Is There a role for Surgery in the treatment of Diabetes?

George S. Ferzli, MD, FACS

DISCLOSURE

I HAVE NOTHING TO DISCLOSE

Diabetes

• Considered major public health problem – emerging as a world wide pandemic. In 1995 ~ 135 million people worldwide

• Currently 240 million, expected to rise to close to 380 million by 2025

• 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. Annals of Surgery. Volume 251, Number 3, March 2010

Prevalence of Diabetes

• From 1980 through 2006, the number of Americans with diabetes tripled (from 5.6 million to 16.8 million).

• ~24 million in 2009.

2.6

10.8

23.1

0

5

10

15

20

25

20-39 40-59 60+

Perc

ent

Age Group

Estimated prevalence of diagnosed and undiagnosed diabetes in people aged 20

years or older, by age group, United States, 2007

CDC. National Diabetes Fact Sheet, 2007.Source: 2003–2006 National Health and Nutrition Examination Survey estimates of total prevalence (both diagnosed and undiagnosed) were projected to year 2007.

Obesity and the Metabolic Syndrome

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

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

County-level Estimates of Obesity among Adults aged ≥ 20 years: United States

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

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

Rates of Remission of Diabetes in Obese patients

Adjustable

Gastric Banding

Roux-en-Y

Gastric Bypass

Biliopancreatic

Diversion

>95%(Immediate)

48%(Slow)

84%(Immediate)

1995-“Who Would Have Thought 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

Others thought about it !!!• 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 (BII 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

“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?

What do we know?

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

Rehfeld J, 2004

1967 – Gastric Bypass

DISCOVERY OF GASTROINTESTINAL HORMONES

Hormonal Changes after Bariatric Surgery

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”

Potential Cure for Diabetes Hypothesis

HypoglycemiaHypoglycemiaHypoglycemiaHypoglycemia

Rubino et al; Ann. Surg. 2002

Hypothesis

Rubino et al; Ann. Surg. 2002

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

Hypothesis

Rubino et al; Ann. Surg. 2002

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

Hypothesis

Rubino et al; Ann. Surg. 2002

2004: Rubino et al. Duodenal-Jejunal Exclusion – Foregut

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

2004: Rubino et al. Duodenal-Jejunal Exclusion

“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: Rubino et al. Duodenal Exclusion

2006: Rubino et al. Duodenal exclusion

“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 et al. Duodenal-Jejunal Exclusion and Glucose Metabolism

• 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: Pacheco et al.

Duodenal-Jejunal Exclusion

2007:Pacheco et al. Duodenal-Jejunal Exclusion

• 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

•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 LRYGB

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

2008: 2008: Karamanakos et al. RYGB vs SLEEVE

Karamanakos et al , 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. 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”

2008: Karamanakos et al. RYGB vs SLEEVE2008: Karamanakos et al. RYGB vs SLEEVE

Karamanakos et al , 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. Ann Surg. 2008 Mar; 247(3): 401-7.

2008: Vidal et al. RYGB vs SLEEVE

• 12 mos prospective study 9 severely obese T2DM patients LSG (SG; n = 39) or LRYGB (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

Vidal et al , Type 2 Diabetes Mellitus and the Metabolic Syndrome Following Sleeve Gastrectomy in Severely Obese Subjects.. Obes. Surg. June 2008

• 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

2008: Vidal et al. RYGB vs SLEEVE

Vidal et al, Type 2 Diabetes Mellitus and the Metabolic Syndrome Following Sleeve Gastrectomy in Severely Obese Subjects. Obes. Surg. 2008

• Goal:

– Compare the effects of LRYGB to the effects of LSG on glycemcic control in morbidly obese

• 13 pts randomized to LRYGB and 14 pts to LSG

• Results:

– Markedly increased postprandial plasma insulin and GLP-1 level

– LRYGB- early and augmented insulin responses within 1week

– No significant difference in insulin and GLP-1 levels between two group after 3months.

Aug. 2009: PeterliAug. 2009: Peterli

• Conclusion– Both procedures markedly improved glucose

homeostasis– Lack of support for proximal small intestine

mediating improvement in glucose homeostasis

2009: Peterli et al. RYGB vs SLEEVE

Peterli et al. Improvement in glucose metabolism after bariatric surgery: comparison of laparoscopic Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy: a prospective randomized trial Ann Surg. 2009 Aug;250(2):234-41.

2009: Kasama et al. DJB with SLEEVE

• Laparoscopic sleeve gastrectomy with Duodenojejunal bypass (SG/DJB)

• Goal: – Procedure without exclusion –allow

better surveillance for gastric ca in high prevalence area (Asia)

– Restrictive and malabsorptive procedure

• 21 pts with mean BMI 41.0 kg/m2

• High risks of gastric cancer-H. pylori positive

Kasama et al Laparoscopic Sleeve Gastrectomy with Duodenojejunal Bypass:. Obesity Surgery sept. 2009

2009: Kasama et al. RYGB with SLEEVE

• Effective weight loss– Reduction of ghrelin

• Resolution of Co-morbidities– Similar outcome compare with RYGB

• T2DM resolution– Adding the proximal intestinal exclusion

compare to SG• Avoid dumping phenomenon

– Preserve intergrity of latarjet nerve and pylorus Kasama et al. Laparoscopic Sleeve Gastrectomy with Duodenojejunal Bypass:. Obesity Surgery sept. 2009

2009: Kasama et al. DJB with SLEEVE

• LSG/DJB is feasible, safe, and effective procedure for treatment of morbidly obese patients with risk of gastric

cancer• Effective in weight loss, resolution of co-morbid conditions

and T2DM

• Kasama et al Laparoscopic Sleeve Gastrectomy with Duodenojejunal Bypass:. Obesity Surgery sept. 2009

Feb 2010: Schouten

• Objective:– To determine the safety and efficacy of

EndoBarrier Gastrointestinal Liner

• Duodenal-jejunal bypass sleeve

• Designed to achieve weight loss in morbidly obese patients.

