Clinical Improvement Proceeds Glycemic Homeostasis After Duodenal-jejunal Bypass for Non-obese Type 2 Diabetes

Clinical Improvement Precedes Glycemic Homeostasis After Duodenal-Jejunal Bypass for Non-Obese Type 2 Diabetes Dominique Elvita,DO Marc Ciaglia,DO George S. Ferzli, Jr, MS George S. Ferzli, MD, FACS Chairman of Surgery, Lutheran Medical Center Professor of Surgery, SUNY HSC Brooklyn, New York, USA

Derived from Center for Disease Control and Prevention website www.cdc.gov Percent of Obese (BMI ≥ 30) in US Adults

National Hospital Discharge Survey Public-use data file and documentation. Multi-year data CD-ROM. National Center for Health Statistics, 1979-1996. Nguyen et al. Accelerated growth of bariatric surgery with the introduction of minimally invasive surgery. Arch Surg 2005; 140: 1198-202. Griffen et al. The decline and fall of the jejunoileal bypass. Surg Gynecol Obstet 1983; 157: 301-8. Shirmer et al. Bariatric Surgery Training: Getting Your Ticket Punched. J Gastrointest Surg 2007;11: 807-12. Popularity of Surgical Management Period or Decades Incidence of Surgery Reason for Change Late 1970’s Early 1980’s 25,000 procedures per year Innovative procedures gastroplasty loop GBP jejuno-ileal bypass Late 1980’s 1990’s 5,000 procedures per year Multifactorial: High M&M Ineffective long-term Perceived failure Surgeon experience 2000’s 80,000 to 110,000 procedures per year Multifactorial: Laparoscopy Long-term data Centers of Excellence

Metabolic Syndrome Also Known as: 1. Syndrome “X” 2. Insulin Resistance Syndrome 3. Reaven’s Syndrome 4. Deadly Quartet 5. CHAOS C oronary Artery Disease H ypertension A dult Onset Diabetes O besity S troke

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

Diabetes Considered major public health problem – emerging as a world wide pandemic. In 1995 ~ 135 million people worldwide Expected to rise to close to 300 million by 2025 CDC (2008) cases of diabetes have increased to 15% in just the past two years 1998-Annual direct health care cost was estimated to be $60 billion in US Complications Peripheral vascular disease (PVD) accounts for 20-30% 10% of cerebral vascular accident Cardiovascular disease accounts for 50% of total mortality 1. Venkat et al Diabetes–a common, growing, serious, costly, and potentially preventable public health problem. Diabetes Res Clin Pract. 2000; 5 (Suppl2): S77–S784. 2. H. King et Global burden of diabetes, 1995-2025: prevalence, numerical estimates and projections. Diabetes Care 21 (1998) 1414-1431. 3. CDC website @ www.CDC.com

Prevalence of Diabetes 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 Annual number (in thousands) of new cases of diagnosed diabetes among adults aged 18-79 years, United States, 1980–2005

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. 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. 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% Resolution of: Diabetes: 70% HTN: 62% Sleep apnea: 86% Swedish Obese Subject trial (SOS) Prospective matched cohort n = 4,047 pts At 10 years: Med: 1.6% gain Surg: 16% loss Improved by surgery: Diabetes Lipid profile HTN Hyperuricemia

Schauer et al. Effect of laparoscopic Roux-en Y gastric bypass on type 2 diabetes mellitus. Ann Surg. 2003 Oct; 238(4): 467-84 1160 patients underwent LRYGBP 5-year period LRYGBP resulted in significant weight loss (60% percent of excess body weight loss) and resolution (83%) of T2DM Fasting plasma glucose and HBA1C normalized (83%) or markedly improved (17%) in all patients Patients with the shortest duration and mildest form of T2DM had a higher rate of T2DM resolution after surgery suggesting that early surgical intervention is warranted to increase the likelihood of rendering patients euglycemic

Biliopancreatic Diversion (BPD) 312 BPD, obese patients with type 2 DM were followed for pre and postoperative serum glucose, triglycerides, cholesterol & arterial pressure measurements After BPD, fasting serum glucose fell within normal values in 310 patients; remained normal up to 10 years in all but 6 patients Evidence of hypertension disappeared in majority of patients Glycemic control translates into a reduced mortality for these patients as well as a low frequency of death from cardiovascular events TRUE CLINICAL RECOVERY 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

