Diabetes.surgery.research.v2

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  • 1. Bariatric Surgery and the Treatment of Type II Diabetes Ross Finesmith MD Obesity is the most common cause of type 2 diabetes. Bariatric and gastric bypass surgeries have been established to be an effective intervention in treatment of morbidly obesity individuals that are not responsive to diet and drug therapy. In a bariatric surgery metaanalysis, of 136 studies and 22,094 subjects, found that the over 75% of the obese subjects with associated diabetes showed improvement of glucose homeostasis after surgery. (Buchwald 2004)It was logical to assume the lost weight after surgery was responsible for improvement in blood glucose levels and the clinical symptoms of diabetes. After all, weight loss is the first strategy in preventing and treating type 2 diabetes. It was observed that glucose control in obese diabetes that underwent bariatric surgery began to show improvement before a significant amount of weight was lost. Thus it became evident the surgical change in the gastrointestinal tract likely played a role in the improvement of glucose control in diabetics. In a 2010 review of the literature report on the treatment of type 2 diabetes in non-obese patients reported that resolution of type 2 diabetes was greatest following malabsorptive/restrictive procedures, such as the Roux-en-Y gastric bypass (RYGB) procedure. The majority of lower weight patients experienced resolution of laboratory and clinical manifestations of type 2 diabetes without inappropriate weight loss. (Fried 2010). A study published in the Journal of the American Medical Association (JAMA) in June of 2013, found similar results in mildly overweight patients. (Maggard-Gibbons 2013) One small study of 10 patients evaluated the effectiveness bariatric surgery in treating type 2 diabetes in non-obese patients. The authors reported that, “This preliminary study demonstrated the resolution of hyperglycemia in 70% of non-obese type 2 diabetes patients (BMI 25-30 kg/m(2)). Although long-term follow-up data are required, early operative outcomes were satisfactory in terms of glycemic control and safety of the procedure.” (Kim 2011) Specially, the RYGBprocedure has been reported to be the most effective surgical procedure to reduce obesity related diabetes. Three independent studies reported that improvement in glucose homeostasis occurred early after the RYGB procedure, before any appreciable weight loss, and patients are often able to discontinue their antidiabetic medications before hospital discharge. (Mingrone 2012, Schauer 2012, Carlsson 2012). RYGB is considered a “Restrictive” and “Malabsorptive” procedure. The stomach pouch is greatly reduced compared to the size of the stomach. In addition, a significant section of the small intestine is bypassed so less foodstuffs are absorbed.The RYGB procedure is considered to be the gold standard by the American Society for Bariatric Surgery (ASBS) and the NIH, and it is the most frequently performed weight loss surgery in the United States and throughout the world. The procedure involves the division of the stomach to create a small gastric pouch of not more than 3 ounces in capacity. The rest of the stomach or the gastric remnant is left in the abdomen untouched. The small bowel is divided and the
  • 2. gastric transit is reconstituted by joining the divided small bowel or Roux-limb to the gastric pouch. The remaining small bowel is connected to the roux limb from entertaining a “Y” shape (roux-en Y) (see figure below). This operation can be performed “open” through a standard midline incision in the abdomen or via the laparoscopic approach using a small video camera with small instruments that are inserted through small incisions made in the abdominal wall. The Roux-en-Y procedure is very effective with patients losing up to 75% of their excess weight in 15 years. Gastric Bypass Roux-en-Y. 1- Gastric Remnant; 2-Roux Limb; 3- Gastric Pouch; 4 – Roux –en –Y Possible mechanisms of action for surgical type 2 diabetes improvement. In detailed animal research on the morphologic, physiologic and metabolic gastrointestinal changes that occurred as a result of RYGB many changes were found they explain the effects of the surgery on diabetes. Animal studies are critical in understanding the underlying mechanism of this surgical effect because tissue samples and metabolic activity can be measured through invasive methods that can not be accomplished in humans without causing serious damage to the individual.
