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Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?
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Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?

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    • 1. Surgery for Obesity: Duodeno-Jejunal Bypass for Type 2 Diabetes in Non-Obese – a Cure ? George S. Ferzli, MD, FACS Chairman of Surgery, Lutheran Medical Center Professor of Surgery, SUNY HSC Brooklyn, New York, USA
    • 2. Derived from Center for Disease Control and Prevention website www.cdc.gov Percent of Obese (BMI ≥ 30) in US Adults
    • 3. Derived from Center for Disease Control and Prevention website www.cdc.gov Percent of Obese (BMI ≥ 30) in US Adults
    • 4. <ul><li>National Hospital Discharge Survey Public-use data file and documentation. Multi-year data CD-ROM. National Center for Health Statistics, 1979-1996. </li></ul><ul><li>Nguyen et al. Accelerated growth of bariatric surgery with the introduction of minimally invasive surgery. Arch Surg 2005; 140: 1198-202. </li></ul><ul><li>Griffen et al. The decline and fall of the jejunoileal bypass. Surg Gynecol Obstet 1983; 157: 301-8. </li></ul><ul><li>Shirmer et al. Bariatric Surgery Training: Getting Your Ticket Punched. J Gastrointest Surg 2007;11: 807-12. </li></ul>Popularity of Surgical Management Period or Decades Incidence of Surgery Reason for Change Late 1970’s Early 1980’s 25,000 procedures per year <ul><li>Innovative procedures </li></ul><ul><li>gastroplasty </li></ul><ul><li>loop GBP </li></ul><ul><li>jejuno-ileal bypass </li></ul>Late 1980’s 1990’s 5,000 procedures per year <ul><li>Multifactorial: </li></ul><ul><li>High M&amp;M </li></ul><ul><li>Ineffective long-term </li></ul><ul><li>Perceived failure </li></ul><ul><li>Surgeon experience </li></ul>2000’s 80,000 to 110,000 procedures per year <ul><li>Multifactorial: </li></ul><ul><li>Laparoscopy </li></ul><ul><li>Long-term data </li></ul><ul><li>Centers of Excellence </li></ul>
    • 5. Current Procedures
    • 6. Metabolic Syndrome <ul><li>Also Known as: </li></ul><ul><li>1. Syndrome “X” </li></ul><ul><li>2. Insulin Resistance Syndrome </li></ul><ul><li>3. Reaven’s Syndrome </li></ul><ul><li>4. CHAOS </li></ul><ul><li>C oronary Artery Disease </li></ul><ul><li>H ypertension </li></ul><ul><li>A dult Onset Diabetes </li></ul><ul><li>O besity </li></ul><ul><li>S troke </li></ul>
    • 7. Obesity Associated Conditions Diabetes Hypertension Sleep apnea Congestive heart failure Hyperlipidemia Stroke Coronary artery disease Osteoarthritis Gastroesophageal reflux disease Non-alcoholic fatty liver Psychological disturbances
    • 8. Diabetes <ul><li>Considered major public health problem – emerging as a world wide pandemic. In 1995 ~ 135 million people worldwide </li></ul><ul><li>Expected to rise to close to 300 million by 2025 </li></ul><ul><li>CDC (2008) cases of diabetes have increased to 15% in just the past two years </li></ul><ul><li>2002-Annual direct health care cost was estimated to be $132 billion in US </li></ul><ul><li>Complications </li></ul><ul><ul><li>Peripheral vascular disease (PVD) accounts for 20-30% </li></ul></ul><ul><ul><li>10% of cerebral vascular accident </li></ul></ul><ul><ul><li>Cardiovascular disease accounts for 50% of total mortality </li></ul></ul><ul><ul><li>Retinopathy, ESRD </li></ul></ul><ul><ul><li>1. Venkat et al Diabetes–a common, growing, serious, costly, and potentially preventable public health problem. Diabetes Res </li></ul></ul><ul><ul><li>Clin Pract. 2000; 5 (Suppl2): S77–S784. </li></ul></ul><ul><ul><li>2. H. King et Global burden of diabetes, 1995-2025: prevalence, numerical estimates and projections. Diabetes Care 21 (1998) </li></ul></ul><ul><ul><li>1414-1431. </li></ul></ul><ul><ul><li>3. CDC website @ www.CDC.com </li></ul></ul>
    • 9. Prevalence of Diabetes <ul><li>From 1980 through 2005, the number of adults aged 18-79 with newly diagnosed diabetes almost tripled from 493,000 in 1980 to 1.4 million in 2005 in the United States </li></ul><ul><li>Annual number (in thousands) of new cases of diagnosed diabetes among adults aged 18-79 years, United States, 1980–2005 </li></ul>
    • 10. <ul><li>Buchwald H, Avidor Y, Braunwald E, Jensen MD, Pories W, Fahrbach K, et al. Bariatric surgery: a systematic review and meta-analysis. JAMA 2004; 292: 1724-37. </li></ul><ul><li>Sjostrom L, Lindros AK, Peltonem M, Torgerson J, Bouchard C, Carlsson B, et al. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med 2004; 351: 2683-93. </li></ul>Long-term Weight Control Analysis Studies Type and Size Effect on Weight Effect on Comorbidities Buchwald et al. Meta-analysis n = 22,094 pts Mean excess weight loss: 61% <ul><li>Resolution of: </li></ul><ul><li>Diabetes: 70% </li></ul><ul><li>HTN: 62% </li></ul><ul><li>Sleep apnea: 86% </li></ul>Swedish Obese Subject trial (SOS) Prospective matched cohort n = 4,047 pts <ul><li>At 10 years: </li></ul><ul><li>Med: 1.6% gain </li></ul><ul><li>Surg: 16% loss </li></ul><ul><li>Improved by surgery: </li></ul><ul><li>Diabetes </li></ul><ul><li>Lipid profile </li></ul><ul><li>HTN </li></ul><ul><li>Hyperuricemia </li></ul>
    • 11. Schauer et al. Effect of laparoscopic Roux-en Y gastric bypass on type 2 diabetes mellitus. Ann Surg. 2003 Oct; 238(4): 467-84 <ul><li>1160 patients underwent LRYGBP 5-year period </li></ul><ul><li>LRYGBP resulted in significant weight loss (60% percent of excess body weight loss) and resolution (83%) of T2DM </li></ul><ul><li>Fasting plasma glucose and HBA1C normalized (83%) or markedly improved (17%) in all patients </li></ul><ul><li>Patients with the shortest duration and mildest form of T2DM had a higher rate of T2DM resolution after surgery </li></ul><ul><ul><li>suggesting that early surgical intervention is warranted to increase the likelihood of rendering patients euglycemic </li></ul></ul>
    • 12. Biliopancreatic Diversion (BPD) <ul><li>312 BPD, obese patients with type 2 DM were followed for pre and postoperative serum glucose, triglycerides, cholesterol &amp; arterial pressure measurements </li></ul><ul><li>After BPD, fasting serum glucose fell within normal values in 310 patients; remained normal up to 10 years in all but 6 patients </li></ul><ul><li>Evidence of hypertension disappeared in majority of patients </li></ul><ul><li>Glycemic control translates into a reduced mortality for these patients as well as a low frequency of death from cardiovascular events </li></ul><ul><li>TRUE CLINICAL RECOVERY </li></ul>Scopinaro N, Marinari GM, Camerini GB et al. Specific Effects of Biliopancreatic Diversion on the Major Components of Metabolic Syndrome. Diabetes Care . 2005. 28:2406-2411
    • 13. Dixon et al. Adjustable Gatric Banding and conventional therapy for type 2 diabetes: a randomized control trial JAMA 2008 <ul><ul><li>Un-blinded randomized control trial </li></ul></ul><ul><ul><li>60 obese patients (BMI &gt;30 &amp; &lt;40) with T2DM </li></ul></ul><ul><ul><li>Interventions : </li></ul></ul><ul><ul><li>- Conventional diabetes control with lifestyle modification vs. LAGB </li></ul></ul><ul><ul><li>Results: </li></ul></ul><ul><ul><ul><li>-55 (92%) completed with 2 year follow-up </li></ul></ul></ul><ul><ul><ul><li>-Remission of diabetes was achieved in 73% in surgical group and 13% in the conventional-therapy group </li></ul></ul></ul>
    • 14. Dixon et al. Adjustable Gatric Banding and conventional therapy for type 2 diabetes: a randomized control trial JAMA 2008 <ul><ul><li>CONCLUSIONS: </li></ul></ul><ul><ul><ul><li>Participants randomized to surgical therapy were more likely to achieve remission of type 2 diabetes through greater weight loss. </li></ul></ul></ul><ul><ul><ul><li>These results need to be confirmed in a larger, more diverse population and have long-term efficacy assessed. </li></ul></ul></ul>
    • 15. Rates of Remission of Diabetes Adjustable Gastric Banding Roux-en-Y Gastric Bypass Biliopancreatic Diversion &gt;95% (Immediate) 48% (Slow) 84% (Immediate)
    • 16. <ul><li>“ Gastric bypass and biliopancreatic diversion </li></ul><ul><li>seem to achieve control of diabetes as a primary and </li></ul><ul><li>independent effect, not secondary </li></ul><ul><li>to the treatment of overweight.” </li></ul><ul><li>Potential of Surgery for Curing Type 2 Diabetes Mellitus. Rubino, Francesco, MD; Gagner, </li></ul><ul><li>Michel MD, FACS, FRCSC Annals of Surgery; 236 (5): 554-559, November 2002 </li></ul>2002: Antidiabetic Effect of Bariatric Surgery: Direct or Indirect?
    • 17. 1995-“Who Would Have Though It? Pories et al. Annals of Surgery <ul><li>NIDDM is no longer an uncontrollable disease </li></ul><ul><li>The correction on NIDDM occurs within days following gastric bypass, long before significant weight loss has occurred </li></ul><ul><li>Decrease caloric intake and changes in incretin stimulation of the islets by the gut may play a role </li></ul>
    • 18. Historical Perspective <ul><li>1955- Friedman </li></ul><ul><ul><li>3 patients with poorly control DM </li></ul></ul><ul><ul><li>3-4 days after subtotal gastrectomy: all 3 pateints showed an improvement in their DM </li></ul></ul><ul><ul><ul><li>Occurred sooner than associated weight loss </li></ul></ul></ul><ul><ul><ul><li>Patients later regained their weight without an associated loss of glucose control or glycosuria </li></ul></ul></ul><ul><li>Mingrone 1977 : Case report </li></ul><ul><ul><li>Young, non obese woman with DM who underwent BPD for chylomicronemia </li></ul></ul><ul><ul><li>Plasma insulin and blood glucose levels normalized within 3 months </li></ul></ul><ul><li>Bittner –1981- subtotal gastrectomy and gastrointestinal reconstructions that excluded duodenal passage (B2 and RYGB) </li></ul><ul><ul><li>Lowered plasma glucose and insulin </li></ul></ul><ul><ul><li>Conclusion: Plasma glucose and insulin fall rapidly post-operatively </li></ul></ul><ul><ul><ul><li>antidiabetic medications can be reduced or stopped shortly after gastrointestinal bypass interventions </li></ul></ul></ul><ul><ul><li>Rubino F. Bariatric Surgery:effects on glucose homeostasis. Curr. Opin. Clin. Nutr. Metab. Care 9: 497-507 </li></ul></ul><ul><ul><li>Bittner R. Homeostasis of glucose and gastric resection: the influence of food passage through the duodenum Z Gastroenterology 1981; 19: 698-707. </li></ul></ul><ul><ul><li>Friedman NM et al. The amelioration of diabetes mellitus following subtotal gastrectomy. Surg. Gynecol. Obstetr. 1955; 100:201-204 </li></ul></ul>
    • 19. Rehfeld J, 2004 1967 – Gastric Bypass DISCOVERY OF GASTROINTESTINAL HORMONES
    • 20. How Does Bariatric Surgery Effect glucose homeostasis? <ul><li>Intestinal Malabsorption? </li></ul><ul><ul><li>Weight loss reduces insulin resistance </li></ul></ul><ul><ul><li>Glucose malabsorption reduces stress on islet cells </li></ul></ul><ul><ul><li>Fat malabsorption reduces circulating free fatty acids and improves insulin sensitivity </li></ul></ul><ul><li>Hormonal Changes? </li></ul><ul><ul><li>Re-routing of food alters the dynamic of gut-hormone secretion </li></ul></ul><ul><ul><ul><li>Increased levels of glucagon-like peptide 1 (GLP-1) </li></ul></ul></ul><ul><ul><ul><li>Decrease in plasma levels of leptin &amp; Grhelin </li></ul></ul></ul><ul><ul><ul><li>Increased levels of adiponectin &amp; peptide YY3-36 </li></ul></ul></ul><ul><li>Rearrangement of GI anatomy? </li></ul><ul><ul><ul><li>“ Hindgut hypothesis” </li></ul></ul></ul><ul><ul><ul><li>“ Foregut hypothesis” </li></ul></ul></ul>
    • 21. 1. Pathophysiology DIABETES OBESITY <ul><ul><ul><li>Excess adipose tissue increases </li></ul></ul></ul><ul><ul><ul><li>available triglyceride stores </li></ul></ul></ul><ul><ul><ul><li>Breakdown of TG leads to overabundance </li></ul></ul></ul><ul><ul><ul><li>of circulating fatty acids </li></ul></ul></ul><ul><ul><ul><li>INCREASED FATTY ACIDS </li></ul></ul></ul>INSULIN RESISTANCE INCREASES HEPATIC TRIGLYCERIDE SYNTHESIS &amp; PRODUCTION OF VLDL LOSS OF VASODILATORY EFFECT OF INSULIN PRESERVED SODIUM REABSORPTION HYPERCHOLESTEROLEMIA HYPERTENSION
    • 22. 2. Hormonal Changes after Bariatric Surgery
    • 23. GIP and GLP-1 <ul><li>Stimulated by enteral nutrients </li></ul><ul><li>insulin secretion / action </li></ul><ul><li> -cell proliferation </li></ul>3. Anti-Incretin Theory <ul><li>Stimulated by enteral nutrients </li></ul><ul><li>insulin secretion / action </li></ul><ul><li> -cell proliferation </li></ul>Anti-incretin
    • 24. Hypothesis <ul><ul><ul><li>Rubino et al; Ann. Surg. 2002 </li></ul></ul></ul>
    • 25. Anti-Incretin Insulin resistance Beta cell depletion Hyperglycemia Too Much Dumping Syndrome Nesidioblastosis Hyperinsulinemia Hypoglycemia Not Enough TYPE 2 DIABETES
    • 26. Hypothesis <ul><ul><ul><li>Rubino et al; Ann. Surg. 2002 </li></ul></ul></ul>
    • 27. Slides taken from: DIABETES IS NO LONGER A HOPELESS DISEASE The Guilty Gut Walter Pories, MD, FACS, Chief, Metabolic Institute East Carolina University Greenville, North Carolina 2006:
    • 28. Slides taken from: DIABETES IS NO LONGER A HOPELESS DISEASE The Guilty Gut Walter Pories, MD, FACS, Chief, Metabolic Institute East Carolina University Greenville, North Carolina 2006:
    • 29. 2006: “ This study shows that bypassing a short segment of proximal intestine directly ameliorates type 2 diabetes, independently of effects on food intake, body weight, malabsorption, or nutrient delivery to the hindgut.” The Mechanism of Diabetes Control After Gastrointestinal Bypass Surgery Reveals a Role of the Proximal Small Intestine in the Pathophysiology of Type 2 Diabetes. Rubino, Francesco, MD; Forgione, Antonello, MD; Cummings, David E MD; Vix, Michel MD; Gnuli, Donatella MD; Mingrone, Geltrude MD; Castagneto, Marco, MD (S); Marescaux, Jacques MD, FRCS Annals of Surgery; 244 (5): 741-749, November 2006
    • 30. <ul><li>Bariatric Surgery clearly has an antidiabetic effect </li></ul><ul><li>Direct effect of the surgical bypass of proximal intestines </li></ul><ul><li>Hormonal Regulation of Glucose Metabolism </li></ul><ul><ul><ul><li>Insulin, glucagons-like peptide (GLP-1), glucose-dependent insulinotropic peptide (GIP), glucagon and leptin </li></ul></ul></ul>Pacheco D, et al. The effects of duodenal-jejunal exclusion on hormonal regulation of glucose metabolism in Goto-Kakizaki rats. Am J Surgery; 194 (2007): 221-224 2007: Pacheco Bypass &amp; Glucose Metabolism
    • 31. Animal Model of DJ Bypass and Glycemic Control <ul><li>Animal Model of non-obese type 2 diabetes; Goto-Kakizaki rats </li></ul><ul><li>Twelve (12-14 wk old) rats randomly underwent </li></ul><ul><li>gastrojejeunal bypass or no intervention </li></ul><ul><li>* All fed with same type of diet </li></ul><ul><li>* All fed with same amount of diet </li></ul><ul><li>* Pre-op, post-op 1 wk &amp; 1 month </li></ul><ul><li>weight assessment &amp; fasting glycemia </li></ul><ul><li>* Oral Glucose Tolerance Test performed at each </li></ul><ul><li>time point </li></ul><ul><li>* Hormone levels were measured after 20 minutes of oral </li></ul><ul><li>overload </li></ul>Pacheco D, et al. The effects of duodenal-jejunal exclusion on hormonal regulation of glucose metabolism in Goto-Kakizaki rats. Am J Surgery; 194 (2007):221-224
    • 32. 2007- Results of DJ Bypass on Glycemic Control <ul><li>Group 1 and Group 2 rats remained the same weight during the experiment </li></ul><ul><li>OGTT improved in DJ bypass group </li></ul><ul><li>Glucose levels were better at 1 week &amp; 1 month after DJ bypass in all times of OGTT (basal, 10 min, 120 min) </li></ul><ul><li>Post-oral glucose load levels of glucagon, insulin, GLP-1 and GIP remained unchanged in both groups </li></ul><ul><li>In DJ bypass group there is a significant decrease in leptin levels noted </li></ul>Pacheco D, et al. The effects of duodenal-jejunal exclusion on hormonal regulation of glucose metabolism in Goto-Kakizaki rats. Am J Surgery; 194 (2007): 221-224
    • 33. Leptin??? <ul><li>Adipocyte-derived hormone </li></ul><ul><li>In mice, leptin acts as a hormonal signal on the afferent limb of a negative feedback loop between the adipose tissue and hypothalmic centers </li></ul><ul><li>Physiological increase in plasma leptin has been shown to significantly inhibit glucose-stimulated insulin secretion in vivo and to determine insulin resistance </li></ul>Pacheco D, et al. The effects of duodenal-jejunal exclusion on hormonal regulation of glucose metabolism in Goto-Kakizaki rats. Am J Surgery; 194 (2007): 221-224
    • 34. Cohen -SAGES 2008
    • 35. Cohen -SAGES 2008
    • 36. Cohen -SAGES 2008
    • 37. <ul><ul><li>Double blind study: 16 patients assigned to LRYGBP and 16 Pts to LSG </li></ul></ul><ul><ul><li>Patients reevaluated on the 1st, 3rd, 6th, and 12th mos </li></ul></ul><ul><ul><li>Results: </li></ul></ul><ul><ul><ul><li>No change in ghrelin levels after LRYGBP Significant decrease in ghrelin after LSG ( P &lt; 0.0001 ) </li></ul></ul></ul><ul><ul><ul><li>Fasting PYY levels increased after either surgical procedure ( P &lt;= 0.001) </li></ul></ul></ul><ul><ul><ul><li>Appetite decreased in both groups but to a greater extend after LSG </li></ul></ul></ul>Weight loss, appetite suppression, and changes in fasting and postprandial ghrelin and peptide-YY levels after Roux-en-Y gastric bypass and sleeve gastrectomy: a prospective, double blind study. Karamanakos et al Ann Surg . 2008 Mar; 247(3): 401-7.
    • 38. <ul><li>“ PYY levels increased similarly after either procedure. </li></ul><ul><li>The markedly reduced ghrelin levels in addition to increased </li></ul><ul><li>PYY levels after LSG, are associated with greater appetite </li></ul><ul><li>suppression and excess weight loss compared with LRYGBP” </li></ul><ul><li>March 2008: Weight loss, appetite suppression, and changes in fasting and postprandial ghrelin and peptide-YY levels after </li></ul><ul><li>Roux-en-Y gastric bypass and sleeve gastrectomy: a prospective, double blind study. Karamanakos et al Ann Surg. 2008 Mar; </li></ul><ul><li>247(3): 401-7. </li></ul>March 2008:
    • 39. Vidal et al. Type 2 Diabetes Mellitus and the Metabolic Syndrome Following Sleeve Gastrectomy in Severely Obese Subjects. Obes. Surg. June 2008 <ul><li>12 mos prospective study 9 severely obese T2DM patients LSG (SG; n = 39) or LRYGP (GBP; n = 52) </li></ul><ul><li>Matched for DM duration, type of DM treatment, and glycemic control </li></ul><ul><li>Results </li></ul><ul><ul><li>T2DM resolved 84.6% SG and (84.6%) GBP (p = 0.618) </li></ul></ul><ul><ul><li>Shorter DM duration and DM treatment and glycemic control associated with both groups </li></ul></ul>
    • 40. <ul><li>SG is as effective as GBP in inducing remission </li></ul><ul><li>of T2DM and the MS. </li></ul><ul><li>SG and GBP represent a successful an integrated strategy for the management of the different cardiovascular risk components of the MS in subjects with T2DM </li></ul><ul><li>Type 2 Diabetes Mellitus and the Metabolic Syndrome Following Sleeve Gastrectomy in Severely Obese </li></ul><ul><li>Subjects. Obes. Surg. 2008, Vidal et al </li></ul>June 2008
    • 41. Non-Obese Patients <ul><li>Slides taken from: DIABETES IS NO LONGER A HOPELESS DISEASE The Guilty Gut,Walter Pories, MD, FACS </li></ul>
    • 42. <ul><li>First Clinical description of laparoscopic stomach-preserving DJB for treatment of T2DM in non-obese </li></ul><ul><li>2 patients with &gt;12 mos f/u (13/15 mos) </li></ul><ul><li>By 5 th week of surgery, both patients were euglycemic and free of all antidiabetic medications </li></ul><ul><li>Conclusion: </li></ul><ul><ul><li>LDJB is a feasible and safe </li></ul></ul><ul><ul><li>could represent valuable therapeutic option </li></ul></ul>
    • 43. <ul><li>39 patients underwent laparoscopic ileal interposition into proximal jejunum via sleeve or diverted sleeve gastrectomy </li></ul><ul><ul><li>BMI &lt; 35 </li></ul></ul><ul><ul><li>All had type II DM for at least 3 years </li></ul></ul><ul><ul><li>Mean post-op follow up was 7 months </li></ul></ul><ul><ul><li>Mean operative time was 185 minutes </li></ul></ul><ul><ul><li>87% of patients discontinued preop oral hypoglycemics, insulin or both </li></ul></ul><ul><ul><li>Hemoglobin A1c decreased from 8.8% to 6.3% </li></ul></ul><ul><li>All but one patient experienced normalization of cholesterol </li></ul>DePaula AL. et al. Laparoscopic treatment of type 2 DM for patients with BMI less than 35. Surg. Endosc.