Biliopancreatic Diversion (BPD) 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

Clinical Evidence: Bariatric Surgery & Impact on Metabolic Syndrome

Rates of Remission of Diabetes Adjustable Gastric Banding Roux-en-Y Gastric Bypass Biliopancreatic Diversion >95% (Immediate) 48% (Slow) 84% (Immediate)

“ Gastric bypass and biliopancreatic diversion seem to achieve control of diabetes as a primary and independent effect, not secondary to the treatment of overweight.” Potential of Surgery for Curing Type 2 Diabetes Mellitus. Rubino, Francesco, MD; Gagner, Michel MD, FACS, FRCSC Annals of Surgery; 236 (5): 554-559, November 2002 2002: Antidiabetic Effect of Bariatric Surgery: Direct or Indirect?

1995-“Who Would Have Though It? Pories et al. Annals of Surgery NIDDM is no longer an uncontrollable disease The correction on NIDDM occurs within days following gastric bypass, long before significant weight loss has occurred Decrease caloric intake and changes in incretin stimulation of the islets by the gut may play a role

Historical Perspective 1955- Friedman 3 patients with poorly control DM 3-4 days after subtotal gastrectomy all 3 pateints showed an improvement in their DM Occurred sooner than associated weight loss Patients later regained their weight without an associated loss of glucose control or glycosuria Mingrone 1977 : Case report Young, non obese woman with DM who underwent BPD for chylomicronemia Plasma insulin and blood glucose levels normalized within 3 months Bittner –1981- subtotal gastrectomy and gastrointestinal reconstructions that excluded duodenal passage (B2 and RYGB Lowered plasma glucose and insulin Conclusion: Plasma glucose and insulin fall rapidly post-operatively antidiabetic medications can be reduced or stopped shortly after gastrointestinal bypass interventions Rubino F. Bariatric Surgery:effects on glucose homeostasis. Curr. Opin. Clin. Nutr. Metab. Care 9: 497-507 Bittner R. Homeostasis of glucose and gastric resection: the influence of food passage through the duodenum Z Gastroenterology 1981; 19: 698-707. Friedman NM et al. The amelioration of diabetes mellitus following subtotal gastrectomy. Surg. Gynecol. Obstetr. 1955; 100:201-204

Rehfeld J, 2004 1967 – Gastric Bypass DISCOVERY OF GASTROINTESTINAL HORMONES

How Does Bariatric Surgery Effect glucose homeostasis? Intestinal Malabsorption? Weight loss reduces insulin resistance Glucose malabsorption reduces stress on islet cells Fat malabsorption reduces circulating free fatty acids and improves insulin sensitivity Hormonal Changes? Re-routing of food alters the dynamic of gut-hormone secretion Decrease in plasma levels of leptin & insulin Increased levels of adiponectin & peptide YY3-36 Increased levels of glucagon-like peptide 1 (GLP-1) Rearrangement of GI anatomy? “ Hindgut hypothesis” “ Foregut hypothesis”

1. Pathophysiology DIABETES OBESITY Excess adipose tissue increases available triglyceride stores Breakdown of TG leads to overabundance of circulating fatty acids INCREASED FATTY ACIDS INSULIN RESISTANCE INCREASES HEPATIC TRIGLYCERIDE SYNTHESIS & PRODUCTION OF VLDL LOSS OF VASODILATORY EFFECT OF INSULIN PRESERVED SODIUM REABSORPTION HYPERCHOLESTEROLEMIA HYPERTENSION

2. Hormonal Changes after Bariatric Surgery

3. Anti-Incretin Insulin resistance Beta cell depletion Hyperglycemia Too Much Dumping Syndrome Nesidioblastosis Hyperinsulinemia Hypoglycemia Not Enough TYPE 2 DIABETES

GIP and GLP-1 Stimulated by enteral nutrients insulin secretion / action  -cell proliferation … Anti-Incretin Stimulated by enteral nutrients insulin secretion / action  -cell proliferation Anti-incretin

Potential Cure for Diabetes Hypothesis Hypoglycemia Rubino et al; Ann. Surg. 2002