  • 3. The metabolic analysis showed increased concentrations of glucose-6-phosphate, dgluconate, 6-phospho-d-gluconate and nicotinamide adenine dinucleotide phosphate (NADP+) in the Roux limb (area 2 above), suggesting that the oxidative activity of the pentose phosphate pathway (PPP) is stimulated and more active than in the control animals that had a “sham” surgery. These higher levels of theses compounds in the surgery group means there is more glucose metabolism (breakdown) in the small intestine (jejunum) of the surgical subjects. In fact, twice as much glucose was broken down in the intestines in RYGB subjects compared to the normal, control group. Therefore, fewer glucose molecules are available to cross the intestinal wall to be absorbed into the blood stream resulting in lower blood glucose levels after eating (the precise problem in type 2 diabetes). In addition, the glucose breakdown products mentioned above (NADP etc) in higher concentrations in the Roux limb indicates that the accumulation of glycolytic intermediates are shunted to metabolic pathways that support cellular growth and proliferation. This allows for more healthy function of intestinal cells and less glucose absorption. This intestinal area in the RYBG surgical animals showed increased intestinal cell growth (hypertrophy) that is supported by the increased byproducts of glucose metabolism in the surgical animal. These same results were found in normal weight animals with the RYBG procedure performed. (Saeidi 2013). In these same tissue samples of the small intestines, gene and protein expression patterns of enzymes involved in glucose metabolism were analyzed. In comparison with intestinal segments of the jejunum of sham-operated (control) rats, the Roux limb of RYGB-treated rats showed increased RNA and protein levels of hexokinase 2 (HK2), glyceraldehyde 3phosphate dehydrogenase (GAPDH), and lactate dehydrogenase (LDH), which are key glycolytic (glucose breakdown) enzymes. Equally importantly, gene activity of glucose producing enzymes was found to be suppressed in the RYGB surgically treated animals. Summarizing the findings of the effect of RYGB surgery supports the hypothesis that the intestinal cells in the Roux limb exhibits reprogramming of intestinal glucose metabolism to meet the increased anabolic demands of intestinal tissue growth and maintenance. A pharmacological goal would be to mimic these metabolic intestinal effects with an oral substance and thereby avoiding surgery altogether. In human hormonal studiesGlucagon-like peptide-1 (GLP-1), Peptide YY (PYY)and Ghrelin are believed to play an important role in RYGB patients. GLP-1 is secreted from cells in thedistal ileum (small intestine) and colon in response to energy (food) intake. GLP-1 has found in higher levels after patients undergo RYGB surgery. GLP-1 is considered an appetite-regulating hormonebecause secretion of it reduces hunger and imparts satiety (the feeling of fullness). The mechanism by which GLP1promotes satiety is thought to be due to several factors because it slows gastric emptying, increases insulin release, inhibits glucagon secretion (glucagon increases blood glucose levels), and signals the brain directly induce the feeling of satiety and decrease food intake.