    • 44. DePaula AL. et al. Laparoscopic treatment of type 2 DM for patients with BMI less than 35. Surg. Endosc. <ul><li>Conclusion: </li></ul><ul><ul><li>Laparoscopic ileal interposition via either a sleeve gastrectomy or diverted sleeve gastrectomy seems to be a promising procedure for the control of T2DM and the metabolic syndrome </li></ul></ul>
    • 45. CLINICAL TRIAL: Duodenal-Jejeunal Bypass for Type 2 Diabetes (DJBD) <ul><li>SUMMARY: </li></ul><ul><li>Clinical Evaluation of the Effect of Duodenal-Jejunal Bypass on Type 2 Diabetes </li></ul><ul><li>FACILITY: </li></ul><ul><li>Center for Advanced Medicine </li></ul><ul><li>Santo Domingo, Dominican Republic </li></ul><ul><li>STUDY OFFICIALS/INVESTIGATORS: </li></ul><ul><li>George Ferzli, MD, FACS - Study Principal Investigator, </li></ul><ul><li>SUNY Downstate, Brooklyn, New York, USA </li></ul><ul><li>Abel Gonzalez, MD - Center for Advanced Medicine, </li></ul><ul><li>Santo Domingo, Dominican Republic </li></ul><ul><li>Martin Bluth, MD, PhD - Director of Research, Assistant Professor, </li></ul><ul><li>Departments of Surgery and Pathology, Brooklyn, NY USA) </li></ul>
    • 46. Dominican Republic 2007 <ul><li>Prospective controlled clinical trial </li></ul><ul><li>Seeking to recruit total of 50 patients </li></ul><ul><li>www. clinicaltrials .gov </li></ul><ul><li>Unique Protocol ID: AS07006 </li></ul><ul><li>Clinicaltrials.gov ID: NCT00487526 . </li></ul>
    • 47. Lutheran Medical Center Clinical Trial 2008 <ul><li>Prospective study </li></ul><ul><li>Seeking to recruit total of 50 patients </li></ul><ul><li>www. clinicaltrials .gov </li></ul><ul><li>ID: NCT00694278, LMC 95 </li></ul>
    • 48. Clinical Trial Eligibility Inclusion Criteria <ul><li>Adults age 20-65 </li></ul><ul><li>Clinical diagnosis of type II diabetes: </li></ul><ul><ul><li>a) A normal or high C-peptide level (to exclude type 1 diabetes) (&gt;.9ng/ml) </li></ul></ul><ul><ul><li>b) A random plasma glucose of 200mg/dl or more with typical symptoms of diabetes </li></ul></ul><ul><ul><li>c)A fasting plasma glucose of 126mg/dl or more on more than one occasion </li></ul></ul><ul><li>BMI 22-34 KG/m2, </li></ul><ul><li>Patients on oral hypoglycemic medications or insulin to control T2DM Inadequate control of diabetes as defined as HbA1c&gt;7.5 </li></ul><ul><li>No contraindications for surgery or general anesthesia </li></ul><ul><li>Ability to understand and describe the mechanism of action and risks and benefits of the operation </li></ul>
    • 49. Clinical Trial Eligibility Exclusion Criteria <ul><li>Diagnosis of type 1 diabetes </li></ul><ul><li>Planned pregnancy within 2 years of entry into the study </li></ul><ul><li>Previous gastric or esophageal surgery, immunosuppressive drugs including corticosteroids, coagulopathy, anemia, any contraindication to laparoscopic gastric bypass or medical hypoglycemic therapy </li></ul><ul><li>Severe concurrent illness likely to limit life (e.g. cancer) or requiring extensive disorder (e.g. pancreatic insufficiency, Celiac sprue, or Crohn’s disease) </li></ul><ul><li>Pre-existing major complications of diabetes, significant proteinuria (&gt;250mg/dl), severe proliferate retinopathy, severe neuropathy or clinical diagnosis of gastroperesis </li></ul><ul><li>MI in the previous year </li></ul><ul><li>Unable to comply with study requirements, follow-up or give verbal consent </li></ul><ul><li>Liver cirrhosis </li></ul><ul><li>Previous abdominal surgery (those that involve the stomach and proximal bowel). </li></ul>
    • 50. Preoperative work up <ul><li>Detailed informed consent explain to patient. </li></ul><ul><li>Baseline assessment by multidisciplinary surgical team </li></ul><ul><ul><li>Surgeon, primary physician, endocrinologist, cardiologist, gastroenterologist, psychiatrist, nutritionist </li></ul></ul><ul><li>Routine work-up and blood work </li></ul><ul><ul><li>(CBC, electrolytes, serum creatinine, fasting glucose, HbA 1c , fasting lipid profile (HDL and LDL cholesterol, triglycerides), free fatty acids, leptin, insulin like growth factor 1 (ILGF-1), Glucagon, Glucagon-like peptide 1 (GLP-1), CCK, FFA, Cholesterol, Ghrelin, C-peptide and Gastro-inhibitory peptide (GIP) levels. ) </li></ul></ul><ul><li>Studies </li></ul><ul><ul><li>Electrocardiogram (ECG), chest radiograph, and Esophagogastroduodenoscopy (EGD), PFT’S (if indicated) </li></ul></ul>
