[The expression of insulin signal transduction molecules and islet alpha cell insulin resistance].
OBJECTIVE
To study the changes of insulin signal transduction molecules in islet alpha cells in high-fat-diet plus beta cell-deleting rat models and its underlying mechanism.


METHODS
Thirty SD rats were randomly divided into 2 equal groups and fed with high-fat-diet (HF group) or normal diet (normal control group, NC group) respectively. At the end of twenty-week feeding, the fasting serum insulin (Ins), glucagon (Glc), free fatty acid (FFA), and triglyceride (TG were measured. The glucose infusion rate (GIR) was measured by using euglycemic hyperinsulinemia clamp to evaluate the peripheral insulin resistance. At the same time, large dose streptozocin (100 mg/kg) was injected so as to establish beta cell-deleting rat models, i.e., HF-B group (n = 8) and NC-B group (n = 8). Five days later, the rats of the HF-B and NC-B subgroups were sacrificed, and the pancreatic islets were isolated and collected. The expression of Glc, insulin receptor substrate-1 (IRS-1), IRS-2, and phosphatidylinositol-3-kinase (PI3K) gene in the islets were detected by RT-PCR.


RESULTS
(1) The serum FFA, insulin and Glc concentrations of the HF group were 508 (394 - 622) micromol/L, 23.7 (14.0 - 33.4) mIU/L, and 345 (298.6 - 391.4) pg/ml respectively, all significantly higher than those of the NC group [325 (240 - 410) micromol/L, 11.5 (3.6 - 19.4) mIU/L, 256 (226.4 - 285.6) pg/ml; respectively, all P < 0.05]. The GIR of the HF group was 5.25 mgxmin(-1)xkg(-1) +/- 1.2 mgxmin(-1)xkg(-1), significantly lower than that of the NC group (13.6 mgxmin(-1)xkg(-1) +/- 1.7 mgxmin(-1)xkg(-1), P < 0.01)). (2) The gene expression of Glc of the HF-B subgroup was significantly higher than that of the NC-B subgroup by 34.2% +/- 2.1%. In contrast, the expression of IRS-2, and PI3K of the HF-B subgroup was significantly lower than that of the NC-B subgroup by 28.5% +/- 1.8% and 21.3% +/- 1.6% respectively (both P < 0.01). (3) The plasma FFA concentration was asignificantly negatively correlated with GIR (r = -0.675, P < 0.05) and IRS-2 gene expression in islet alpha cells (r = -0.458, P < 0.05) in the HF-B group.


CONCLUSIONS
High-fat-diet feeding plus beta cell-deleting rat model shows an impaired expression of insulin signal transduction molecules in islet alpha cells which may relate with the increased plasma FFA concentration.
Du
Rui-qin
RQ
Department of Endocrinology, China Japan Friendship Hospital, Peking Union Medical College, Beijing 100029, China.
Li
Hong-liang
HL
Yang
Wen-ying
WY
Xiao
Jian-zhong
JZ
Lou
Da-jun
DJ
Wang
Bing
B
Bai
Xiu-ping
XP
Pan
Lin
L
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000008:administration & dosage / Q000097:blood; D015870:Gene Expression; D005934:Glucagon / Q000097:blood; D015309:Glucose Clamp Technique; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000235:genetics*; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*; D014280:Triglycerides / Q000097:blood
D048868:Adaptor Proteins, Signal Transducing; D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D012333:RNA, Messenger; D014280:Triglycerides; D005934:Glucagon; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin