SS  Vol.6 No.8 , August 2015
A Large Animal Survival Model to Evaluate Bariatric Surgery Mechanisms
Background: The impact of Roux-en-Y gastric bypass (RYGB) on type 2 diabetes mellitus is thought to result from upper and/or lower gut hormone alterations. Evidence supporting these mechanisms is incomplete, in part because of limitations in relevant bariatric-surgery animal models, specifically the lack of naturally insulin-resistant large animals. With overfeeding, Ossabaw swine develop a robust metabolic syndrome, and may be suitable for studying post-surgical physiology. Whether bariatric surgery is feasible in these animals with acceptable survival is unknown. Methods: Thirty-two Ossabaws were fed a high-fat, high-cholesterol diet to induce obesity and insulin resistance. These animals were assigned to RYGB (n = 8), RYGB with vagotomy (RYGB-V, n = 5), gastrojejunostomy (GJ, n = 10), GJ with duodenal exclusion (GJD, n = 7), or sham operation (n = 2) and were euthanized 60 days post-operatively. Post-operative changes in weight and food intake are reported. Results: Survival to scheduled necropsy among surgical groups was 77%, living an average of 57 days post-operatively. Cardiac arrest under anesthesia occurred in 4 pigs. Greatest weight loss (18.0% ± 6%) and food intake decrease (57.0% ± 20%) occurred following RYGB while animals undergoing RYGB-V showed only 6.6% ± 3% weight loss despite 50.8% ± 25% food intake decrease. GJ (12.7% ± 4%) and GJD (1.2% ± 1%) pigs gained weight, but less than sham controls (13.4% ± 10%). Conclusions: A survival model of metabolic surgical procedures is feasible, leads to significant weight loss, and provides the opportunity to evaluate new interventions and subtle variations in surgical technique (e.g. vagus nerve sparing) that may provide new mechanistic insights.

Cite this paper
Simianu, V. , Sham, J. , Wright, A. , Stewart, S. , Alloosh, M. , Sturek, M. , Cummings, D. , Flum, D. (2015) A Large Animal Survival Model to Evaluate Bariatric Surgery Mechanisms. Surgical Science, 6, 337-345. doi: 10.4236/ss.2015.68050.

[1]   Sjostrom, L., Lindroos, A.K., Peltonen, M., Torgerson, J., Bouchard, C., Carlsson, B., et al. (2004) Lifestyle, Diabetes, and Cardiovascular Risk Factors 10 Years after Bariatric Surgery. New England Journal of Medicine, 351, 2683-2693.

[2]   Sjostrom, L., Narbro, K., Sjostrom, C.D., Karason, K., Larsson, B., Wedel, H., et al. (2007) Effects of Bariatric Surgery on Mortality in Swedish Obese Subjects. New England Journal of Medicine, 357, 741-752.

[3]   Buchwald, H., Avidor, Y., Braunwald, E., Jensen, M.D., Pories, W., Fahrbach, K., et al. (2004) Bariatric Surgery: A Systematic Review and Meta-Analysis. JAMA, 292, 1724-1737.

[4]   Pories, W.J., Swanson, M.S., MacDonald, K.G., Long, S.B., Morris, P.G., Brown, B.M., et al. (1995) Who Would Have Thought It? An Operation Proves to Be the Most Effective Therapy for Adult-Onset Diabetes Mellitus. Annals of Surgery, 222, 339-350.

[5]   Schauer, P.R., Burguera, B., Ikramuddin, S., Cottam, D., Gourash, W., Hamad, G., et al. (2003) Effect of Laparoscopic Roux-en Y Gastric Bypass on Type 2 Diabetes Mellitus. Annals of Surgery, 238, 467-484.

[6]   Thaler, J.P. and Cummings, D.E. (2009) Minireview: Hormonal and Metabolic Mechanisms of Diabetes Remission after Gastrointestinal Surgery. Endocrinology, 150, 2518-2525.

[7]   Flum, D.R., Devlin, A., Wright, A.S., Figueredo, E., Alyea, E., Hanley, P.W., et al. (2007) Development of a Porcine Roux-en-Y Gastric Bypass Survival Model for the Study of Post-Surgical Physiology. Obesity Surgery, 17, 1332-1339.

