The Metabolic Surgery Action Group
PI: Nils Wierup
The emergence of morbidly obese patients has prompted novel approaches to achieve weight reduction. Given that energy reduction by dieting is largely unsuccessful in this paitent group, surgical procedures have instead been developed to dramatically restrict food intake. Indeed, over the course of months patients may loose up to 50% in body weight. In addition, the majority of patients maintain a lower, and less harmful, body weight.
It is not surprising that Type 2 diabetes (T2D), which very frequently is present in the morbidly obese subjects, is resolved postoperatively as a consequence of weight loss. In fact, Roux-en-Y gastric bypass (GBP) (Fig 1) is endowed with an 85% resolution of hyperglycemia. It is, however, very intriguing that glucose homeostasis is normalized prior to substantial weight loss . This suggests that weight loss in itself can not account for resolution of T2D in morbidly obese subjects. Furthermore, meal size cannot be held responsible since merely restrictive procedures, such as gastric banding, do not alleviate T2D neither as rapidly nor as effectively as the rerouting procedures (gastric bypass, biliopancreatic diversion w/o duodenal switch) . Instead, the explanation must be found in how the GI tract interacts with the pancreatic islets, and the target tissues of insulin. Elucidating these processes is the objective of the action group. Such advances could lead to the development of novel treatment modalities for T2D.
A plethora of surgical techniques exist for the treatment of obesity, known as metabolic surgery. They mainly interfere with GI function in two ways: i. restriction of food delivered to the intestine; ii. rerouting of GI contents. While the first measure seems to be essential for weight loss, the second is critical for the anti-diabetic effect of metabolic surgery. Particularly, diversion of gastroduodenal food passage to the more distal part of the jejunum appears to be important. This is a dominating feature of GBP. Based on these observations, foregut and hindgut theories have been formulated. The foregut theory holds that release or triggering of a factor(s) that inhibits insulin secretion or impairs insulin sensitivity is prevented by the diversion. The hindgut theory holds that increased or direct delivery of food to the jejunum triggers a factor(s), which enhances insulin secretion and/or sensitivity . Candidates for these factors are neurohormonal peptides released from endocrine cells in the GI tract, the largest endocrine organ in the body. One of the candidate hormones is Ghrelin, which is released from endocrine cells in the upper part of the GI tract . It is endowed with orexigenic and insulinostatic effects, and is thus a candidate for mediating the foregut effect of GBP in T2D. Conversely, incretin hormones, such as glucagon-like peptide 1 (GLP-1) and gastric insulinotropic polypeptide (GIP), are released from the GI tract and potentiate the effect of glucose on insulin release from pancreatic β-cells . GLP-1-secreting cells are enriched in the more distal parts of the small intestine and are therefore potential mediators of the hindgut effect in T2D. It is established that levels of GLP-1 increase upon GBP; Ghrelin levels have been reported to either fall or to be unaffected after GBP, the effect on GIP levels are still controversial. Taken together, the mechanism behind the curative effect of GBP on hyperglycemia remains to be identified.
To reach the main goal of the project – understanding how a manipulation of the GI tract can resolve T2D – the following specific aims have been formulated:
- Establish whether the curative effects of metabolic surgery are conferred by increased insulin secretion or reduced insulin resistance
- Investigate whether changes in splanchnic blood flow underlies improved glycemia
- Identify changes in gene and protein expression in gastric and gut mucosa induced by GBP
- Identify messengers and metabolites that are changed in the blood after GBP
- Identify changes in gut microbiota induced by GBP
For more infomation, contact nils [dot] wierup [at] med [dot] lu [dot] se (Nils Wierup)