Research On The Mechanism And Intervention Of Hepatic Insulin Resistance In Chronic Pancreatitis

Objective:To observe the changes of glycometabolism, hepatic IKK-βand IRS-1 phosphorylated on serine 307(Ser307p-IRS-1) expression, hepatic NF-κB activity and TNF-αmRNA level in chronic pancreatitis rats, and the intervention of aspirin, rosiglitazone and chaihushugansan on the changes. Methods:Wistar rats were divided into control group, model group, aspirin-treated group, rosiglitazone-treated group and chaihushugansan-treated group randomly. After 6 weeks was chronic pancreatitis model established, aspirin, rosiglitazone and chaihushugansan was administrated at the dose 50 mg/kg,0.92 mg/kg and 2.8 g/kg in the three medicine-treated groups respectively, and distilled water was administrated in control group and model group for 4 weeks. And then OGTT, ITT, serum insulin levels, pancreatic and hepatic pathological changes and glucose release test of isolated hepatic cells were investigated. Rats were killed and samples of hepatic tissue were dissected out. Hepatic IKK-βmRNA and protein expression levels were determined by RT-PCR and Western blot. Meanwhile, determination of hepatic Ser307p-IRS-1 protein expression levels was performed by Western blot. Hepatic NF-κB activities were determined by immunohistochemical method, and hepatic TNF-αmRNA levels were determined by RT-PCR. Results:Compared with control group, glucose tolerance and insulin tolerance was abnormal, serum insulin levels were significantly decreased(p<0.05), destruction of pancreatic small ducts and acini, lymphocytic infiltration and fibroplasias were observed, the inhibition ratios of hepatocellular glucose release by insulin were significantly lower(p<0.05), hepatic IKK-βmRNA and protein expression levels and Ser307p-IRS-1 protein expression levels were significantly higher (p<0.05), the ratios of hepatic NF-κB-positive cell and TNF-αmRNA levels were significantly higher (p< 0.05) in model group. Aspirin, rosiglitazone and chaihushugansan can improve those abnormalities in various degrees. The best therapeutic effect on glucose tolerance abnormal was observed in rosiglitazone-treated group, and reparation of destructive pancreatic structure was observed in chaihushugansan-treated group. Hepatic IKK-βexpression levels in aspirin-treated group showed no significant difference from model group (p> 0.05). But in both rosiglitazone- treated and chaihushugansan-treated groups, hepatic IKK-βexpression levels were decreased significantly (p<0.05 compared with model group). In addition, hepatic Ser307p-IRS-1 protein expression levels, the ratios of hepatic NF-κB-positive cell and TNF-αmRNA levels were significantly lower in all of the three medicine-treated groups than those in model group (p<0.05). Conclusion: Chronic pancreatitis induces abnormal glycometabolism. Apart from reduced insulin secretion, hepatic insulin resistance is an important mechanism. Chronic pancreatitis increases hepatic serine 307 phosphorylation of IRS-1, NF-κB activity and TNF-αgene transcription through up-regulating IKK-βexpression, thereby blocks the insulin signal transduction pathway, which might be a molecular mechanism on leading to hepatic insulin resistance. Aspirin, rosiglitazone and chaihushugansan can treat the abnormal glycometabolism induced by chronic pancreatitis through improving hepatic insulin resistance. Aspirin may exert the therapeutic effects on hepatic insulin resistance through inhibiting the serine kinase activity of IKK-β, but rosiglitazone and chaihushugansan through down-regulating hepatic IKK-βexpression, resulting in the attenuation of NF-κB activity and TNF-αgene transcription. Our research interprets the molecular mechanism of hepatic insulin resistance in chronic pancreatitis, and investigates the intervention of different medicines, which contributes to open new windows for the clinical treatment of abnormal glycometabolism induced by chronic pancreatitis.