Anti-Diabetes Operations:The Foundation for New Procedures

George S.Ferzli, M.D., Giancarlo Cires, M.D., Benjamin Chandler, Rosemarie E.Hardin, M.D.

Metabolic Surgery SymposiumNew Mexico, 2007

Background

• Impaired insulin secretion and insulin resistance both contribute to Type II DM

• The causes of these alterations are not fully elucidated

• Current therapies include: diet, exercise, oral hypoglycemics, insulin, and behavior modification

Problem??? None of these options offers a cure!!!

Solution: BARIATRIC SURGERY??

Francesco Rubino. Bariatric Surgery:Effects on Glucose Homeostasis. Curr Opin Clin Nutr Metab

Care. 9:497-507

• Bariatric surgery may provide new possibilities for “cure” of Type 2 DM

• Clinical evidence supports operations for morbid obesity induces significant weight loss but leads to improvement or resolution of comorbid disease states, particularly Type 2 DM

• RYGB and BPD are the most effective in controlling DM

• Both result in sustained normal concentrations of plasma glucose, insulin & Hgb A1C in 80-100% of morbidly obese patients with DM

• Insulin sensitivity is increased 4-5 x after RYGB-induced weight loss

• RYGB and BPD prevents progression from impaired tolerance to DM

Francesco Rubino. Bariatric Surgery:Effects on Glucose Homeostasis. Curr Opin Clin Nutr Metab

Care. 9:497-507

• The resoultion of DM after RYG and BPD occurs too fast to be accounted for by weight loss alone

• RYGB and BPD must have direct impact on glucose homeostasis

 

Buchwald H, Avidor Y, Braunwald E. et al. Bariatric Surgery: A Systemic Review & Meta-analysis. JAMA 2004;

292:1724-1737

• Involved 136 studies

• N=22,094 patients

• Focused on the effect of bariatric surgery on obesity co-morbidities

• T2 DM completely resolved in 76.8 % of patients

• Improved in 86 %

• Lowered the rate of progression from impaired glucose tolerance to DM by 30 fold

Buchwald H, Avidor Y, Braunwald E. et al. Bariatric Surgery: A Systemic Review & Meta-analysis. JAMA 2004;

292:1724-1737

• With respect to diabetes resolution; ability to discontinue all diabetes-related medications,maintain normal fasting glycemia,normalization of glycosylated hemoglobin a gradation of effect was demonstrated

– 98.9% for BPD or duodenal switch– 83.7% for RYGB– 71.6% for VBG– 47.9% for LAGB

Anti-diabetic Effect of Bariatric Surgery

• Intestinal Malabsorption– Weight loss reduces insulin resistance– Glucose malabsoprtion 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”

Foregut vs. Hindgut

• Foregut hypothesis suggests exclusion of duodenum and proximal jejunum from the transit of nutrients may interrupt signals that lead to insulin resistance and Type 2 DM

• Hindgut hypothesis suggests enhanced delivery of nutrients to distal ileum alters secretion of hormones & improves glucose metabolism

*** GLP-1 may be a major mediator of this effect

Rubino F. Bariatric Surgery:effects on glucose homeostasis. Curr Opin Clin Nutr Metab Care 9:497-507

Proposed Mechanism?

Rubino F. Bariatric Surgery: Effects on Glucose Homeostasis. Curr Opin Clin Nutr Metab Care 9:497-507

• Rubino et al tested hypothesis on Goto-Kakizaki rats

• Rats underwent either DJ bypass or gastrojejunostomy

• DJ bypass = Forgut hypothesis

• Gastrojejunostomy = Hindgut Hypothesis

Rubino F. Bariatric Surgery: Effects on Glucose Homeostasis. Curr Opin Clin Nutr Metab Care 9:497-507

RESULTS

• DJ bypass rats had better oral glucose tolerance

• Gastrojejunostomy did not affect glucose homeostasis

• Rats with GJ who then had duodenal exclusion had improved glucose homeostasis

• Supports proximal intestinal bypass for treatment of DM

Pacheco D. The effects of duodenal-jejunal exclusion on hormonal regulation of glucose metabolism in Goto-Kakazi rats. Am J Surgery;

194 (2007):221-224

• 12 rats underwent either DJ bypass or no intervention

• Basal glucose levels at time 0 in basal time, at 1 week, and at 1 month were lower in group 1 than group 2.