Hypothesis Rubino et al; Ann. Surg. 2002

2004: Duodenal-Jejunal Exclusion - Foregut

2004: “ Results of our study support the hypothesis that the bypass of duodenum and jejunum can directly control type 2 diabetes and not secondarily to weight loss or treatment of obesity.” Effect of Duodenal-Jejunal Exclusion in a Non-obese Animal Model of Type 2 Diabetes: A New Perspective for an Old Disease. Rubino, Francesco, MD; Marescaux, Jacques MD, FRCS Annals of Surgery; 239 (1): 1-11, January 2004

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:

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

Bariatric Surgery clearly has an antidiabetic effect; thought to be secondary to surgically induced weight loss and decreased caloric intake But, how do we explain the finding that glycemic control occurs within days, before significant weight loss has been achieved??? Direct effect of the surgical bypass of proximal intestines Hormonal Regulation of Glucose Metabolism Insulin, glucagons-like peptide (GLP-1), glucose-dependent insulinotropic peptide (GIP), glucagon and leptin 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 & Glucose Metabolism

Animal Model of DJ Bypass and Glycemic Control Animal Model of non-obese type 2 diabetes; Goto-Kakizaki rats Twelve (12-14 wk old) rats randomly underwent gastrojejeunal bypass or no intervention * All fed with same type of diet * All fed with same amount of diet * Pre-op, post-op 1 wk & 1 month weight assessment & fasting glycemia * Oral Glucose Tolerance Test performed at each time point * Hormone levels were measured after 20 minutes of oral overload 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- Results of DJ Bypass on Glycemic Control Group 1 and Group 2 rats remained the same weight during the experiment OGTT improved in DJ bypass group Glucose levels were better at 1 week & 1 month after DJ bypass in all times of OGTT (basal, 10 min, 120 min) Post-oral glucose load levels of glucagon, insulin, GLP-1 and GIP remained unchanged in both groups In DJ bypass group there is a significant decrease in leptin levels noted 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

Leptin??? Adipocyte-derived hormone In mice, leptin acts as a hormonal signal on the afferent limb of a negative feedback loop between the adipose tissue and hypothalmic centers Physiological increase in plasma leptin has been shown to significantly inhibit glucose-stimulated insulin secretion in vivo and to determine insulin resistance 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

Double blind study: 16 patients assigned to LRYGBP and 16 Pts to LSG Patients reevaluated on the 1st, 3rd, 6th, and 12th mos Results: No change in ghrelin levels after LRYGBP Significant decrease in ghrelin after LSG ( P < 0.0001) Fasting PYY levels increased after either surgical procedure ( P <= 0.001) Appetite decreased in both groups but to a greater extend after LSG 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.

“ PYY levels increased similarly after either procedure. The markedly reduced ghrelin levels in addition to increased PYY levels after LSG, are associated with greater appetite suppression and excess weight loss compared with LRYGBP” March 2008: 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. March 2008:

Vidal et al. Type 2 Diabetes Mellitus and the Metabolic Syndrome Following Sleeve Gastrectomy in Severely Obese Subjects. Obes. Surg. June 2008 12 mos prospective study 9 severely obese T2DM patients LSG (SG; n = 39) or LRYGP (GBP; n = 52) Matched for DM duration, type of DM treatment, and glycemic control Results T2DM resolved 84.6% SG and (84.6%) GBP (p = 0.618) Weight loss was not associated with T2DM resolution after SG or GBP Shorter DM duration and DM treatment and glycemic control associated with both groups

SG is as effective as GBP in inducing remission of T2DM and the MS. 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 Type 2 Diabetes Mellitus and the Metabolic Syndrome Following Sleeve Gastrectomy in Severely Obese Subjects. Obes. Surg. 2008, Vidal et al June 2008

Non-Obese Patients Slides taken from: DIABETES IS NO LONGER A HOPELESS DISEASE The Guilty Gut,Walter Pories, MD, FACS

First Clinical description of laparoscopic stomach-preserving DJB for treatment of T2DM 2 patients with >12 mos f/u (13/15 mos) By 5 th week of surgery, both patients were euglycemic and free of all antidiabetic medications Conclusion: LDJB is a feasible and safe could represent valuable therapeutic option

39 patients underwent laparoscopic ileal interposition into proximal jejunum via sleeve or diverted sleeve gastrectomy BMI < 35 All had type II DM for at least 3 years Mean operative time was 185 minutes Mean post-op follow up was 7 months 87% of patients discontinued preop oral hypoglycemics, insulin or both Hemoglobin A1c decreased from 8.8% to 6.3% All but one patient experienced normalization of cholesterol DePaula AL. et al. Laparoscopic treatment of type 2 DM for patients with BMI less than 35. Surg. Endosc.

