Bariatric surgery: beta cells in type 2 diabetes remission.
Roux-en-Y gastric bypass (RYGB) surgery induces remission of type 2 diabetes (T2D) at higher rates than restrictive bariatric surgeries (1) or intensive medical treatment (2). While weight loss induced by lifestyle interventions or bariatric surgery improves glucose tolerance gradually by enhancing insulin sensitivity (3–5), some of the antidiabetic effect of RYGB is immediate and independent of the amount of weight loss (5–7). The dramatic resolution of diabetes after RYGB is consistent with processes rapidly engaged by the restructured gastrointestinal system to alter postprandial glucose regulation. Individuals with RYGB have larger postprandial glucose excursions, with higher and earlier peaks and lower glucose nadirs, as early as 1 week after surgery (7). In parallel with this change in glycemia, meal ingestion shifts the postprandial insulin response upward and to the left (7), with more rapid insulin secretion over a shorter period. It is not clear to what extent the increased b-cell secretion is a response to greater glycemic stimulus or whether other factors are at play. There is experimental support for greater stimulation by gastrointestinal hormones, especially glucagon-like peptide 1 (8), and neural inputs to the b-cell (9) following RYGB are increased. Regardless of the underlying mechanism, a majority of patients with T2D benefit from RYGB in the short term, and the enhanced insulin response is thought to contribute significantly to this outcome. Interestingly, beneficial effects of surgery on b-cell function are more difficult to ascertain in nondiabetic subjects after RYGB, since many measures of insulin secretion are actually diminished over time as insulin sensitivity improves (10). It is now apparent that RYGB also has a significant impact on glucagon secretion. The notable feature after surgery is postprandial hyperglucagonemia, a finding reported in several cohorts including both diabetic and nondiabetic subjects (8,11–13). The significantly greater glucagon concentrations after meals present a paradox given the improved glucose tolerance with surgery and the deleterious effects of relative hyperglucagonemia on postprandial glycemia (14). In this issue, a new study by Camastra et al. (15) provides some new insights into islet function and glycemic regulation following RYGB. In this study, cohorts of T2D and nondiabetic subjects were examined before and 1 year following surgery with a mixed-meal test that included administration of glucose tracers to measure enteral, hepatic, and systemic glucose fluxes; b-cell function was assessed using a modeling approach that this group has developed and validated. The findings in this study confirm previous reports that postprandial peaks of glucose are greater and occur earlier in people with RYGB, and that this is the result of more rapid entry of intestinally absorbed glucose into the circulation (16). Additionally, mealstimulated glucagon increased significantly after RYGB and was associated with apparent hepatic insulin resistance, with higher rates of endogenous glucose production during the test meal. Finally, sensitivity of peripheral glucose disposal to insulin improved, a finding associated with weight loss and consistent with previous studies (10). These effects were similar in diabetic and nondiabetic subjects. While many responses to RYGB were common to diabetic and nondiabetic subjects, effects on b-cell function differed somewhat. Similar to previous reports, rates of fasting and prandial insulin secretion were decreased in nondiabetic subjects, with a significant reduction in b-cell glucose sensitivity, a measure of the insulin:glycemic dose response. However, RYGB increased the b-cell response to the rate of change in blood glucose, model-derived index of dynamic insulin secretion separate from glucose sensitivity (17). This change suggests an adaptive response to surgery whereby the principal glycemic driver of insulin secretion shifts to accommodate the dramatically increased appearance of enteral glucose caused by RYGB. b-Cell rate sensitivity also increased to a comparable degree in the T2D subjects, approximately threefold, supporting this as a generalized response to surgery. However, b-cell sensitivity to glucose also increased in this cohort, nearly doubling 1 year after RYGB, although not returning to nondiabetic levels. One straightforward explanation for the discrepancy in glucose sensitivity between the diabetic and nondiabetic subjects is the resolution of chronic hyperglycemia in the former group, who had a drop in HbA1c from 7.1 to 5.4%, and possibly resolution of glucose toxicity on b-cell function. The findings reported here raise interesting questions about the alterations in physiology induced by RYGB and how the islet responds to these. The notion of distinct b-cell responses to changing glucose concentrations, and to the rate at which these occur, is incorporated into mathematical models like the one used by Camastra et al., but was originally advanced to explain patterns of glucosestimulated insulin secretion in vitro (18) and in physiologic studies of humans (19). That these parameters are changed significantly by RYGB in nondiabetic subjects speaks to an ability of b-cells to adapt to differences in glucose appearance, in this case to the “dumping-like” pattern of postprandial glycemia described by the authors. If this reciprocal adaptation can be verified it would provide From the Department of Medicine, Division of Endocrinology, University of Cincinnati, Cincinnati, Ohio; and the Cincinnati VA Medical Center, Cincinnati, Ohio. Corresponding author : David A. D’Alessio, email@example.com. DOI: 10.2337/db13-1213 2013 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. 3709.