Duodenal-jejeunal Bypass in Non-obese Adults with Type 2 Diabetes

Preliminary Data:

Duodenal-jejunal bypass in non-obese adults with type 2 diabetes

George Ferzli MD, FACS

Abel Gonzalez MD, FACS

Abel Gonzalez Jr MD

Edgar Manon MD

and Martin Bluth MD, PhD

SUNY Downstate

Medical Center

LUTHERANLUTHERANMEDICAL CENTERMEDICAL CENTER

TYPE 2 DIABETES – BACKGROUNDTYPE 2 DIABETES – BACKGROUND

Diabetes mellitus is a chronic disease requiring long-term medical attention. Diabetics accounted for 6.2% of the US population in 2002 (18.2 million people).

Per capita cost of healthcare: $13,243 for people with diabetes and $2560 for people without diabetes.

Pathophysiology - type 2 diabetes typically affects individuals older than 40 years, but has been diagnosed in children as young as 2 years of age. (epidemic of childhood obesity).

It is characterized by peripheral insulin resistance with an insulin-secretory defect that varies in severity. About 90% of patients who develop type 2 diabetes are obese.

Frequency - 13 million people in the United States have been diagnosed, with another 5 million undiagnosed. Approximately 10% have type 1 diabetes, and the rest have type 2.

Complications - hypoglycemia and hyperglycemia, increased risk of infections, microvascular complications (retinopathy, nephropathy), neuropathic complications, and macrovascular disease.

Major cause of blindness in adults (20-74 years) / leading cause of nontraumatic lower-extremity amputation and end-stage renal disease (ESRD).

Race - more prevalent among Hispanics, Native Americans, African Americans, and Asians/Pacific Islanders than in non-Hispanic whites.

Sex - incidence is equal in women and men in all populations.

Diabetes Mellitus, Type 2 - A Review Article: Jun 6, 2007 Scott R Votey, MD, Assistant Dean for Graduate Medical Education, Associate Professor of Medicine/Emergency Medicine, UCLA School of Medicine, UCLA Medical Center

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

2002:2002:

Objective: To review the effect of morbid obesity surgery on type 2 diabetes mellitus, and to analyze data that might explain the mechanisms of action of these surgeries and that could answer the question of whether surgery for morbid obesity can represent a cure for type 2 diabetes in nonobese patients as well.

Summary Background Data: Diabetes mellitus type 2 affects more than 150 million people worldwide. Although the incidence of complications of type 2 diabetes can be reduced with tight control of hyperglycemia, current therapies do not achieve a cure. Some operations for morbid obesity not only induce significant and lasting weight loss but also lead to improvements in or resolution of comorbid disease states, especially type 2 diabetes.

Methods: The authors reviewed data from the literature to address what is known about the effect of surgery for obesity on glucose metabolism and the endocrine changes that follow this surgery.

Results: Series with long-term follow-up show that gastric bypass and biliopancreatic diversion achieve durable normal levels of plasma glucose, plasma insulin, and glycosylated hemoglobin in 80% to 100% of severely obese diabetic patients, usually within days after surgery. Available data show a significant change in the pattern of secretion of gastrointestinal hormones. Case reports have also documented remission of type 2 diabetes in nonmorbidly obese individuals undergoing biliopancreatic diversion for other indications.

Conclusions: Gastric bypass and biliopancreatic diversion seem to achieve control of diabetes as a primary and independent effect, not secondary to the treatment of overweight. Although controlled trials are needed to verify the effectiveness on nonobese individuals, gastric bypass surgery has the potential to change the current concepts of the pathophysiology of type 2 diabetes and, possibly, the management of this disease.

