Abstract
Diabetes and obesity are strongly associated and are risk factors for cholesterol gallstone disease. Leptinde ficient and leptin-resistant diabetic obese mice have enlarged, hypomotile gallbladders. In addition, bile from gallbladders of leptin-deficient mice has enhanced cholesterol crystal formation, whereas bile from gallbladders of leptin-resistant mice has delayed crystal observation time. To determine the effect of diabetes alone, we hypothesized that leptin-normal, nonobese diabetic (NOD) mice would have reduced biliary motility and rapid crystal formation. Twenty control and 9 prediabetic and 11 diabetic NOD, 12- to 26-week-old mice underwent glucose measurement and cholecystectomy for muscle bath stimulation with neurotransmitters. An additional group of 200 control and 78 NOD 12-week-old mice underwent microscopic bile examination for cholesterol crystal formation. Compared with control mice, prediabetic NOD mice had similar glucose levels and gallbladder volumes. Diabetic NOD mice had higher sugar levels and larger gallbladder volumes (P < 0.001) than control mice. Prediabetic NOD gallbladders had less contractility (P < 0.01) than control gallbladders, and contractility worsened (P < 0.01) in diabeticNODmice.NODmice formed cholesterol crystals earlier than did control mice (P<0.05). Nonobese diabetic NOD mice have (1) decreased gallbladder contraction to neurotransmitters, which worsens with development of diabetes, and (2) rapid crystal formation. We conclude that diabetes alone alters gallbladder motility and cholesterol crystal formation.
Similar content being viewed by others
References
Centers for Disease Control and Prevention. National diabetes fact sheet: General information and national estimates on diabetes in the United States, 2003. Atlanta, GA, 2003, US Dept of Health and Human Services, Centers for Disease Control and Prevention.
Mokdad AH, Ford ES, Bowman BA, et al. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA 2003;289:76–79.
Kayacetin E, Kisakol G, Kaya A, Akpinar Z. Real-time sonography for screening of gallbladder motility in diabetic patients: Relation to autonomic and peripheral neuropathy. Neuroendocrinol Lett 2003;24:73–76.
Resnick HE, Howard BV. Diabetes and cardiovascular disease. Annu Rev Med 2002;53:245–267.
Hahm JS, Park JY, Park KG, et al. Gallbladder motility in diabetes mellitus using real time ultrasonography. Am J Gastroenterol 1996;91:2391–2394.
Goldblatt MI, Swartz-Basile DA, Svatek CL, Nakeeb A, Pitt HA. Decreased gallbladder response in leptin-deficient obese mice. J GASTROINTEST SURG 2002;6:438–442.
Tran KQ, Swartz-Basile DA, Nakeeb A, Pitt HA. Gallbladder motility in Agouti-yellow and leptin-resistant obese mice. J Surg Res 2003;113:56–61.
Tran KQ, Goldblatt MI, Swartz-Basile DA, et al. Diabetes and hyperlipidemia correlate with gallbladder contractility in leptin-related murine obesity. JGASTROINTEST SURG 2003;7:857–862.
Goldblatt MI, Choi SH, Swartz-Basile DA, Nakeeb A, Pitt HA. Cholesterol crystal formation in congenitally obese mice. Surg Forum 2000;51:1–2.
Goldblatt MI, Swartz-Basile DA, Svatek CL, Nakeeb A, Pitt HA. Increased 46, 61, and 84 kDa gallbladder bile nonmucin proteins in genetically obese mice. Surg Forum 2001;52:36–37.
Tran K, Swartz-Basile D, Goldblatt MI, et al. Carboxylesterase is a cholesterol crystal pronucleator in leptin-deficient obese mice. J Am Coll Surg 2002;195:S13.
Tran KQ, Graewin SJ, Swartz-Basile DA, et al. Leptin-resistant obese mice have paradoxically low biliary cholesterol saturation. Surgery 2003;134:372–377.
Festing MFW. Inbred strains of mice. In Mouse genome informatics. Bar Harbor, Me, 1999, The Jackson Laboratory, www.informatics.jax.org
Bouchard G, Johnson D, Carver T, Paigen B, Carey MC. Cholesterol gallstone formation in overweight mice establishes that obesity per se is not linked directly to cholelithiasis risk. J Lipid Res 2002;43:1105–1113.
Nakeeb A, Sonnenberg GE, Touzios J, et al. Altered glucose metabolism is associated with impaired gallbladder motility. HPB 2004;6:48–49.
Grider JR. Role of cholecystokinin in the regulation of gastrointestinal motility. J Nutr 1994;124:1334S-1339S.
Yu P, Chen Q, Xiao Z, et al. Signal transduction pathways mediating CCK-induced gallbladder muscle contraction. Am J Physiol 1998;275:G203-G209.
Mawe GM, Talmage EK, Cornbrooks EB, et al. Innervation of the gallbladder: Structure, neurochemical coding, and physiological properties of guinea pig gallbladder ganglia. Micro Res Tech 1997;39:1–13.
Hanyu N, Dodds WJ, Layman RD, et al. Mechanism of cholecystokinin-induced contraction of the opossum gallbladder. Gastroenterology 1990;98:1299–1306.
Parkman HP, Pagano AP, Ryan JP. Subtypes of muscarinic receptors regulating gallbladder cholinergic contractions. Am J Physiol 1999;276:G1243-G1249.
Ordog T, Takayama I, Cheung WKT, Ward SM, Sanders KM. Remodeling of networks of interstitial cells of Cajal in a murine model of diabetic gastroparesis. Diabetes 2000;49:1731–1739.
Graewin SJ, Lee K-H, Kiely JM, et al. Gallbladder myocytes are short and CCK-resistant in obese diabetic mice. Surgery 2004;136:431–436.
Singh R, Barden A, Mori T, Beilin L. Advanced glycation end-products: A review. Diabetologia 2001;44:129–146.
Bucala R. Lipid and lipoprotein modification by AGE’s: Role in atherosclerosis. Exp Physiol 1997;82:327–337.
Uchida K, Makino S, Akiyoshi T. Altered bile acid metabolism in nonobese, spontaneously diabetic (NOD) mice. Diabetes 1985;34:79–83.
Author information
Authors and Affiliations
Additional information
This work was supported by National Institutes of Health grant R01-DK44279.
Rights and permissions
About this article
Cite this article
Graewin, S.J., Kiely, J.M., Lee, KH. et al. Nonobese diabetic mice have diminished gallbladder motility and shortened crystal observation time. J Gastrointest Surg 8, 824–830 (2004). https://doi.org/10.1016/j.gassur.2004.06.014
Issue Date:
DOI: https://doi.org/10.1016/j.gassur.2004.06.014