DePaula AL. et al. Laparoscopic treatment of type 2 DM for patients with BMI less than 35. Surg. Endosc.

DePaula AL. et al. Laparoscopic treatment of type 2 DM for patients with BMI less than 35. Surg. Endosc. Conclusion: 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

CLINICAL TRIAL: Duodenal-Jejeunal Bypass for Type 2 Diabetes (DJBD) SUMMARY: Clinical Evaluation of the Effect of Duodenal-Jejunal Bypass on Type 2 Diabetes FACILITY: Center for Advance Medicine Santo Domingo, Dominican Republic STUDY OFFICIALS/INVESTIGATORS: George Ferzli, MD, FACS - Study Principal Investigator, SUNY Downstate, Brooklyn, New York, USA Abel Gonzalez, MD - Center for Advanced Medicine, Santo Domingo, Dominican Republic Martin Bluth, MD, PhD - Director of Research, Assistant Professor, Departments of Surgery and Pathology, Brooklyn, NY USA)

Dominican Republic 2007 Prospective controlled clinical trial Seeking to recruit total of 50 patients www. clinicaltrials .gov Unique Protocol ID: AS07006 Clinicaltrials.gov ID: NCT00487526 .

Lutheran Medical Center Clinical Trial 2008 Prospective study Seeking to recruit total of 50 patients www. clinicaltrials .gov ID: NCT00694278, LMC 95

Clinical Trial Eligibility Inclusion Criteria Adults age 20-65 Clinical diagnosis of type II diabetes: a) A normal or high C-peptide level (to exclude type 1 diabetes) (>.9ng/ml) b) A random plasma glucose of 200mg/dl or more with typical symptoms of diabetes c)A fasting plasma glucose of 126mg/dl or more on more than one occasion BMI 22-34 KG/m2, Patients on oral hypoglycemic medications or insulin to control T2DM Inadequate control of diabetes as defined as HbA1c>7.5 No contraindications for surgery or general anesthesia Ability to understand and describe the mechanism of action and risks and benefits of the operation

Clinical Trial Eligibility Exclusion Criteria Diagnosis of type 1 diabetes Planned pregnancy within 2 years of entry into the study Previous gastric or esophageal surgery, immunosuppressive drugs including corticosteroids, coagulopathy, anemia, any contraindication to laparoscopic gastric bypass or medical hypoglycemic therapy Severe concurrent illness likely to limit life (e.g. cancer) or requiring extensive disorder (e.g. pancreatic insufficiency, Celiac sprue, or Crohn’s disease) Pre-existing major complications of diabetes, significant proteinuria (>250mg/dl), severe proliferate retinopathy, severe neuropathy or clinical diagnosis of gastropathy MI in the previous year Unable to comply with study requirements, follow-up or give verbal consent Liver cirrhosis Previous abdominal surgery

Preoperative work up Detailed informed consent explain to patient and Baseline assessment by multidisciplinary surgical team Surgeon, primary physician, endocrinologist, cardiologist, gastroenterologist, psychiatrist, nutritionist Routine work-up and blood work (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. ) Studies Electrocardiogram (ECG), chest radiograph, and Esophagogastroduodenoscopy (EGD), PFT’S (if indicated)

Operative Course Laparoscopic Duodenal-Jejunal bypass under GETA Preoperative prophylaxis antibiotic (Ancef or Clinda in PCN allergy) Sequential compression devices for deep venous thrombosis (DVT) prophylaxis in addition to LMWH (5,000units SQ). Operative/Intraoperative data OR time, EBL, complications, unusual findings NPO until upper gastrointestinal (UGI) on POD#1 Clear fluids are begun following the UGI study, and continue for 5-7 days Patient follow up with nutritionist for dietary guidelines