[8]   Varga, O., Harangi, M., Olsson, I.A. and Hansen, A.K. (2010) Contribution of Animal Models to the Understanding of the Metabolic Syndrome: A Systematic Overview. Obesity Reviews, 11, 792-807.

[9]   Otis, C.R., Wamhoff, B.R. and Sturek, M. (2003) Hyperglycemia-Induced Insulin Resistance in Diabetic Dyslipidemicyucatan Swine. Comparative Medicine, 53, 53-64.

[10]   Brisbin Jr., I.L. and Mayer, J.J. (2001) Problem Pigs in a Poke: A Good Pool of Data. Science, 294, 1280-1281.

[11]   Martin, R.J., Gobble, J.L., Hartsock, T.H., Graves, H.B. and Ziegler, J.H. (1973) Characterization of an Obese Syndrome in the Pig. Experimental Biology and Medicine, 143, 198-203.

[12]   Martin, R.J. and Herbein, J.H. (1976) A Comparison of the Enzyme Levels and the in Vitro Utilization of Various Substrates for Lipogenesis in Pair-Fed Lean and Obese Pigs. Experimental Biology and Medicine, 151, 231-235.

[13]   Wangsness, P.J., Martin, R.J. and Gahagan, J.H. (1977) Insulin and Growth Hormone in Lean and Obese Pigs. American Journal of Physiology, 233, E104-E108.

[14]   Edwards, J.M., Neeb, Z.P., Alloosh, M.A., Long, X., Bratz, I.N., Peller, C.R., et al. (2010) Exercise Training Decreases Store-Operated Ca2+ Entry Associated with Metabolic Syndrome and Coronary Atherosclerosis. Cardiovascular Research, 85, 631-640.

[15]   Etherton, T.D. and Kris-Etherton, P.M. (1980) Characterization of Plasma Lipoproteins in Swine with Different Propensities for Obesity. Lipids, 15, 823-829.

[16]   Neeb, Z.P., Edwards, J.M., Alloosh, M., Long, X., Mokelke, E.A. and Sturek, M. (2010) Metabolic Syndrome and Coronary Artery Disease in Ossabaw Compared with Yucatan Swine. Comparative Medicine, 60, 300-315.

[17]   Dyson, M.C., Alloosh, M., Vuchetich, J.P., Mokelke, E.A. and Sturek, M. (2006) Components of Metabolic Syndrome and Coronary Artery Disease in Female Ossabaw Swine Fed Excess Atherogenic Diet. Comparative Medicine, 56, 35-45.

[18]   Lee, L., Alloosh, M., Saxena, R., Van Alstine, W., Watkins, B.A., Klaunig, J.E., et al. (2009) Nutritional Model of Steatohepatitis and Metabolic Syndrome in the Ossabaw Miniature Swine. Hepatology, 50, 56-67.

[19]   Rao, R.S., Rao, V. and Kini, S. (2010) Animal Models in Bariatric Surgery—A Review of the Surgical Techniques and Postsurgical Physiology. Obesity Surgery, 20, 1293-1305.

[20]   National Research Council (US) Committee for the Update of the Guide for the Care and Use of Laboratory Animals (2011) Guide for the Care and Use of Laboratory Animals. Eighth Edition, The National Academies Press, Washington DC.

[21]   AVMA Panel on Euthanasia (2001) 2000 Report of the AVMA Panel on Euthanasia. Journal of the American Veterinary Medical Association, 218, 669-696.

[22]   Lombardo, C., Damiano, G., Cassata, G., Palumbo, V.D., Cacciabaudo, F., Spinelii, G., et al. (2010) Surgical Vascular Access in the Porcine Model for Long-Term Repeated Blood Sampling. Acta Bio-Medica, 81, 101-103.

[23]   Harris, W.H. (1974) A Technique for Chronic Venous Cannulation in Swine. Laboratory Animals, 8, 237-240.

[24]   Hu, C., Cheang, A., Retnam, L. and Yap, E.H. (1993) A Simple Technique for Blood Collection in the Pig. Laboratory Animals, 27, 364-367.

[25]   Swindle, M.M. (2004) Chronic Intravascular Catheterization in Swine: Peripheral Vessels. Sinclair Research Institute, Inc., Columbia.

