Insulin Resistance Causes Human Gallbladder Dysmotility Attila Nakeeb, M.D., Anthony G. Comuzzie, Ph.D., Hayder Al-Azzawi, M.D., Gabriele E. Sonnenberg, M.D., Ahmed H. Kissebah, M.D., Ph.D., Henry A. Pitt, M.D. Obesity, diabetes, and hyperlipidemia are known risk factors for the development of gallstones. A grow- ing body of animal and human data has correlated insulin resistance with organ dysfunction. The rela- tionship among obesity, diabetes, hyperlipidemia, and abnormal gallbladder motility remains unclear. Therefore, we designed a study to investigate the association among obesity, insulin resistance, hyperlip- idemia, and gallbladder dysmotility. One hundred ninety-two healthy adult nondiabetic volunteers were studied. Gallbladder ultrasounds were performed before and after a standardized fatty meal. A gallblad- der ejection fraction (EF) was calculated, and an EF of !25% was considered abnormal. Serum was an- alyzed for cholesterol, triglycerides, cholecystokinin, leptin, glucose, and insulin. The homeostasis assessment model (HOMA) was used to determine insulin resistance. The volunteers had a mean age of 38 years (range, 18À77), and 55% were female. Thirty subjects (15%) had gallstones and were ex- cluded from the study. Thirty subjects (19%) had abnormal gallbladder motility (EF !25%). In lean subjects (n 5 96) fasting glucose was significantly increased in the 16 subjects with gallbladder EF !25% versus the 80 subjects with gallbladder EF O25% (109 6 20 mg/dl versus 78 6 2 mg/dl, P ! 0.05). Similarly, the HOMA index was significantly greater in subjects with gallbladder EF !25% versus gallbladder EF O25% (3.3 6 1.2 versus 2.0 6 0.2, P ! 0.05). In obese subjects (n 5 66), fasting glucose, insulin, and insulin resistance were not associated with a gallbladder EF !25%. These data suggest that in lean, nondiabetic volunteers without gallstones, gallbladder dysmotility is associated with an elevated fast- ing glucose as well as a high index of insulin resistance. We conclude that insulin resistance alone may be responsible for gallbladder dysmotility that may result in acalculous cholecystitis or gallstone formation. (JGASTROINTEST SURG 2006;10:940–949) Ó 2006 The Society for Surgery of the Alimentary Tract KEY WORDS: Insulin resistance, gallbladder motility, obesity Gallbladder disease represents a major health care problem in the United States. Approximately 12% of the U.S. population, or 30 million Americans, have gallstones. More then 700,000 cholecystectomies are performed each year, and the cost of caring for these patients is between $8 and $10 billion dollars annually. 1 Approximately three-fourths of the pa- tients with gallstones in the United States have stones that are composed primarily of cholesterol. The pathogenesis of cholesterol gallstones is known to be multifactorial, with the key factors including (1) cholesterol supersaturated bile, (2) nucleation and growth of cholesterol monohydrate crystals, and (3) altered biliary motility. 2 Obesity, diabetes, and hyperlipidemia have all been identified as significant risk factors for the development of gallstones. 3,4 However, the role that each of these factors play in this process remains unclear because many patients have two or all three of these problems. Recent studies from our labora- tory in obese, diabetic leptin-deficient and leptin-re- sistant mice have correlated body weight, serum glucose, insulin, cholesterol, and triglycerides with poor gallbladder motility. 5,6 In addition, a study in nonobese diabetic mice has demonstrated poor gall- bladder emptying in young insulin resistant animals without frank diabetes. 7 Moreover, a growing body of animal and human data have correlated insulin re- sistance with organ dysfunction. While obesity, dia- betes, and hypertriglyceridemia are risk factors for gallstone formation, the relationship among obesity, diabetes, hyperlipidemia, and abnormal gallbladder Presented at The Society for Surgery of the Alimentary Tract, May 15À18, 2005, Chicago, Illinois (oral presentation). From the Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana (A.N., H.A.-A., H.A.P.); the Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, Texas (A.G.C.); and the Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin (G.E.S., A.H.K.). Supported by National Institutes of Health grants K23 DK62260 and R-01 DK44279. Reprint requests: Attila Nakeeb, M.D., Department of Surgery, Indiana University School of Medicine, 535 Barnhill Drive, RT 130, Indian- apolis, IN 46202. e-mail: anakeeb@iupui.edu 940 Ó 2006 The Society for Surgery of the Alimentary Tract Published by Elsevier Inc. 1091-255X/06/$dsee front matter doi:10.1016/j.gassur.2006.04.005