Postoperative follow up Follow up with multidisciplinary team 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 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 Nutritionist follow up – continue to puree diet Attend support group

Outcomes/Measures The primary outcome Reversion of hyperglycemia to euglycemia (normalization of HbA 1c to <7%) Secondary outcomes - lipid profiles, and C-peptide

Clinical Evaluation of the Effect of Duodenal -Jejunal Bypass on Type 2 Diabetes (June 2007) Patient Demographic, June 6, 2007 LDJB was performed successfully in 7 patients Mean age of 43.3 range (33-52) Limb was 75cm/75cm Operative time average 98 min Length of stay 3 days

Results Overall, no complications were observed that in any way stemmed from the procedure One patient developed a liver abscess required drainage unrelated to the procedure All patients consistently felt relief from their preoperative symptoms. No deaths

Clinical Evaluation of the Effect of Duodenal -Jejunal Bypass on Type 2 Diabetes (June 2007) Patient Duration of Type 2 Diabetes Pre-Operative Medication 1 Year Medication Requirement #1 19 Metformin 850mg One tablet daily Metformin 850 mg half tablet daily #2 10 30/10 Units Insulin 30/10 Units Insulin #3 12 40/20/20/20 Units Insulin 30 Units occasionally at night #4 12 2 Metformin 850mg daily; 40/20 Units Insulin 1 Metformin 850mg daily; 5 Units n occasionally #5 12 40/20 Units Insulin 5 Units Insulin three times per week #6 * 6 20/12 Units Insulin No Medication #7 4 Clormin 1000mg daily; 30/20 Units Insulin Diaformin 500mg daily; 30/20 Units Insulin

Clinical Evaluation of the Effect of Duodenal-Jejunal Bypass on Type 2 Diabetes ( June 2007) HBA1c, Fasting Blood Glucose (FBG), Triglycerides (TG), Cholesterol (Chol) and C-peptide (Cpep) were measured at pre-op and 1 year Patient nos. 3, 4and 7 demonstrated marked drop (2.8 – 4.3%) in their HbA1c values through one year post op compared with pre op values, where as only 2/3 of these patients (3 &4) had reductions (>100mg/dl) in their FBG levels. In contrast, TG levels increased in these two patients. Interestingly, some patients demonstrated an increase in HbA1c (patient nos. 1&2), FBG (patient nos. 1&7), TG (patient nos. 1&6), and c-pep (patient nos. 1&7) at one-year post op compared with pre-op values. HBA1C FBG Cholesterol TG C-Peptide Pre-op 1w 3m 1yr Pre-op 1w 3m 1yr Pre-op 1w 3m 1yr Pre-op 1w 3m 1yr Pre-op 1w 3m 1yr #1 8 11.8 9.4 12 256 68 218 315 180 143 164 164 58 44 76 87 <0.5 2.2 1.2 1.3 #2 6.7 8.6 11.9 8.5 180 232 324 123 157 171 157 132 88 143 99 84 1.2 0.9 1.1 0.2 #3 11.8 12.3 8.8 7.5 252 202 176 90 160 152 138 141 70 52 93 98 2.5 1.8 2.1 2.2 #4 11.2 8.4 7.7 7.7 195 211 88 84 158 156 151 151 97 77 74 109 1.8 1.9 0.5 1.2 #5 9.4 12.3 9.8 8.6 181 184 95 110 227 204 200 211 195 136 303 119 <0.5 <0.5 <0.5 <0.5 #6 6.6 6.6 8.1 6.3 112 163 84 63 179 157 171 271 44 58 47 276 1.3 1.3 0.5 0.2 #7 11.7 13.4 11.7 8.9 286 210 322 299 225 199 263 232 235 120 224 118 1.8 1.4 2.6 2.3