2003:2003:

Effect of Laparoscopic Roux-En Y Gastric Bypass on Type 2 Diabetes Mellitus Philip R Schauer, MD, Bartolome Burguera, MD, Sayeed Ikramuddin, MD, Dan Cottam, MD, William Gourash, CRNP, Giselle Hamad, MD, George M. Eid, MD, Samer Mattar, MD, Ramesh Ramanathan, MD, Emma Barinas-Mitchel, PhD, R. Harsha Rao, MD, Lewis Kuller, MD DrPH, and David Kelley, MD Annals of Surgery. 238(4): 467-485, October 2003

Objective: To evaluate pre- and postoperative clinical parameters associated with improvement of diabetes up to 4 years after laparoscopic Roux-en-Y gastric bypass (LRYGBP) in patients with type 2 diabetes mellitus (T2DM).

Summary Background Data: The surgical treatment of morbid obesity leads to dramatic improvement in the comorbidity status of most patients with T2DM. However, little is known concerning what preoperative clinical factors are associated with postoperative long-term improvement in diabetes in the morbidly obese patient with diabetes.

Methods: We evaluated pre- and postoperative data, including demographics, duration of diabetes, metabolic parameters, and clinical outcomes, in all patients with impaired fasting glucose (IFG) and type T2DM undergoing LRYGBP from July 1997 to May 2002.

Results: During this 5-year period, 1160 patients underwent LRYGBP and 240 (21%) had IFG or T2DM. Follow up was possible in 191 of 240 patients (80%). There were 144 females (75%) with a mean preoperative age of 48 years (range, 26–67 years). After surgery, weight and body mass index decreased from 308 lbs and 50.1 kg/m2 to 211 lbs and 34 kg/m2 for a mean weight loss of 97 lbs and mean excess weight loss of 60%. Fasting plasma glucose and glycosylated hemoglobin concentrations returned to normal levels (83%) or markedly improved (17%) in all patients. A significant reduction in use of oral antidiabetic agents (80%) and insulin (79%) followed surgical treatment. Patients with the shortest duration (<5 years), the mildest form of T2DM (diet controlled), and the greatest weight loss after surgery were most likely to achieve complete resolution of T2DM.

Conclusion: LRYGBP resulted in significant weight loss (60% percent of excess body weight loss) and resolution (83%) of T2DM. 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.

2004:2004:

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

Background: The Roux-en-Y gastric bypass and the biliopancreatic diversion effectively induce weight loss and long-term control of type 2 diabetes in morbidly obese individuals. It is unknown whether the control of diabetes is a secondary outcome from the treatment of obesity or a direct result of the duodenal–jejunal exclusion that both operations include. The aim of this study was to investigate whether duodenal–jejunal exclusion can control diabetes independently on resolution of obesity-related abnormalities.

Methods: A gastrojejunal bypass (GJB) with preservation of an intact gastric volume was performed in 10- to 12-week-old Goto-Kakizaki rats, a spontaneous nonobese model of type 2 diabetes. Fasting glycemia, oral glucose tolerance, insulin sensitivity, basal plasma insulin, and glucose-dependent-insulinotropic peptide as well as plasma levels of cholesterol, triglycerides, and free fatty acids were measured. The GJB was challenged against a sham operation, marked food restriction, and medical therapy with rosiglitazone in matched groups of animals. Rats were observed for 36 weeks after surgery.

Results: Mean plasma glucose 3 weeks after GJB was 96.3 ± 10.1 mg/dL (preoperative values were 159 ± 47 mg/dL; P = 0.01). GJB strikingly improved glucose tolerance, inducing a greater than 40% reduction of the area under blood glucose concentration curve (P < 0.001). These effects were not seen in the sham-operated animals despite similar operative time, same postoperative food intake rates, and no significant difference in weight gain profile. GJB resulted also in better glycemic control than greater weight loss from food restriction and than rosiglitazone therapy.

Conclusions: 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. These findings suggest a potential role of the proximal gut in the pathogenesis the disease and put forward the possibility of alternative therapeutic approaches for the management of type 2 diabetes.

