Bariatric surgery, specifically Roux-en-Y gastric bypass (RYGB), has a rapid and drastic effect in obese patients with type 2 diabetes (T2D), many of whom show complete remission of the disease within days of the procedure. This has introduced the option of a surgical mode of diabetes therapy (1–3). The exact mechanisms by which RYGB drives clinical remission of T2D are not well understood. T2D develops when patients have a combination of two core defects—insulin resistance along with defects in insulin secretion (4). The significant weight loss induced by the procedure is obviously associated with increased insulin sensitivity. On the other hand, the rapid resolution of T2D prior to major weight loss may hint that the procedure directly affects β-cell function, independent of weight loss.
RYGB consists of two major anatomical modifications: restriction of gastric volume by creation of a small pouch and division of the jejunum in a manner that reroutes nutrients from the pouch directly into the jejunum while bypassing the proximal small bowel. These modifications have led to the development of two hypotheses explaining the effects of the gut following RYGB on β-cell function (5). According to the “foregut hypothesis,” a yet-unidentified “anti-incretin” is secreted in patients with T2D upon exposure of the foregut to nutrients. Preventing contact of nutrients with the upper gut may lead to reduction of such a factor and thus relieve/unstress the β-cell. The “hindgut” hypothesis suggests that early exposure of the jejunum to nutrients results in a modification of gut-derived hormones, specifically incretins, leading to boosting of β-cell function (6).
To elucidate the effects of the gut on β-cell function following RYGB, Dutia et al. (7) performed an elegant longitudinal evaluation of β-cell function in obese patients with T2D who underwent RYGB along with a comparison with obese nondiabetic subjects and lean healthy control subjects. The authors performed oral glucose tolerance tests (OGTTs) followed by an isoglycemic intravenous glucose clamp. The clamp attempts to achieve plasma glucose levels that are identical to those recorded during the OGTT, thus exposing the β-cell to identical glucose concentrations achieved using different routes of glucose administration. The authors demonstrate that following an oral glucose load, indices of insulin secretion and β-cell function nearly normalized in the obese diabetic participants. This improvement was associated with a major increase in glucagon-like peptide 1 (GLP-1) secretion. In contrast, following the intravenous glucose challenge, the same indices remained well below those of normal control subjects and demonstrated minimal if any improvement. Not surprisingly, baseline indices of β-cell function along with the degree of weight loss were the best predictors of postoperative β-cell function and glucose tolerance.
Insulin secretion indices have limited value when not presented within the context of the individual’s insulin sensitivity. This is the purpose of the disposition index (DI), the product of insulin sensitivity and secretion (8). The DI was originally described using data from intravenous glucose tolerance tests and is based on the hyperbolic relation of the derived insulin sensitivity and secretion indices. The DI has since been calculated using intravenous as well as oral glucose challenges. Both have been shown to reliably predict the development of diabetes over time and can be used to identify subjects at risk for glucose tolerance deterioration (9–12). Dutia et al. report seemingly conflicting results regarding the DI: during repeated intravenous glucose challenges over 3 years and while at clinical remission, the low baseline DI of patients with T2D minimally changed and remained well below that of lean and obese nondiabetic control subjects. In contrast, upon repeated oral glucose challenges, the DI significantly improved and normalized to levels of lean and obese nondiabetic control subjects. Which DI should the reader believe to be a reliable predictor of the future clinical course of these patients (Fig. 1)? The few longitudinal studies of diabetic patients who underwent RYGB suggest that a 10–15% diabetes relapse per year occurs among patients who experienced clinical remission (13,14). As this number is much higher than that expected for obese nondiabetic or lean control subjects, it seems that the low and unchanged DI derived from the intravenous glucose challenge better reflects the effects of RYGB on islet function. The seemingly improved oral DI may be less reliable as a predictor of the future clinical course or as a true indicator of β-cell function in this scenario. Thus, there is limited recovery of β-cell function following RYGB.
How can one explain the discrepant results of the oral and intravenous DIs shown in the study by Dutia et al.? The two DI indices, oral and intravenous, have been shown to be modestly correlated in subjects with normal gastrointestinal anatomy (15,16). As both DIs were calculated in this study using the same surrogate of insulin sensitivity, the problematic component of the calculation must be the surrogate of insulin secretion. The modified kinetics of systemic glucose absorption along with the boosted incretin response following RYGB (17) may affect the calculations of indices of insulin secretion derived from an OGTT. Furthermore, the underlying assumption that the insulin sensitivity and secretion surrogates used in this analysis indeed behave as a hyperbolic function following RYGB must be proven to validate the two DI calculations. It would be important to study β-cell function in response to a mixed meal in this specific context. Individual macronutrients have a synergistic effect on the acute insulin and GLP-1 secretion (18), explaining the greater response in comparison with oral glucose. The impact of early exposure of the jejunum to such nutrients may boost these responses further following RYGB.
Dutia et al. (7) show convincing evidence that RYGB has a very modest effect on validated indices of islet function. Sleeve gastrectomy, which does not exclude the foregut, has a similar clinical effect on diabetes remission (19,20) and a very low-calorie diet can induce the identical very early effects of RYGB (21) in patients with diabetes. Taken together, these observations suggest that an effect of foregut exclusion on islet function is not the main driver of diabetes remission following RYGB. Further investigation into the mechanism by which foregut exclusion affects glucose metabolism above and beyond improving hepatic and muscle insulin sensitivity, such as the effects on other intestine-derived molecules and autonomic output, are warranted (22). Identification of such mechanisms may promote development of less invasive yet equally effective innovative diabetes modes of therapy.
See accompanying article, p. 1214.
Duality of Interest. No potential conflicts of interest relevant to this article were reported.