[Role of apoptosis and mitochondrial apoptotic pathway in glucolipotoxicity-induced islet beta-cell dysfunction].
OBJECTIVE
To investigate the mechanism of beta-cell dysfunction induced by glucolipotoxicity in high fat-fed obese rats.


METHODS
Eighteen high-fat obese male Wistar rats were assigned into 3 groups and underwent 48-hour infusion through the jugular vein with normal saline (n=6), 20% intralipid + heparin (FFA group, n=6), or 25%glucose +20% intralipid + heparin (GS-FFA group, n=6). The plasma beta-hydroxybutyric acid (beta-HBA) was measured before and at the end of the infusion. After the infusion, the rats were sacrificed following an intravenous glucose tolerance test (IVGTT) to remove the tail of the pancreas for detection of apoptotic islet cells using TUNEL method. Immunohistochemical staining was performed to detect the expression of cytochrome c (cyt c), apoptosis-inducing factor (AIF), caspase-9 and caspase-3 in the islet cells.


RESULTS
At the end of the infusion, all the rats exhibited increased plasma beta-HBA levels, which was the highest in the GS-FFA group (P<0.05). IVGTT performed after the infusion showed a significantly lower insulinogenic index in GS-FFA group than that in NS and FFA groups. Greater number of apoptotic islet cells was found in the GS-FFA group than in the FFA and NS groups (P<0.05), and the islets had significantly higher levels of cyt c, AIF, caspase-9 and caspase-3 in the former group than in the latter two groups (P<0.05).


CONCLUSIONS
Hyperglycemia and high free fatty acid level synergistically impair insulin secretions to cause ketone overproduction in high fat-fed obese rats. The beta-cell dysfunction due to glucolipotoxicity is associated with increased beta-cell apoptosis and activation of mitochondrial apoptotic pathway.
Zhao
Nai-Qian
NQ
Department of Endocrinology, West China Hospital, Sichuan University, Chengdu 610041, China. naiqianzhao@sohu.com.cn
Yu
Ye-Rong
YR
Tan
Hui-Wen
HW
Deng
Gang
G
Zhang
Xiang-Xun
XX
D020155:3-Hydroxybutyric Acid / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D005217:Fat Emulsions, Intravenous / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology*; D005951:Glucose Tolerance Test; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000473:pathology*; D008297:Male; D008928:Mitochondria / Q000187:drug effects; D009765:Obesity / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar
D005217:Fat Emulsions, Intravenous; D005947:Glucose; D020155:3-Hydroxybutyric Acid