[The relationship between islet alpha cell insulin resistance and inflammatory pathway activation and its mechanism].

Objective: To study the changes of inflammatory path molecules in the islet alpha cells in high-fat-diet fed plus beta cell-deleted rat models and the effects of pioglitazone intervention.

Methods: Forty five normal male SD rats, 8 week old, were randomly divided into 3 groups, i.e., a normal diet group (NC), a high fat diet fed group (HF), and a high fat diet fed and pioglitazone treated group (HP, pioglitazone 15 mg kg(-1) d(-1)). At the end of twenty weeks of feeding, fasting serum insulin (FIns), glucagon, free fatty acid (FFA) and high sensitive C reactive protein (hsCRP) were determined. Glucose infusion rate (GIR) was measured by using euglycemic hyperinsulinemia clamp to evaluate the peripheral insulin resistance. The contents of glucagon in perfusion medium during islet cell perfusion was measured with RIA. At the same time, beta cell-deleted rat models were established by injecting large dose streptozocin (100 mg/kg) in 8 rats in each of the three groups, i.e., HF-B group, P-B group and NC-B group. Five days later, the rats were sacrificed and the pancreatic islets were isolated and collected. The expression of NF-kappaB and inhibitor kappaBalpha (IkappaBalpha) gene in the islets was detected with real-time PCR.

Results: (1) GIR was decreased significantly in HF group as compared with NC group (P < 0.01). The concentrations of serum FIns, glucagon, FFA and hsCRP in HF group were higher than those in NC group. Pioglitazone intervention could reverse these effects. (2) 16.7 mmol/L glucose could inhibit the glucagon secretion by the islet alpha cells of the NC group rats, but not of the HF group rats. Pioglitazone intervention could reverse these effects. (3) The gene expression of NF-kappaB was significantly increased by 20.5% in the HF-B group than in the NC-B group (P < 0.01). In contrast, the expression of IkappaBalpha was significantly decreased by 24.3% (P < 0.01). The expression of NF-kappaB and IkappaBalpha mRNAs in HP-B group, when compared with that of HF-B group, was improved 78.3% and 58.8%, respectively.

Conclusions: High-fat-diet feeding induces islet alpha cell insulin resistance and activates the mRNA expression of inflammatory path molecules in beta cell-deleted rat models and it may relate with the increased plasma FFA concentration. Pioglitazone intervention can reverse these effects.