20062006

METHODS: Goto-Kakizaki (GK) type 2 diabetic rats underwent duodenal-jejunal bypass (DJB), a stomach preserving RYGB that excludes the proximal intestine, or a gastrojejunostomy (GJ), which creates a shortcut for ingested nutrients without bypassing any intestine. Controls were pair-fed (PF) sham-operated and untreated GK rats. Rats that had undergone GJ were then reoperated to exclude the proximal intestine; and conversely, duodenal passage was restoredin rats that had undergone DJB. Oral glucose tolerance (OGTT), food intake, body weight, and intestinal nutrientabsorption were measured.

RESULTS: no differences in food intake, body weight, or nutrient absorption among surgical groups. DJB-treated ratshad markedly better oral glucose tolerance compared with control groups as shown by lower peak and area-under-thecurve glucose values (P < 0.001 for both). GJ did not affect glucose homeostasis, but exclusion of duodenal nutrientpassage in reoperated GJ rats significantly improved glucose tolerance. Conversely, restoration of duodenal passageIn DJB rats reestablished impaired glucose tolerance.

CONCLUSIONS: “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. These findings suggest that a proximal intestinal bypass could be considered for diabetes treatment and that potentially undiscovered factors from the proximal bowel might contribute to the pathophysiology of type 2 diabetes”

The Mechanism of Diabetes Control After Gastrointestinal Bypass Surgery Reveals a Role of the The Mechanism of Diabetes Control After Gastrointestinal Bypass Surgery Reveals a Role of the Proximal Small Intestine in the Pathophysiology of Type 2 Diabetes.Proximal Small Intestine in the Pathophysiology of Type 2 Diabetes. Original Articles Original Articles Rubino, Rubino, Francesco MD; Forgione, Antonello MD; Cummings, David E. MD; Vix, Michel MD; Gnuli, Donatella MD; Francesco MD; Forgione, Antonello MD; Cummings, David E. MD; Vix, Michel MD; Gnuli, Donatella MD; Mingrone, Geltrude MD; Castagneto, Marco MD; Marescaux, Jacques MD Mingrone, Geltrude MD; Castagneto, Marco MD; Marescaux, Jacques MD Annals of SurgeryAnnals of Surgery. 244(5): 741-749, . 244(5): 741-749, November 2006. November 2006.

The Mechanism of Diabetes Control After Gastrointestinal Bypass Surgery Reveals The Mechanism of Diabetes Control After Gastrointestinal Bypass Surgery Reveals a Role of the Proximal Small Intestine in the Pathophysiology of Type 2 Diabetes.a Role of the Proximal Small Intestine in the Pathophysiology of Type 2 Diabetes. Original Articles Original Articles Rubino, Francesco MD; Forgione, Antonello MD; Cummings, David E. MD; Rubino, Francesco MD; Forgione, Antonello MD; Cummings, David E. MD; Vix, Michel MD; Gnuli, Donatella MD; Mingrone, Geltrude MD; Castagneto, Marco MD; Vix, Michel MD; Gnuli, Donatella MD; Mingrone, Geltrude MD; Castagneto, Marco MD; Marescaux, Jacques MDMarescaux, Jacques MD Annals of SurgeryAnnals of Surgery. 244(5): 741-749, November 2006. . 244(5): 741-749, November 2006.

DUODENAL-JEJUNAL LAP BYPASS T2DM DUODENAL-JEJUNAL LAP BYPASS T2DM Surgical treatment - human data, BrazilSurgical treatment - human data, Brazil

PatientsFollow-upFasting Fasting

Glycemia Glycemia

Pre-op Post-op

1. RG 7m 216 98

2. CD 7m 168 110

3. MC 6m 157 79

4. MM 5m 148 82

5. RD 2m 225 94

6. JG 1m 173 92

Ramos, A, Galvao Neto M, Galvao, MRamos, A, Galvao Neto M, Galvao, M

3 NON-OBESE DIABETICS – 6 mos follow up3 NON-OBESE DIABETICS – 6 mos follow upM. Lackdawalya, Bombay, IndiaM. Lackdawalya, Bombay, India