  • 4. Instudies comparing RYGB patients to nonsurgical patientswho were lean, overweight, or with obesity, found that GLP-1 levels were significantly higher after RYGB, therefore reducing the sensation of hunger. PYY is secreted from the cells of thegut after a meal and is also considered an appetiteregulating hormone because secretion of it reduces hunger and causes satiety. PYY delays gastric emptying and inhibits gastric acid secretion resulting in slower food breakdown and passage from the stomach. Intravenous PYY infusion has been found todecrease food intake and reduce hunger in healthy individuals and those with obesity. (Batterham 2002) The general consensus among studies is that postprandial (after meal) PYY levels are higher in post-RYGB subjects compared to lean normal weight, overweight and obese individuals. The studies determined that thePYY response to a test meal or oral glucose tolerance testwas exaggerated, occurred earlier, and remained elevatedabove baseline levels for the remainder of the sampling. This means that after the surgery, levels of PYY increased much more dramatically and suppressed appetite. Ghrelin is another appetite regulating hormone, but in opposite fashion of GLP-1 and PYY, it stimulates the feeling of hunger and stimulates appetite. Ghrelin is produced and released in the pituitary gland of the brain and by cells in the stomach.Ghrelin levels significantly increase with energy/food restriction following RYGB surgery. This suggests that RYGB has a positive effect on the hunger hormone effect of Ghrelin whereas other methodsof weight loss have not shown this benefit. (Beckman 2010) Studies have shown RYGB promotes long-term weight loss and glucose control as a result of the physiologicaland gastrointestinal hormone changes associatedwith the procedure. RYGB glucose homeostasis improvement related to RYGB hormonal changes appears to be related to appetite and hunger regulation. Animal studies provide evidence that hypertrophy of intestinal cells following RYGB surgery; activate genes that increase production of enzyme that degrade glucose before it can be absorbed into the bloodstream. There is a large randomized, placebo-control study underway at the Cleveland Clinic testing the effectiveness of RYGB surgery in the treatment of type 2 diabetes in non-obese patients. (Kashyap 2010) This study is called the Surgical Therapy And Medications Potentially Eradicate Diabetes Efficiently trial (STAMPEDE). According to the National Institutes of Health, the cost of bariatric surgery varies widely, ranging from about $12,000 to $35,000 or more, depending upon factors such as: Type of procedure performed Hospital that performs the surgery Length of hospital stay Area of the country where the surgery is performed Occurrence of medical complications
  • 5. At this time, insurance coverage for bariatric surgery is strictly limited for weight loss and a minimal BMI of 35-40. This is considered morbidly obese and doctors must provide evidence that traditional weight loss options and medications have not been effective in a given patient. References 1. Buchwald, H., et al., Bariatric surgery: a systematic review and meta-analysis. JAMA, 2004. 292(14): p. 1724-37. 2. Fried, M., et al., Metabolic surgery for the treatment of type 2 diabetes in patients with BMI <35 kg/m2: an integrative review of early studies.ObesSurg, 2010. 20(6): p. 776-90. 3. Maggard-Gibbons, M., et al., Bariatric surgery for weight loss and glycemic control in nonmorbidly obese adults with diabetes: a systematic review. JAMA, 2013. 309(21): p. 2250-61. 4. Kim, Z. and K.Y. Hur, Laparoscopic mini-gastric bypass for type 2 diabetes: the preliminary report. World J Surg, 2011. 35(3): p. 631-6. 5. Mingrone, G., et al., Bariatric surgery versus conventional medical therapy for type 2 diabetes. N Engl J Med, 2012. 366(17): p. 1577-85. 6. Schauer, P.R., et al., Bariatric surgery versus intensive medical therapy in obese patients with diabetes. N Engl J Med, 2012. 366(17): p. 1567-76. 7. Carlsson, L.M., et al., Bariatric surgery and prevention of type 2 diabetes in Swedish obese subjects. N Engl J Med, 2012. 367(8): p. 695-704. 8. Saeidi, N., et al., Reprogramming of intestinal glucose metabolism and glycemic control in rats after gastric bypass. Science, 2013. 341(6144): p. 406-10. 9. Batterham, R.L., et al., Gut hormone PYY(3-36) physiologically inhibits food intake. Nature, 2002. 418(6898): p. 650-4. 10. Beckman, L.M., T.R. Beckman, and C.P. Earthman, Changes in gastrointestinal hormones and leptin after Roux-en-Y gastric bypass procedure: a review. J Am Diet Assoc, 2010. 110(4): p. 571-84. 11. 1. Kashyap, S.R., D.L. Bhatt, and P.R. Schauer, Bariatric surgery vs. advanced practice medical management in the treatment of type 2 diabetes mellitus: rationale and design of the Surgical Therapy And Medications Potentially Eradicate Diabetes Efficiently trial (STAMPEDE). Diabetes ObesMetab, 2010. 12(5): p. 452-4.