The Great Debate: Medicine or Surgery

What Is Best for the Patient With Type 2 Diabetes?

David Lautz, MD; Florencia Halperin, MD; Ann Goebel-Fabbri, PHD; Allison B. Goldfine, MD


Diabetes Care. 2011;34(3):763-770. 

In This Article

Mechanisms of Weight Loss after Bariatric Surgery

The effectiveness of bariatric surgical procedures in improving type 2 diabetes was originally ascribed to substantial dietary changes and weight loss.[13] More recently, several lines of evidence suggest that bariatric surgical procedures, especially the Roux-en-Y gastric bypass (RYGB), have glycemic effects in part independent of weight loss. Such evidence includes 1) animal data showing that diversion of enteral flow from the duodenum, which occurs in RYGB, improves type 2 diabetes even in nonobese animals;[14]2) patients receiving RYGB experience greater early improvements in glycemia compared with patients receiving laparoscopic adjustable gastric band (LAGB) on the same postoperative diet;[15]3) in contrast with LABG, very early improvements in insulin sensitivity and β-cell function have been demonstrated;[15,16]4) a small group of patients have recently been identified who have developed late-onset hyperinsulinemic hypoglycemia after RYGB, usually manifesting after maximal weight loss results have been realized,[17,18] implicating a potential chronic stimulatory effect on the β-cell; and 5) altered nutrient delivery through the gastric compared with gastric bypass route alters glucose tolerance, insulin dynamics, and other metabolic measures.[19,20]

Ongoing controversy exists as to the mechanism(s) underlying metabolic improvements following bariatric surgical procedures in type 2 diabetes. Initial ideas focused on restrictive and malabsorptive processes. However, increasingly recognized are the enterohormonal changes and neuronal events elicited by post-RYGB anatomy. These involve communication directly to the central nervous system to regulate feeding behavior and energy balance, and alterations in liver, adipose, muscle, and pancreatic physiology to directly and indirectly alter glycemia, and insulin secretion and action. Competing theories have been popularized as to the mechanisms of these effects. The proposed "lower intestinal hypothesis" is based on the documented substantial changes in incretin and other entero-endocrine responses from more direct nutrient delivery to the distal intestine.[21,22] The importance of early nutrient delivery to the distal small bowel is clearly supported by ileal transposition experiments, in which a segment of the ileum is moved proximally to the duodenal-jejunal junction, leading to reduced food intake and weight loss without fat malabsorption and associated with increased glucagon-like peptide-1 (GLP-1), peptide YY, and preproglucagon.[23] Alternatively, an "upper intestinal hypothesis" theorizes that diverting nutrient flow from the proximal small bowel removes the stimulus for the production of a "diabetogenic signal",[14,24] as best demonstrated by Rubino and colleagues[25] in a series of elegant surgical experiments demonstrating glycemic improvement with duodenal-jejunal bypass (DJB) compared with sham-operated or diet-treated GK nonobese diabetic rats. Glycemic improvements were not sustained when gastrojejunal nutrient transit was restored. Glycemic improvement without weight loss has also been seen in humans with DJB procedures. Perhaps the RYGB is so effective in reducing weight and hyperglycemia because it incorporates the multiple mechanisms discussed above.

The study of enterohormonal changes after different bariatric surgeries and how these relate to metabolic change and sustained weight loss is an emerging field. Among the best studied enterohormones is ghrelin, which is synthesized in the stomach. Concentrations increase before meals and stimulate appetite, participating in the initiation of feeding. Specific dietary lipids may serve as substrates for acylation of ghrelin, which modify its activity, thereby providing a mechanism for communication between nutrient availability and metabolic status.[26] With diet-induced weight loss ghrelin concentrations increase, driving appetite and promoting weight regain. In contrast, after RYGB ghrelin levels decrease, contributing to reduced food seeking activity and promoting sustained weight loss.[27] At the same time, peptides produced postprandially from the L-cells of the ileum, including GLP-1, peptide YY, and oxyntomodulin, all increase, likely because of early nutrient delivery to the ileum and neuronal mechanisms.[21,22] All of these peptides have been associated with satiation, likely further contributing to sustained weight loss. These changes are not seen with LABG or diet-induced weight loss. Some of these enterohormonal changes, including increased GLP-1, may promote pancreatic islet regeneration or maintenance of mass or function. Expression of pancreatic duodenal homeobox-1, an early and essential transcription factor in the β-cell lineage, and bromodeoxyuridine (a synthetic thymidine analog that gets incorporated into a cell's DNA when the cell is dividing) uptake into β-cells are both increased after RYGB, supporting positive islet effects.[28] However, whether there is increased islet mass or function after gastric bypass remains highly controversial.[29] Very recent feeding tube case reports suggest that the route of nutrient delivery seems to be a primary and potentially reversible event in eliciting this enteroendocrine and β-cell response.[19,20]


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