytotoxicity assay was measured by cell counting kit-8.


RESULTS
Islets exposed to elevated palmitate for 48 hours showed an increased basal and a decreased glucose-stimulated insulin secretion (P < 0.01). The mRNA level of UCP-2 was increased by 3.7 fold in the 0.5 mmol/L concentration of palmitate. When islets were cultured with palmitate (0.5 mmol/L) in the presence of rosiglitazone (1.0 micromol/L), both basal and glucose-stimulated insulin secretion reversed to a pattern of control islets (P < 0.05, P < 0.01). The addition of rosiglitazone in the culture medium decreased the mRNA level of UCP-2 by 2.2 fold, having a statistically significant difference (P < 0.05) as compared with islets cultured with palmitate alone. The cell viability was not affected.


CONCLUSIONS
The protective effects of rosiglitazone on insulin secretion of isolated pancreatic islets under chronic exposure to palmitate might be mediated through the downregulation of UCP-2 expression.
Tian
Jing-yan
JY
Shanghai Institute of Endocrinology and Metabolism, Shanghai Clinical Center of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Second Medical University, Shanghai 200025, China.
Li
Guo
G
Gu
Yan-yun
YY
Zhang
Hong-li
HL
Zhou
Wen-zhong
WZ
Wang
Xiao
X
Zhu
Hong-da
HD
Luo
Tian-hong
TH
Luo
Min
M
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007473:Ion Channels; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000235:genetics*; D047495:PPAR gamma / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D000071246:Uncoupling Protein 2
D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D007328:Insulin; D007473:Ion Channels; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D047495:PPAR gamma; D012333:RNA, Messenger; D045162:Thiazolidinediones; C000604391:Ucp2 protein, rat; D000071246:Uncoupling Protein 2; D000077154:Rosiglitazone