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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?????