Postprandial Insulin Secretion After Gastric Bypass Surgery

Given the availability of human studies of the relatively specific and potent glucagon-like peptide (GLP)-1 receptor antagonist exendin (Ex) 9–39, it was just a question of time for the first study of GLP-1 receptor blockade after gastric bypass surgery to appear. In this issue of Diabetes, Salehi et al. (1) report such studies in two groups of individuals previously operated on for obesity with Roux-en-Y gastric bypass (RYGB) surgery: one asymptomatic group and one control group with recurrent hypoglycemia after the operation. The background is that these operations not only bring about a massive weight loss (reductions in BMI from 52 to 33/32 kg/m in the current study), but also bring about resolution of type 2 diabetes, if present, in a high percentage (80–90%) of patients. In the current study, three of twelve individuals in both operated groups had type 2 diabetes before the operation, which was resolved completely in all cases. RYGB was originally conceived as a restrictive and malabsorptive procedure, but actually it is neither. The normal function of the stomach is to retain and process food stuff until allowing a controlled emptying precisely adjusted to the digestive capacity of the proximal intestine. The reservoir is lost after the operation and, in effect, a straight tube is constructed that allows unimpeded passage of ingested nutrients directly to the alimentary limb of the Y-anastomosis and directly onwards to the “common limb,” where nutrients are admixed with digestive secretions and digestion starts. This is nicely illustrated in studies of acetaminophen absorption, which proceeds at a maximal rate immediately upon meal ingestion without the slightest retardation (2). Furthermore, balance studies have documented that there is no malabsorption of macronutrients after RYGB (3). So what is the mechanism of both the weight loss and the diabetes resolution? The abnormal passage of nutrients to a site some 1.5–2 m more distal to the duodenum clearly poses a dramatic exposure of nutrients to the mucosa there, and this is clearly reflected in a grossly exaggerated secretion of gut hormones (4,5). These include peptide YY (PYY)3–36, a powerful anorexic hormone (6), and GLP-1, a peptide that powerfully inhibits appetite and food intake and, in addition, stimulates insulin secretion (7). While PYY has no effect on insulin secretion, the effects of GLP-1 are sufficiently powerful to allow development of GLP-1 receptor agonists for the treatment of diabetes (8). Clinical studies have clearly supported an association between the exaggerated secretion of these two hormones and the weight loss (3). Regarding diabetes resolution, it was recently reported that a patient with type 2 diabetes who was newly operated on received a test meal either orally (following the bypass) or via a gastrostomy catheter (following the preoperative nutritional pathway) on 2 consecutive days. When fed via the bypass, the patient had normal glucose tolerance, but when fed through the stomach he had diabetes. Bypass feeding was associated with a large insulin response and a grossly exaggerated GLP-1 response; in fact, the two were highly correlated (r = 0.93) (9). In the current study by Salehi et al. (1), meal-infused responses were studied under the conditions of a hyperglycemic clamp (of approximately 14 mmol/L) with or without a high rate, primed infusion of Ex 9–39 (in other studies was demonstrated to block the actions of exogenous GLP-1). After plateau glucose levels were established, a 375-kcal test meal (Ensure) was given, and insulin secretion and gut hormone profiles were followed. Compared with control subjects, the surgical group had greatly elevated insulin responses, approximately half of which were eliminated by the GLP-1 receptor antagonist. As expected, GLP-1 responses to the test meal were also greatly increased (and, in agreement with previous studies [10,11], the antagonists actually increased GLP-1 responses). These observations seem to strongly support the hypothesis that an important part of the antidiabetic effect of RYGB is due to exaggerated secretion of GLP-1, which in turn stimulates insulin secretion (Fig. 1). One can discuss whether the infusion rate of Ex 9–39 and the design of the study allow for a full appreciation of the effects of GLP-1, but at any rate, the difference in insulin responses must reflect the effects of GLP-1 receptor activation. So far, so good. But the picture seems to be more complicated. The study included two groups of operated individuals—one that developed recurrent hypoglycemia, which was also demonstrated during a separate meal tolerance test. Surprisingly, the two groups had almost identical insulin and GLP-1 responses (as well as secretion of GIP, the other incretin hormone from the proximal gut, which is variably influenced by bypass surgery). This, however, is at variance with earlier studies of patients with postbypass hypoglycemia (which typically develops 1–3 years after surgery), where both exaggerated GLP-1 and insulin responses were typically found (12,13). This raises the question of whether the mechanism of the postoperative hypoglycemia can be studied appropriately using the clamp From the Department of Biomedical Sciences, Panum Institute, University of Copenhagen, Copenhagen, Denmark. Corresponding author: Jens Juul Holst, [email protected]. DOI: 10.2337/db11-0798 2011 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by -nc-nd/3.0/ for details. See accompanying original article, p. 2308.