It is well established that RYGB is effective in improving insulin resistance and ameliorating type 2 diabetes. The beneficial metabolic effects of RYGB were initially attributed to the substantial weight reduction achieved with surgery; however, subsequent investigations revealed an improvement in insulin sensitivity at 6 days after RYGB without appreciable weight loss (15
). We have confirmed these findings by demonstrating a 25% improvement in insulin sensitivity (HOMA-IR) within 1 week after RYGB before any apparent weight loss. Interestingly, obese subjects, albeit with a nonsignificantly lower body weight, who consumed a post–bariatric surgery liquid diet for 4 days replicated the improved insulin sensitivity observed in the RYGB subjects. The parallel improvements occurred with minimal noticeable differences in weight loss between the two groups. HOMA-IR is a fasting measure of whole-body insulin resistance that has been shown to correlate with other dynamic measures of insulin sensitivity in obese subjects, such as the hyperinsulinemic-euglycemic clamp (16
). Such studies suggest that a short duration, very-low-calorie diet can reduce hepatic glucose production (17
) and improve skeletal muscle insulin sensitivity (4
). Our data demonstrate that the improvement in insulin sensitivity, as measured by HOMA-IR, precedes appreciable weight loss and is largely achieved with caloric restriction. However, we must consider the possibility that the immediate improvements in insulin sensitivity after RYGB could have been blunted consequent to the associated stress/inflammatory responses of surgery, thus masking a greater improvement in insulin sensitivity with RYGB than with caloric restriction.
Fasting levels of GLP-1 have been reported to remain stable 2–10 weeks after RYGB (1
), consistent with our current observations within the 1st postoperative week. Our data show increases in peak GLP-1 levels and total GLP-1 release after ingestion of a mixed meal 1 week after RYGB, in agreement with previous short-term follow-up investigations (11
). This increase in GLP-1 could not be attributed to the restrictive nature of the surgical procedure, because the caloric-restricted diet group did not show enhanced an GLP-1 release in response to the mixed meal. The findings with GIP are novel; GIP is released sooner but not to a greater extent with a meal within the 1st week after RYGB. Laferrère et al. (11
) and Campos et al. (10
) compared incretin levels in two groups of subjects after a 10-kg weight loss via RYGB or diet and reported an increase in GLP-1 only after RYGB; their findings for GIP were disparate, with one reporting an increase (11
) and the other reporting no change (10
). Our results, however, show altered incretin release after RYGB before substantial weight loss. The proposed mechanism of enhanced incretin release after RYGB is most likely related to the increased and more rapid nutrient stimulus to the intestinal neuroendocrine cells.
The effects of the changes in incretin levels on the improved metabolic responses after RYGB remain controversial. In our study, the observed increase in GLP-1 and shift to an earlier GIP peak within 1 week after RYGB was accompanied by improved insulin sensitivity, whereas the improvement in insulin sensitivity after caloric restriction occurred without alterations in either GLP-1 or GIP. Thus, the improvements in insulin sensitivity in our study are unlikely to be due to altered incretin-induced insulin release but rather to the caloric restriction. In fact, in both surgical and caloric-restricted diet groups we observed similar decreases in insulin release () accompanied by improved insulin sensitivity. These findings contrast with previous reports of either no early changes in insulin release (10
) or an increase in insulin release (11
) after RYGB. The discrepancy with our findings may be related to the associated losses (10 kg) in body weight in these studies (10
). In addition, GLP-1 could exert extrapancreatic effects on improving insulin sensitivity (22
), which in our RYGB group could have been blunted as a result of the associated inflammatory responses immediately after surgery. Lastly, perhaps the improved GLP-1 response in the 1st week after RYGB is not robust enough to elicit increased insulin secretion and glucose-lowering effects and may take longer to exert such effects.
Levels of the orexiogenic hormone ghrelin are diminished in obesity (23
), perhaps indicating a positive energy balance. The short-term effect of RYGB on fasting total ghrelin is controversial. We observed 20% decreases in fasting levels of acylated and total ghrelin within 1 week after RYGB; these are consistent with previously reported decreases in fasting total ghrelin at 6 weeks (24
) but different from another report showing no change 1 month after RYGB (12
). Whether the decreased levels of acylated and total ghrelin levels play a role in the improvement in insulin sensitivity after RYGB remains to be determined. Vestergaard et al. (6
) demonstrated that exogenous infusion of a pharmacological dose of acyl-ghrelin acutely induced insulin resistance independent of growth hormone and cortisol.
Alterations in adipokines, such as leptin and adiponectin, after RYGB have been attributed to fat mass loss and are responsible for the long-term improvements in insulin resistance (2
). The similarities in the decrease in plasma leptin in the RYGB and diet groups suggest that this immediate change in leptin after surgery can be accounted for by caloric restriction. A similar finding was reported 1 month after RYGB and diet, coinciding with a 10-kg weight loss (12
). The stable adiponectin concentrations during caloric restriction via RYGB and diet could indicate dissociation in the regulation of these two adipokines between nutrient exposure and fat mass.
In summary, our present data suggest that caloric restriction without substantial weight loss is of primary importance in the rapid improvement of insulin sensitivity within the 1st week after RYGB. Early alterations in the incretin response can be attributed to the surgery; however, the enhanced incretin response does not seem to have any additional benefit beyond caloric restriction on glucose homeostasis and insulin sensitivity. It is important to note that our cohorts of obese subjects were balanced for type 2 diabetes, and the measured parameters were similar at baseline (except for HOMA-IR, which was higher in the subjects with type 2 diabetes) and changed similarly after intervention. Further investigations in the immediate postoperative period with more dynamic measures of insulin resistance are also warranted to determine the mechanisms/site of improved insulin sensitivity, along with a direct assessment of the incretin effect on insulin production.