GASTRIC BYPASS: ITS ROLE IN TREATING DIABETES IS MORE THAN JUST FORCED FOOD INTAKE REDUCTION
Bariatric surgery is an extreme procedure involving gastric bypass as a means of treatment for morbid obesity and obesity. There are many different types of gastric bypass with the Roux-en-Y procedure (RYGB) being one of the more common. The RYGB procedure involves surgically reducing the size of the stomach to a small pouch by stapling off a section of the stomach then attaching this pouch directly to the small intestine, bypassing most of the rest of the stomach and the upper part of the small intestine. RYGB has been shown to induce substantial and sustained weight loss. An interesting and unexpected finding in patients who underwent the RYGB is that the observed improvement in overall glucose homeostasis occurs early after the RYGB procedure, before any appreciable weight loss, and as a result these patients are often able to discontinue their antidiabetic medications before hospital discharge. However, the means by which the RYGB effected these changes in glucose homeostasis have not been determined.
In a recent study published in the prestigious journal Science it has been determined that a major metabolic consequence of the RYGB procedure is an increase in glucose utilization by the intestines resulting in increased disposal of glucose from the blood, thereby, rapidly reducing the hyperglycemia of type 2 diabetes.
The authors of this study hypothesized that that the beneficial effect of RYGB on glucose homeostasis might likely be due to the fact that the jejunum (the middle section of the small intestine), which normally does not see undigested food, now has an altered metabolism necessary to meet the increased bioenergetic demands of tissue growth and maintenance, possibly in response to exposure of this section of the intestine to undigested nutrients.
These studies were carried out in rats and the initial work centered on a comparative analysis of the metabolic profiles in sham operated jejunal tissue versus RYGB jejunal tissue. The results of metabolomic profiling showed increased concentrations of intermediates of the oxidative phase of the pentose phosphate pathway, increased intermediates of the pyrimidine and purine biosynthetic path-ways, increased lactate production was increased, there was increased serine biosynthesis and hexosamine biosynthetic activity (the HBP), two metabolic pathways that branch off from glycolysis. In addition, the glutamine/glutamate pathway was enhanced as was the metabolism of several other amino acids. The observed changes in metabolic profiles following the RYGB indicates that glycolysis may be up-regulated in in order to shunt glucose carbons into metabolic pathways that support the accumulation of biomass necessary for cellular growth and proliferation. Metabolomic changes in the RYGB rats were also mirrored by examination of transcriptomic profiles that demonstrated increased expression of key glycolytic enzymes.
The effectiveness of RYGB, not only at the level of weight loss, but in the resolution of hyperglycemia and insulin resistance in type 2 diabetes attests to the important role of the gastrointestinal tract in overall glucose homeostasis. Most previous studies suggested that these effects of RYGB were due to changes gastrointestinal hormones that control glucose homeostasis such as glucagon-like peptide-1 (GLP-1). Other animal studies have also demonstrated that changes in intestinal gluconeogenesis following a different type of gastric bypass resulted in reduced hepatic gluconeogenesis. However, studies in humans who underwent the RYGB procedure did not show appreciable induction of intestinal gluconeogenesis so there is some controversy as to the role of intestinal gluconeogenesis in the efficacy of gastric bypass in ameliorating the hyperglycemia of type 2 diabetes.
The TAKE HOME from this study first confirms the physiological benefits of the use of the RYGB procedure in the treatment of obesity and type 2 diabetes. Specifically, this study demonstrated that changes in overall metabolism in the jejunal limb of the bypass structure may be primarily responsible for improved glucose homeostasis following RYGB. The resulting reprogrammed intestinal glucose metabolism leads to the intestine becoming a major organ for glucose disposal which in turn contributes to the overall improvement in glycemic control following RYGB and the associated improvement in the hyperglycemia associated with type 2 diabetes.