    • 51. Operative Course <ul><li>Laparoscopic Duodenal-Jejunal bypass under GETA </li></ul><ul><li>Preoperative prophylaxis antibiotic (Ancef or Clinda in PCN allergy) </li></ul><ul><li>Sequential compression devices for deep venous thrombosis (DVT) prophylaxis in addition to LMWH (5,000units SQ). </li></ul><ul><li>Operative/Intra-operative data </li></ul><ul><ul><li>OR time, EBL, complications, unusual findings </li></ul></ul><ul><li>NPO until upper gastrointestinal (UGI) on POD#1 </li></ul><ul><li>Clear fluids are begun following the UGI study, and continue for 5-7 days </li></ul><ul><li>Patient follow up with nutritionist for dietary guidelines </li></ul>
    • 52. Postoperative follow up <ul><li>Follow up with multidisciplinary team </li></ul><ul><ul><li>Surgeon, endocrinologist, primary care physician and nutritionist at 2 weeks, 4 weeks, 3 months, and from then on at intervals of 3 months or more often if necessary, for 2 years </li></ul></ul><ul><li>Blood drawn for fasting glucose and fasting insulin on days 2 and 7 and at 2 weeks and 4 weeks and 3 months after initiation of treatment </li></ul><ul><li>Nutritionist follow up – continue to puree diet </li></ul><ul><li>Attend support group </li></ul>
    • 53. Outcomes/Measures <ul><li>The primary outcome </li></ul><ul><ul><li>Reversion of hyperglycemia to euglycemia (normalization of HbA 1c to &lt;7%) </li></ul></ul><ul><li>Secondary outcomes </li></ul><ul><ul><li>- lipid profiles, and C-peptide </li></ul></ul>
    • 54. Clinical Evaluation of the Effect of Duodenal-Jejunal Bypass on Type 2 Diabetes (June 2007) Results <ul><li>LDJB was performed successfully in 7 patients </li></ul><ul><li>Mean age of 43.3 range (33-52) </li></ul><ul><li>Limb was 75cm/75cm </li></ul><ul><li>Operative time average 98 min </li></ul><ul><li>Length of stay 3 days </li></ul>
    • 55. Clinical Evaluation of the Effect of Duodenal -Jejunal Bypass on Type 2 Diabetes (June 2007) Patient Demographic, June 6, 2007
    • 56. Morbidity <ul><li>Initial symptoms included nausea and vomiting </li></ul><ul><ul><li>resolved in all patients by 3 months post-operatively </li></ul></ul><ul><li>One patient developed a liver abscess </li></ul><ul><ul><li>required drainage unrelated to the procedure </li></ul></ul><ul><li>No deaths </li></ul>
    • 57. Clinical Evaluation of the Effect of Duodenal-Jejunal Bypass on Type 2 Diabetes (June 2007) Results <ul><li>HBA1c, Fasting Blood Glucose (FBG), Triglycerides (TG), Cholesterol (Chol) and C-peptide (Cpep) were measured at pre-op and 1 year </li></ul><ul><li>The mean HBA1c at pre-op and 1 year was 9.371 and 8.500 respectively </li></ul><ul><li>FBG at pre-op and 1 year were 208 and 154 respectively for the seven patients (p=0.057) </li></ul><ul><li>Lipid profiles improved with lower total cholesterol levels and triglycerides 1 year </li></ul>
    • 58. Data Results Clinical Evaluation of the Effect of Duodenal-Jejunal Bypass on Type 2 Diabetes ( June 2007)
    • 59. Clinical Evaluation of the Effect of Duodenal-Jejunal Bypass on Type 2 Diabetes (June 2007) Table 2   N Correlation Sig. HBA1c Pre-op &amp; HBA1c 1yr 7 -0.040 0.933 FBG Pre-op &amp; FBG 1YR 7 0.74 0.057 Chol preop &amp; Chol 1yr 7 0.632 0.128 TG pre-op &amp; TG 1yr 7 -0.245 0.596 Cpep pre-op &amp; Cpep 3 months 7 0.546 0.205
    • 60. !!! <ul><li>One patient required insulin preop, at 6 months she was no longer on insulin and all lab work was normal </li></ul><ul><li>She became pregnant at 6 months following surgery </li></ul><ul><li>Her diabetes returned and her insulin requirement is at the pre-op level </li></ul><ul><li>It is unclear whether she had resolution of her T2DM or had developed gestational diabetes requiring insulin for her pregnancy at the 1-year follow-up </li></ul>
