Pioglitazone increases gallbladder volume in insulin- resistant obese mice

Abstract

Introduction: Both obesity and diabetes are associated with an increased incidence of gallstones. Recent animal and human data from our laboratory suggest that insulin resistance is associated with increased gallbladder volume and/or impaired gallbladder emptying. Pioglitazone is a thiazolidinedione which has been shown to improve insulin resistance and has been employed to treat nonalcoholic fatty steatohepatitis. However, in a prior study with a high carbohydrate (75%) diet pioglitazone did not improve gallbladder motility in obese insulin-resistant mice. Therefore, we tested the hypothesis that pioglitazone would improve insulin resistance, decrease resting gallbladder volume and improve gallbladder response to neurotransmitters in insulin-resistant obese mice. Methods: Twenty eight-week old obese leptin-deficient (Lepob) female mice were fed a low carbohydrate (25%) diet for four weeks. Half of the animals had pioglitazone 0.03% added to their diet. At 12 weeks, all animals were fasted overnight and underwent cholecystectomy. Gallbladder volume(μl), weight and area were measured, and fresh gallbladders were placed in a muscle bath to assess response to acetylcholine(ACh,10−6M), neuropeptide Y (NPY,10−8,−7,−6M) and cholecystokinin (CCK, 10−10,−9,−8,−7M). Serum glucose(mg/dl) and insulin (ηg/ml) were measured, and the HOMA Index, a measure of insulin resistance, was calculated. Results: Pioglitazone did not alter gallbladder weight, area or response to ACh, NPY or CCK. Results for glucose, insulin, HOMA Index and gallbladder (GB) volume were: Conclusion: These data suggest that in obese insulin-resistant mice, pioglitazone 1) lowers insulin and insulin-resistance, 2) does not alter gallbladder response to neurotransmitters, and 3) increases resting gallbladder volume. Therefore, we conclude that pioglitazone, while improving insulin resistance, paradoxically increases gallbladder volume and, thereby, may increase the propensity for gallstone formation by enhancing gallbladder stasis.