Clinical Improvement Precedes Glycemic Homeostasis After Duodenal-Jejunal Bypass

for Non-Obese Type 2 Diabetes

Dominique Elvita,DO Marc Ciaglia,DOGeorge S. Ferzli, Jr, MSGeorge S. Ferzli, MD, FACSChairman of Surgery, Lutheran Medical CenterProfessor of Surgery, SUNY HSCBrooklyn, New York, USA

Derived from Center for Disease Control and Prevention website www.cdc.gov

Percent of Obese (BMI ≥ 30) in US Adults

Derived from Center for Disease Control and Prevention website www.cdc.gov

Percent of Obese (BMI ≥ 30) in US Adults

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’s1990’s

5,000 procedures per year

Multifactorial:• High M&M• Ineffective long-term• Perceived failure• Surgeon experience

2000’s80,000 to 110,000 procedures per year

Multifactorial:• Laparoscopy• Long-term data• Centers of Excellence

1.National Hospital Discharge Survey Public-use data file and documentation. Multi-year data CD-ROM. National Center for Health Statistics, 1979-1996.2.Nguyen et al. Accelerated growth of bariatric surgery with the introduction of minimally invasive surgery. Arch Surg 2005; 140: 1198-202.3.Griffen et al. The decline and fall of the jejunoileal bypass. Surg Gynecol Obstet 1983; 157: 301-8.4.Shirmer et al. Bariatric Surgery Training: Getting Your Ticket Punched. J Gastrointest Surg 2007;11: 807-12.

Popularity of Surgical Management

Current Procedures

Metabolic Syndrome

Also Known as:1. Syndrome “X”

2. Insulin Resistance Syndrome

3. Reaven’s Syndrome

4. Deadly Quartet

5. CHAOSCoronary Artery DiseaseHypertensionAdult Onset DiabetesObesityStroke

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 ResClin 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

Studies Type and Size Effect on WeightEffect on

Comorbidities

Buchwald et al.Meta-analysisn = 22,094 pts

Mean excess weight loss: 61%

Resolution of: • Diabetes: 70%• HTN: 62%• Sleep apnea: 86%

Swedish Obese Subject trial (SOS)

Prospective matched cohortn = 4,047 pts

At 10 years:• Med: 1.6% gain•Surg: 16% loss

Improved by surgery:• Diabetes• Lipid profile• HTN• Hyperuricemia

1. 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.

2. 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

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: 497-507Bittner 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?

1. 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

2. Hormonal Changes?1. 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)

3. Rearrangement of GI anatomy?• “Hindgut hypothesis”• “Foregut hypothesis”

1. Pathophysiology

Excess adipose tissue increasesavailable triglyceride stores

Breakdown of TG leads to overabundanceof circulating fatty acids

INCREASED FATTY ACIDS

INSULIN RESISTANCEINCREASES HEPATIC TRIGLYCERIDE SYNTHESIS & PRODUCTION OF VLDL

LOSS OF VASODILATORY EFFECT OF INSULIN

PRESERVED SODIUM REABSORPTION

HYPERCHOLESTEROLEMIA

HYPERTENSION

DIABETES

OBESITY

2. Hormonal Changes after Bariatric Surgery

3. Anti-Incretin

Insulin resistanceBeta cell depletionHyperglycemia

Insulin resistanceBeta cell depletionHyperglycemia

Too MuchToo Much

Dumping Syndrome

NesidioblastosisHyperinsulinemiaHypoglycemia

Dumping Syndrome

NesidioblastosisHyperinsulinemiaHypoglycemia

Not EnoughNot Enough

TYPE 2 DIABETESTYPE 2 DIABETESTYPE 2 DIABETESTYPE 2 DIABETES

GIP and GLP-1GIP and GLP-1

• Stimulated by enteral nutrients

• insulin secretion / action

-cell proliferation

…Anti-Incretin…Anti-Incretin

• Stimulated by enteral nutrients

• insulin secretion / action

-cell proliferation

Anti-incretinAnti-incretin

Potential Cure for Diabetes Hypothesis

HypoglycemiaHypoglycemiaHypoglycemiaHypoglycemia

Rubino et al; Ann. Surg. 2002

Hypothesis

Rubino et al; Ann. Surg. 2002

Hypothesis

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:Slides taken from:

DIABETES IS NO LONGER A DIABETES IS NO LONGER A HOPELESS DISEASEHOPELESS DISEASE

The Guilty GutThe Guilty Gut

Walter Pories, MD, FACS, Walter Pories, MD, FACS,

Chief, Metabolic Institute Chief, Metabolic Institute

East Carolina University Greenville,East Carolina University Greenville,

North CarolinaNorth Carolina

2006:

Slides taken from:Slides taken from:

DIABETES IS NO LONGER A DIABETES IS NO LONGER A HOPELESS DISEASEHOPELESS DISEASE

The Guilty GutThe Guilty Gut

Walter Pories, MD, FACS, Walter Pories, MD, FACS,

Chief, Metabolic Institute Chief, Metabolic Institute

East Carolina University Greenville,East Carolina University Greenville,

North CarolinaNorth 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): 221-224Pacheco 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

Cohen -SAGES 2008

Cohen -SAGES 2008

Cohen -SAGES 2008

•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 appetitesuppression 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: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 ObeseSubjects. Obes. Surg. 2008, Vidal et al

June 2008

Non-Obese Patients

Slides taken from: Slides taken from: DIABETES IS NO LONGER A HOPELESS DISEASE The Guilty Gut,Walter Pories, MD, FACSDIABETES 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 5th 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 < 35All had type II DM for at least 3 years

Mean operative time was 185 minutesMean post-op follow up was 7 months

87% of patients discontinued preop oral hypoglycemics, insulin or bothHemoglobin 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.

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 Bypassfor Type 2 Diabetes (DJBD)

SUMMARY:Clinical Evaluation of the Effect of Duodenal-Jejunal Bypass on Type 2 Diabetes

FACILITY: Center for Advance MedicineSanto 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 CenterClinical Trial 2008

• Prospective study

• Seeking to recruit total of 50 patients

• www.clinicaltrials.gov

• ID: NCT00694278, LMC 95

Clinical Trial EligibilityInclusion 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 EligibilityExclusion 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, HbA1c, 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 HbA1c 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, 2007Patient 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

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 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)

•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.

Clinical Evaluation of the Effect of Duodenal-Jejunal Bypass on Type 2 Diabetes ( June 2007)

  Mean (SEM)Pre vs post op

Correlation P value*

HBA1C Pre-op 9.371 (0.85)

-0.040 0.933HBA1C 1yr 8.500 (0.67)

FBG Pre-op 208.86 (22.50

0.74 0.057FBG 1YR 154.86 (39.9)

Cholesterol preop 183.71 (11.5)

0.632 0.128Cholesterol 1yr 186.00 (19.9)

TG pre-op 112.43 (27.7)

-0.245 0.596TG 1yr 127.29 (25.3)

Cpep pre-op 1.343 (0.29)

-0.245 0.205Cpep 3 months 1.200 (0.32)

•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

!!!

• 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-up5 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).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).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)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