[26]   Swindle, M.M. (2004) Chronic Intravascular Catheterization in Swine: General Principles. Sinclair Research Center, Inc., Columbia.

[27]   Rubino, F., Schauer, P.R., Kaplan, L.M. and Cummings, D.E. (2010) Metabolic Surgery to Treat Type 2 Diabetes: Clinical Outcomes and Mechanisms of Action. Annual Review of Medicine, 61, 393-411.

[28]   Cummings, D.E., Overduin, J., Foster-Schubert, K.E. and Carlson, M.J. (2007) Role of the Bypassed Proximal Intestine in the Anti-Diabetic Effects of Bariatric Surgery. Surgery for Obesity and Related Diseases, 3, 109-115.

[29]   Rubino, F., Forgione, A., Cummings, D.E., Vix, M., Gnuli, D., Mingrone, G., et al. (2006) The Mechanism of Diabetes Control after Gastrointestinal Bypass Surgery Reveals a Role of the Proximal Small Intestine in the Pathophysiology of Type 2 Diabetes. Annals of Surgery, 244, 741-749.

[30]   Cummings, D.E. (2005) Gastric Bypass and Nesidioblastosis—Too Much of a Good Thing for Islets? New England Journal of Medicine, 353, 300-302.

[31]   Thaler, J.P. and Cummings, D.E. (2008) Metabolism: Food Alert. Nature, 452, 941-942.

[32]   Cummings, D.E., Weigle, D.S., Frayo, R.S., Breen, P.A., Ma, M.K., Dellinger, E.P., et al. (2002) Plasma Ghrelin Levels after Diet-Induced Weight Loss or Gastric Bypass Surgery. New England Journal of Medicine, 346, 1623-1630.

[33]   Cummings, D.E. and Shannon, M.H. (2003) Ghrelin and Gastric Bypass: Is There a Hormonal Contribution to Surgical Weight Loss? The Journal of Clinical Endocrinology & Metabolism, 88, 2999-3002.

[34]   Courcoulas, A.P. and Flum, D.R. (2005) Filling the Gaps in Bariatric Surgical Research. Journal of the American Medical Association, 294, 1957-1960.

[35]   Arner, P. (2005) Resistin: Yet Another Adipokine Tells Us That Men Are Not Mice. Diabetologia, 48, 2203-2205.

[36]   Cefalu, W.T. (2006) Animal Models of Type 2 Diabetes: Clinical Presentation and Pathophysiological Relevance to the Human Condition. ILAR Journal, 47, 186-198.

[37]   Sheikh, S.P., Holst, J.J., Orskov, C., Ekman, R. and Schwartz, T.W. (1989) Release of PYY from Pig Intestinal Mucosa; Luminal and Neural Regulation. Regulatory Peptides, 26, 253-266.

[38]   Adrian, T.E., Bacarese-Hamilton, A.J., Smith, H.A., Chohan, P., Manolas, K.J. and Bloom, S.R. (1987) Distribution and Postprandial Release of Porcine Peptide YY. Journal of Endocrinology, 113, 11-14.

[39]   Hayashida, T., Murakami, K., Mogi, K., Nishihara, M., Nakazato, M., Mondal, M.S., et al. (2001) Ghrelin in Domestic Animals: Distribution in Stomach and Its Possible Role. Domestic Animal Endocrinology, 21, 17-24.

[40]   Salfen, B.E., Carroll, J.A. and Keisler, D.H. (2003) Endocrine Responses to Short-Term Feed Deprivation in Weanling Pigs. Journal of Endocrinology, 178, 541-551.

[41]   Sham, J.G., Simianu, V.V., Wright, A.S., Stewart, S.D., Alloosh, M., Sturek, M., Cummings, D.E. and Flum, D.R. (2014) Evaluating the Mechanisms of Improved Glucose Homeostasis after Bariatric Surgery in Ossabaw Miniature Swine. Journal of Diabetes Research, 2014, Article ID: 526972.

[42]   Berthoud, H.R. (2008) Vagal and Hormonal Gut-Brain Communication: From Satiation to Satisfaction. Neurogastroenterology & Motility, 20, 64-72.

[43]   Cummings, D.E. and Overduin, J. (2007) Gastrointestinal Regulation of Food Intake. Journal of Clinical Investigation, 117, 13-23.