Clinical Evaluation of the Effect of Duodenal-Jejunal Bypass on Type 2 Diabetes ( June 2007) The mean HBA1c at pre-op and 1 year was 9.371 and 8.500 respectively FBG at pre-op and 1 year were 208 and 154 respectively for the seven patients (p=0.057) Lipid profiles improved with lower total cholesterol levels and triglycerides 1 year Mean (SEM) Pre vs post op Correlation P value* HBA1C Pre-op 9.371 (0.85) -0.040 0.933 HBA1C 1yr 8.500 (0.67) FBG Pre-op 208.86 (22.50 0.74 0.057 FBG 1YR 154.86 (39.9) Cholesterol preop 183.71 (11.5) 0.632 0.128 Cholesterol 1yr 186.00 (19.9) TG pre-op 112.43 (27.7) -0.245 0.596 TG 1yr 127.29 (25.3) Cpep pre-op 1.343 (0.29) -0.245 0.205 Cpep 3 months 1.200 (0.32)

!!! One patient required insulin preop, at 6 months she was no longer on insulin and all lab work was normal She became pregnant at 6 months following surgery Her diabetes returned and her insulin requirement is at the pre-op level 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

!!! Our Study- 1 year follow-up 5 patients (71%) T2DM > 10 years (10-19) 1 pre oral/insulin-free from medication at 1 yr 2 required less dosages All 5 patients –no symptoms and improved state of health

!!! 2 patients with c-peptide <1, the HbA1c increased following the procedure Both patients had decreased in medication requirements

SAGES 2008 35 patients T2DM for 2-10 years l underwent LDJB April-Nov 07 15 women, 20 men Comorbidities 75% with HTN 58% Hypercholesteremia 62.5% Hypertriglyceremia Mean OR time = 46 minutes (33-78 min) Hospital stay 30 hrs –81 days PPI for 90 days Patients kept on metformin/glimeperide (metformin withdrawn when HBA1c <6) Cohen, Duodenojejunal bypass for the treatment of T2DM in patients with BMI from 22 to 34. (Nevis).

Complications 1 death 2 intestinal obstruction 1 pos-operative pancreatitis 2 intracavitary bleeding Cohen, Duodenojejunal bypass for the treatment of T2DM in patients with BMI from 22 to 34. (Nevis).

Results HbA1c decreasing from 8.9 to 6.1 and 72.3% 72.3% of patients had control of their hypertension: reduced sympathetic outflow? 13/35 patients reported food intolerance: 8/13 required admission (no women) Oral Ginger and sildenafil are very helpful 75% complained of post-prandial sleepiness These side effects may be attributed to gastroparesis and the postulated diminished sympathetic outflow, a result of central leptin suppression and duodenal bypass Cohen, Duodenojejunal bypass for the treatment of T2DM in patients with BMI from 22 to 34. (Nevis)

Interim Conclusions Very promising initial experience. The vast majority of insulin users do not use it anymore very early in the post-op. 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. In patients with higher BMIs, but still under 35 (32-35), it seems that major weight loss is needed to achieve control of T2DM.

Interim Conclusions What are the correct inclusion/exclusion criteria? Should we cut off at 8, 9, 10 years? Time of T2DM history does not seem important, but C peptide below 1 YES!!!

Interim Conclusions Don ’t rush to withdraw medication. We add an incretin effect, but METFORMIN helps to decrease hepatic defective glucose production. What is the antidiabetes mechanism? Cold pressor test before and after duodenal exclusion to assess sympathetic response ?

Interim Conclusions What are the appropriate limb lengths? 50/80? Is it necessary to bypass the entire duodenum? If yes, how can we assess that? Does it make any difference? Do we need complex operations in this subset of patients? Are the mortality/ complication rates reasonable? Will an added sleeve gastrectomy in selected patients be needed to avoid gastroparesis, mainly in those with BMI>32? Or is a LRYGB more adequate?

What The Future Holds? Zhou et al. In vivo reprogramming of adult pancreatic cells to B-cells. Nature. October 2008 Transcription factors Ngn3, Pdx1 and Mafa reprograms differentiated pancreatic cells in adult mice into cells that closely resemble Beta cells… Department of Stem Cell and Regenerative Biology, Howard Hughes Medical Institute, Harvard University.

The Surgeon and the Diabetologists

Acknowledgements Kell Juliard Martin Bluth, MD, PhD Giancarlo Cires, MD Rosemarie E Hardin, MD Joel Ricci, MD

Clinical Improvement Proceeds Glycemic Homeostasis After Duodenal-jejunal Bypass for Non-obese Type 2 Diabetes

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