• Post oral glucose overload levels of glucagon, insulin,

GLP-1, and GIP remained unchaged during the treatment in both groups.

• In group 1, leptin levels had a significant decrease at 1

week and 1 month after surgery

Diabetes Operations

• Restrictive

• Malabsorptive

• Mixed procedures

Restrictive Procedures

• Create a small gastric pouch • Includes laparoscopic adjustable gastric

band and vertical banded gastroplasty• There is no bypass of intestinal contents• Not as effective in controlling DM

Roux-en-Y Gastric Bypass

• Considered gold standard for obesity surgery

• May be done open or laparoscopically

• Stapler is used to create small gastric pouch

• After RYGB, ingested food bypasses

approximately 95% of the stomach, the entire

duodenum and a portion of the jejeunum;

usually results in 60-70% excess weight loss

and most of this effect is maintained for at least

15 years

Rubino F. Bariatric Surgery: Effects on Glucose Homeostasis. Curr Opin Clin Nutr Metab Care 9:497-507

Malabsorptive Procedures• Reduce the area of intestinal mucosa available for

nutrient absorption

• First attempt to obtain weight loss through this strategy was through the jejunoileal bypass

• JIB diverted nutrients from small intestine by anastomosing the proximal jejunum to terminal ileum

• Drawback: excessive long term nutritional complications and hepatic cirrhosis due to bacterial; overgrowth

Rubino F. Bariatric Surgery: Effects on Glucose Homeostasis. Curr Opin Clin Nutr Metab Care 9:497-507

Jejunoileal Bypass• Proximal jejunum is

anastamosed to terminal ileum

• Diverts enteral nutrients from most of small intestine

• Results:good weight loss

• Long term complications include bacterial overgrowth and cirrhosis

Rubino F. Bariatric Surgery: Effects on Glucose Homeostasis. Curr Opin Clin Nutr Metab Care 9:497-507

Biliopancreatic Diversion• First described by Nicola

Scopinaro of Genoa, Italy in 1979

• Partial gastrectomy,leaves behind a 200-500 cc size upper stomach

• Re-anastomosed to distal 250cm of small intestine

• Bypassed biliopancreatic limb attached 50cm proximal to iliocecal valve

• The last segment of ileum where food and bile mix is referred to as a “common channel” and is responsible for most fat absorption

Rubino F. Bariatric Surgery: Effects on Glucose Homeostasis. Curr Opin Clin Nutr Metab Care 9:497-507

Duodenal Switch

Duodenal switch variant involves sleeve gastrectomy andpreservation of pylorus and short segment of duodenum

Anti-diabetic Effect of Bariatric Surgery

Prospective Swedish Obese Subjects Study

• Involved obese patients who underwent gastric surgery & matched, conventially treated obese controls

• Follow up 2 years (n=4047) & 10 years (n=1703)

• Surgery lead to more dramatic improvement in diabetes control than conventional therapy

Direct Effect or Secondary Gain?

• Evidence suggests control of DM after GI bypass surgery is not secondary to weight loss

• Spontaneous model of non obese Type 2 DM using Goto Kakizaki rats

• Demonstrated that duodenal jejunal bypass ( a stomach sparing experimental model of RYGB) significantly improved glucose tolerance in comparison to sham operations.

• This study allowed the effects of intestinal bypass to be isolated from those related to gastric restriction *

DM Type 2 is a potentially operable disease

Rubino F. Bariatric Surgery: Effects on Glucose Homeostasis. Curr Opin Clin Nutr Metab Care 9:497-507

Bariatric Surgery for Control of DM in non-obese patients???

• Current indications for bariatric surgery include BMI > 40 kg/m2 or BMI between 35-40 kg/m2 with obesity-related co-morbidities

• Bariatric surgery has been occasionally performed in nonmorbidly obese individuals; 1977: Mingrone reported a case of a young, non obese woman with DM who underwent BPD for chylomicronemia

– Result??? – Plasma insulin and blood glucose levels

normalized within 3 months

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

Endosc. In press

• 39 patients underwent

laparoscopic ileal interposition

into proximal jejunum via

sleeve or diverted sleeve

gastrectomy

• Patients had BMI < 35

• All had type II DM for at least 3

years

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

Endosc. In press• 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. In press

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

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

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

FUTURE?????