Pre-surgery N=3 Pre-surgery N=3 Post-surgery 6 monthsPost-surgery 6 months

BMIBMI 1. 27.51. 27.5 27.527.5

2. 282. 28 2727

3. 29.53. 29.5 2929

HbA1CHbA1C 1. 91. 9 5.15.1

2. 10.42. 10.4 6.36.3

3. 9.53. 9.5 6.06.0

Fasting blood sugarFasting blood sugar 1. 1281. 128 9595

2. 1552. 155 9292

3. 1623. 162 9090

PPBSPPBS 1. 2651. 265 104104

2. 2442. 244 134134

3. 2753. 275 124124

CLINICAL TRIAL: DUODENAL-JEJUNAL BYPASS CLINICAL TRIAL: DUODENAL-JEJUNAL BYPASS FOR TYPE 2 DIABETES (DJBD), JUNE 2007FOR TYPE 2 DIABETES (DJBD), JUNE 2007

Clinicaltrials.gov ID: NCT00487526

SUMMARY:Study the effect of duodenal jejunal bypass on human adults withtype 2 diabetes.

DETAILLED DESCRIPTION:Adults non-obese (BMI less than 34) will undergo duodenal jejunal bypass. The outcome measures: Blood sugar, insulin, HbA1c, CCK, gastrin

STUDY OFFICIALS/INVESTIGATORS:George Ferzli, MD, FACS - Study Principal Investigator, SUNY Downstate, Brooklyn, New York, USA

Abel Gonzalez, MD, FACS - Center for Advanced Medicine, Santo Domingo, Dominican Republic

Abel Gonzalez Jr, MD - Center for Advanced Medicine, Santo Domingo, Dominican Republic

Edgar Manon, 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

SPONSOR: TYCO Healthcare

REVIEW BOARD:Approval status - ApprovedBoard Name: Ethics CommitteeBoard Affiliation: Center for Advance medicine, Abel Gonzalez

DATA MONITORING COMMITTEE - yes

OVERSIGHT AUTHORITIES:Dominican Republic: Secretaria del Estado de Salud Publica y Assistencia Social (SESPAS)

FACILITY: Center for Advance MedicineSanto Domingo, Dominican Republic

RECORD VERIFICATION DATE:June 2007

OVERALL STATUS:Recruiting (anticipated enrollment-50)

• Adults age: 20-65

• Clinical diagnosis of type 2 diabetes

• Non-obese with BMI less than 34

• Oral agents or insulin to control T2DM

• Inadequate control of diabetes as defined as HbA1/7.5

• Understanding of the mechanisms of action of the treatment

CLINICAL TRIAL ELIGIBILITYCLINICAL TRIAL ELIGIBILITYINCLUSION CRITERIA EXCLUSION CRITERIAINCLUSION CRITERIA EXCLUSION CRITERIA

• Children with type 1 diabetes• Obese with BMI over 34• Coagulopathy• Liver cirrhosis• Unable to comply with study

requirements, follow-up or give valid consent

• Currently pregnant• Previous upper abdominal surgery• Inability to tolerate general

anesthesia

OUTCOME MEASURESOUTCOME MEASURES

PRIMARYPRIMARY

• Control of type 2 diabetes in non-obese adults (2 year time frame)Control of type 2 diabetes in non-obese adults (2 year time frame)

SECONDARY*SECONDARY*

• Measure: CCK FFA, cholesterol, Ghrelin, C-peptide, HbA1c, Measure: CCK FFA, cholesterol, Ghrelin, C-peptide, HbA1c, Gastrin, GIP, triglycerides, insulin, glucose and secretin Gastrin, GIP, triglycerides, insulin, glucose and secretin

* Research in the laboratory of David E. Cummings, MD, of the University of Washington, shows that ghrelin, a recently discovered peptide that stimulates appetite, is decreased after gastric bypass surgery. Other peptides, including the distal small intestine hormone peptide YY (PYY), and glucagon-like peptide 1 (GLP-1), secreted by intestinal L cells,