• First European experience – 41 patients included

– 30 underwent sleeve implantation.

– 11 - diet control group.

– All followed the same low-calorie diet during the study period.

2010: Schouten et al. Role of EndoBarrier

• 26 devices were successfully implanted

– Mean procedure time -35 min (range: 12–102 min)

– No procedure related adverse events.

– Mean excess weight loss after 3 months

– 19.0% device vs 6.9% for control (P < 0.002)

• Type 2 diabetes mellitus

– 8 pts with baseline Type 2 diabetes mellitus

– Improvement in 7 patients during the study period

Schouten et al. A multicenter, randomized efficacy study of the EndoBarrier Gastrointestinal Liner for presurgical weight loss prior to bariatric surgery. Ann Surg. 2010 Feb;251(2):236-43.

2010: Schouten et al. Role of EndoBarrier

Schouten et al. A multicenter, randomized efficacy study of the EndoBarrier Gastrointestinal Liner for presurgical weight loss prior to bariatric surgery. Ann Surg. 2010 Feb;251(2):236-43.

2010: Schouten et al. Role of EndoBarrier

• The EndoBarrier Gastrointestinal Liner – Feasible and safe noninvasive device

– Excellent short-term weight loss results.

• Type 2 DM – Significant positive effect

– Long-term randomized and sham studies necessary

Schouten et al. A multicenter, randomized efficacy study of the EndoBarrier Gastrointestinal Liner for presurgical weight loss prior to bariatric surgery. Ann Surg. 2010 Feb;251(2):236-43.

The Nonobese Patient

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

2006: DePaula et al. BMI < 35

DePaula et al. Laparoscopic treatment of type 2 DM for patients with BMI less than 35. Surg. Endoscopy 2006

2006: DePaula et al. BMI < 35

DePaula et al. Laparoscopic treatment of type 2 DM for patients with BMI less than 35. Surg. Endoscopy 2006

2006: DePaula et al. BMI < 35

DePaula et al. Laparoscopic treatment of type 2 DM for patients with BMI less than 35. Surg. Endoscopy 2006

2006: DePaula et al. BMI < 35

DePaula et al. Laparoscopic treatment of type 2 DM for patients with BMI less than 35. Surg. Endoscopy 2006

2006: DePaula et al. BMI < 35

DePaula et al. Laparoscopic treatment of type 2 DM for patients with BMI less than 35. Surg. Endoscopy 2006

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

2006: Early results in 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

2007: Cohen2007: Cohen

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 general anesthesia

• 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 - Hypogycemic agents, Clinical symptoms and lipid

profile.

Results

• Overall, no complications were observed that in any way stemmed from the procedure.

• One patient developed a liver abscess six months later

– required drainage.

• All patients consistently felt relief from their preoperative symptoms.

2009: Ferzli et al

2009: Ferzli et al

2009: Ferzli et al. Results at 12 months

• All subjects consistently felt relief from fatigue, pain and/or numbness in the extremities, polyuria, and polydypsia.

• Clinical resolution was obtained for one patient, and the preoperative diabetic medication requirements decreased for most of the other patients.

• The subjects demonstrated an overall improved HbA1c (from 9.4% to 8.5%) and fasting blood glucose level (from 209 to 154 mg/dl).

2009: Ferzli et al. Conclusions

•Clinical improvement was obvious in all of our seven patients

•LDJB may not be effective at inducing remission of T2DM and the MS in certain patients undergoing this operation.

•Larger patient studies should be conducted

• Longer follow-up is required for better evaluation.

SAGES 2008

• 35 patients T2DM for 2-10 years, 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 post-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)

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

Geloneze et al. Surgery for Nonobese Type 2 Diabetic Patients:

An Interventional Study with Duodenal-Jejunal ExclusionObesity Surgery:2009

• 24 weeks prospective trial

• Open (GJB) vs. control group on standard medical care

• T2DM <15yrs, BMI (25-29.9kg/m2)

2009: Geloneze et al.

• Results:

– Fasting FG• 14% vs. 7% on CG

– A1C • 8.78→7.84 (p<0.01)

– Daily Insulin requirement

• 93% vs. 29% (p<0.01)

Geloneze et al. Surgery for Nonobese Type 2 Diabetic Patients:An Interventional Study with Duodenal-Jejunal ExclusionObesity Surgery:2009

2009: Geloneze et al

Geloneze et al. Surgery for Nonobese Type 2 Diabetic Patients: An Interventional Study with Duodenal-Jejunal Exclusion Obesity Surgery:2009

Duodenal-Jejunal bypass (DJB)Effective treatment for nonobese T2DM subjects superior to standard care in achieving better glycemic control.

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

What are the appropriate limb lengths? 50/80?

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 ?

The Diabetes Surgery Summit Consensus Conference

Rubino et al. Annals of Surgery. Vol 251, Number3,300-405, March 2010

45% of type 2 patients with diabetes world-wide demonstrate a BMI less than 30

ADA : “ Bariatric Surgery should be considered for adults with BMI > 35Kg/m2And type 2 diabetes ,especially if the diabetes is difficult to control with lifestyle And pharmacologic therapy

The Surgeon and the Diabetologists

Acknowledgements

• Kell Juliard

• Martin Bluth, MD, PhD

• Giancarlo Cires, MD

• Rosemarie E Hardin, MD

• Joel Ricci, MD

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.

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?