    • 61. !!! <ul><li>Our Study- 1 year follow-up </li></ul><ul><li>5 patients (71%) T2DM &gt; 10 years (10-19) </li></ul><ul><li>1 pre oral/insulin-free from medication at 1 yr </li></ul><ul><li>2 required less dosages </li></ul><ul><li>The remaining two diabetic patients with a clinical diagnosis greater than ten years still require their insulin and oral hypoglycemics. </li></ul><ul><li>All 5 patients –no symptoms and improved state of health </li></ul>
    • 62. !!! <ul><li>2 patients with c-peptide &lt;1, the HbA1c increased following the procedure </li></ul>
    • 63. &nbsp;
    • 64. SAGES 2008 <ul><li>35 patients T2DM for 2-10 years l underwent LDJB </li></ul><ul><li>April-Nov 07 </li></ul><ul><li>15 women, 20 men </li></ul><ul><li>Comorbidities </li></ul><ul><ul><li>75% with HTN </li></ul></ul><ul><ul><li>58% Hypercholesteremia </li></ul></ul><ul><ul><li>62.5% Hypertriglyceremia </li></ul></ul><ul><li>Mean OR time = 46 minutes (33-78 min) </li></ul><ul><li>Hospital stay 30 hrs –81 days </li></ul><ul><li>PPI for 90 days </li></ul><ul><li>Patients kept on metformin/glimeperide (metformin withdrawn when HBA1c &lt;6) </li></ul>
    • 65. Complications <ul><li>1 death </li></ul><ul><li>2 intestinal obstruction </li></ul><ul><li>1 pos-operative pancreatitis </li></ul><ul><li>2 intracavitary bleeding </li></ul>
    • 66. Results <ul><li>HbA1c decreasing from 8.9 to 6.1. </li></ul><ul><li>72.3% of patients had control of their hypertension: reduced sympathetic outflow? </li></ul><ul><li>13/35 patients reported food intolerance: 8/13 required admission (no women) </li></ul><ul><li>Oral Ginger and sildenafil are very helpful </li></ul><ul><li>75% complained of post-prandial sleepiness </li></ul><ul><ul><li>These side effects may be attributed to gastroparesis and the postulated diminished sympathetic outflow, a result of central leptin suppression and duodenal bypass </li></ul></ul>
    • 67. Interim Conclusions <ul><li>Very promising initial experience. </li></ul><ul><li>The vast majority of insulin users do not use it anymore very early in the post-op. </li></ul><ul><li>In most of those patients with overweight or grade 1 obesity, weight loss is not a major player regarding the control of T2DM, as some had no weight modification or regained weight and there was no recurrence. </li></ul>
    • 68. Interim Conclusions <ul><li>What are the correct inclusion/exclusion criteria? Should we cut off at 8, 9, 10 years? </li></ul><ul><li>Time of T2DM history does not seem important, but C peptide below 1  YES!!! </li></ul>
    • 69. Interim Conclusions <ul><li>Don ’t rush to withdraw medication. </li></ul><ul><li>We add an incretin effect, but METFORMIN helps to decrease hepatic defective glucose production. </li></ul><ul><li>What is the antidiabetes mechanism? </li></ul>
    • 70. Interim Conclusions <ul><li>What are the appropriate limb lengths? 50/75/80? </li></ul><ul><li>Is it necessary to bypass the entire duodenum? </li></ul><ul><ul><li>If yes, how can we assess that? </li></ul></ul><ul><ul><li>Does it make any difference? </li></ul></ul><ul><li>Do we need complex operations in this subset of patients? </li></ul><ul><ul><li>Are the mortality/ complication rates reasonable? </li></ul></ul><ul><li>Will an added sleeve gastrectomy in selected patients be needed to avoid gastroparesis, mainly in those with BMI&gt;32? </li></ul><ul><ul><li>Or is a LRYGB more adequate? </li></ul></ul>
    • 71. The Surgeon and the Diabetologists
    • 72. &nbsp;
    • 73. Acknowledgements <ul><li>Kell Juliard </li></ul><ul><li>Martin Bluth, MD, PhD </li></ul><ul><li>Giancarlo Cires, MD </li></ul><ul><li>Rosemarie E Hardin, MD </li></ul><ul><li>Joel Ricci, MD </li></ul>

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