PATIENT DATA (* diabetes > 10 years)PATIENT DATA (* diabetes > 10 years)

PATIENT SEX AGE BMI DIABETESDURATION

COMORBIDCONDITION

PRIORSURGERIES

OR TIME hrs

HOSPITAL

STAY (days)

FM Male 42 28.3 4 yrs Circumcision 1:20 3

FC Female 33 21.7 6 yrs 1:25 3

MC Female 46 29 10 yrs Hypertension Salpingectomy 1:10 3

MG* Male 52 25 12 yrs Hypertension Amputation 1:17 3

KM* Female 41 33 12 yrs Cesareanhysterectomy

abdominoplasty

1:20 3

LJ* Female 40 28.5 12 yrs Cesareanabdominoplastycholecystectomy

1:50 3

CC* Female 49 27 19 yrs Salpingectomy 1:15 3

BLOOD MEASUREMENTS – Blood Glucose (mg/dL)BLOOD MEASUREMENTS – Blood Glucose (mg/dL)

PATIENT PRE-OP DAY 7 DAY 30

FM 286 195 265

FC 112 148 121

MC 180 197 112

MG* 181 500 86

KM* 195 153 89

LJ* 252 164 166

CC* 256 189 257

**Diabetes > 10 YearsDiabetes > 10 Years

BLOOD MEASUREMENTS – HbA1C(%)BLOOD MEASUREMENTS – HbA1C(%)

PATIENT PRE-OP DAY 7 DAY 30

FM 11.7 7.9 8.7

FC 6.6 7.8 8.5

MC 6.7 8.3 9.3

MG* 9.4 9.7 6.6

KM* 11.2 11.7

LJ* 11.8 6.9 8.7

CC* 8.2 8.8

**Diabetes > 10 YearsDiabetes > 10 Years

BLOOD MEASUREMENTSBLOOD MEASUREMENTSTriglycerides (mg/dL) Cholesterol (mg/dL)Triglycerides (mg/dL) Cholesterol (mg/dL)

PATIENT PRE-OP DAY 7 DAY 30

FM 235 189 126

FC 44 64 59

MC 88 100 115

MG* 195 324 290

KM* 97 61 63

LJ* 70 89 120

CC* 58 94 87

PATIENT PRE-OP DAY 7 DAY 30

FM 225 213 213

FC 179 189 191

MC 157 156 156

MG* 227 173

197

KM* 158 129 124

LJ* 160 119 130

CC* 180 178 162

**Diabetes > 10 YearsDiabetes > 10 Years

BLOOD MEASUREMENTSBLOOD MEASUREMENTSCCK GhrelinCCK Ghrelin

PATIENT PRE-OP DAY 7 DAY 30

FM

FC

MC

MG*

KM*

LJ*

CC*

PATIENT PRE-OP DAY 7 DAY 30

FM

FC

MC

MG*

KM*

LJ*

CC*

**Diabetes > 10 YearsDiabetes > 10 Years

BLOOD MEASUREMENTSBLOOD MEASUREMENTSSecretin GIPSecretin GIP

PATIENT PRE-OP DAY 7 DAY 30

FM

FC

MC

MG*

KM*

LJ*

CC*

**Diabetes > 10 YearsDiabetes > 10 Years

PATIENT PRE-OP DAY 7 DAY 30

FM

FC

MC

MG*

KM*

LJ*

CC*

IN THE FUTUREIN THE FUTURE

• Duodenal jejunal bypass for adult, non-obese patients, holds an exciting non-drug maintenance alternative to adults suffering from type 2 diabetes.

• We will continue to publish post-surgical updates on these patients as we monitor their blood enzyme levels over the two year clinical study time frame.

• If this operation proves effective, then we look forward to it technically handled in 2 ways:– A. Endoscopic plication of the pylorus followed by laparoscopic

gastrojejeunostomy– B. N.O.T.E.S. - Endoscopic plication of the pylorus followed by

endoscopic transgastric gastric jejeunostomy