Insulin injections enhance cholesterol gallstone incidence by changing the biliary cholesterol saturation index and apo A-I concentration in hamsters fed a lithogenic diet

Background/Aims: A link between insulin and cholesterol gallstone disease has often been suspected but never demonstrated. The aim was to evaluate the direct implication of insulin in the gallbladder cholesterol gallstone formation process. Methods: Hamsters fed with a soft-inducing lithogenic diet, enriched with sucrose, were injected daily, for 1 week, either with long-acting insulin or saline (controls). Results: Insulin injections doubled the cholesterol gallstone incidence. The cholesterol saturation index (CSI) of bile significantly increased (+19%) and biliary apolipoprotein A-I (apo A-I) decreased, both in concentration (−71%) and the proportion relative to the total biliary proteins (−25%). No modifications in the biliary bile acid composition were noticed. Hepatic HMGCoA reductase activity was higher (+341%), CYP7A1 activity was lower (−52%), whereas CYP27A1 and CYP7B1 were not affected. The hepatic low-density liprotein (LDL)-receptor and SR-BI masses did not vary. The hepatic total cholesterol content increased (+42%). Fasting plasma phospholipid and triglyceride concentrations significantly decreased (−15 and −60%, respectively), but the cholesterol concentration remained constant. Conclusions: These results suggest that insulin injections enhance cholesterol gallstone incidence by increasing the CSI of bile and decreasing the concentration and proportion of a biliary anti-nucleating protein, apo A-I. Insulin modulates the major enzymes of cholesterol and bile acid metabolisms in vivo.