We have shown that RYGB is associated with unique changes in postprandial plasma concentrations of incretin hormones in comparison with BND subjects and overweight controls matched for post-operative BMI. RYGB subjects exhibited an exaggerated GLP-1 response and a suppression of GIP secretion after administration of a test meal. Our previous studies showed significantly greater insulin levels 30 minutes after identical test meals in RYGB compared with both BND and BMI-matched controls3,4
. While peak insulin levels were also greatest in RYGB in this study, the differences did not reach statistical significance. More detailed studies are necessary to better characterize glucose metabolism and insulin sensitivity in these subjects, however, the lower HOMA-IR in RYGB subjects is suggestive of greater insulin sensitivity compared with BND. If this is the case, one may have predicted less postprandial insulin secretion in RYGB. In contrast, there was at least equal, if not greater, postprandial insulin secretion in the RYGB group. Given that GLP-1 augments insulin secretion it is possible that enhanced secretion of this incretin, rather than insulin resistance, is the stimulus for much of the insulin response in RYGB subjects. In support of this notion is the finding that in this group only, peak GLP-1 levels correlated with insulin concentrations. The initial rise in glucose concentration in RYGB compared with BND may have also contributed to increased insulin secretion.
It has been suggested that in the setting of improved insulin sensitivity post-RYGB, enhancement of GLP-1 secretion may on rare occasions result in hyperinsulinemic hypoglycemia11–14
. None of our RYGB participants experienced clinical dumping syndrome, but their glucose levels were significantly lower than both other groups at 60, 90 and 120 minutes, with the lowest values for two different subjects being 38 and 48 mg/dl. Although GLP-1 may also inhibit glucagon secretion, we observed an early robust increase in glucagon levels in the RYGB group, indicating that lower levels of glucose in the RYGB group were not due to impaired glucagon secretion. At 180 minutes, however, lower glucagon levels in the RYGB group (perhaps as a result of elevated GLP-1) may have contributed to lower glucose levels. GIP is another gut hormone that stimulates glucose-dependent insulin secretion, however, we show here that postprandial concentrations are significantly decreased in the RYGB group. The blunted GIP response may help abet further decreases in glucose concentrations. Other glucoregulatory factors, such as cortisol, growth hormone and autonomic nervous system function were not examined in this study.
What accounts for the differences in incretin secretion in our study groups? The most obvious answer is the different paths of nutrient flow. After bypass, nutrients pass directly from the gastric pouch to the distal small intestine. Thus, delivery of concentrated nutrients to L cells in the distal small intestine where GLP-1 is primarily produced may enhance GLP-1 secretion, as was described after jejunoileal bypass15
and total gastrectomy16
. It has also been shown that postprandial levels of peptide YY (PYY), which is also produced by L cells, are enhanced after RYGB compared BND and lean subjects, and BMI-matched controls3, 17
. Since GIP is synthesized primarily in the proximal small intestine, diversion of nutrients from this segment would be expected to reduce postprandial GIP levels as we have shown. It is unlikely that the difference in weight loss contributed to the different patterns of incretin secretion given that the degree of weight loss did not correlate with either GLP-1 or GIP secretion.
Other studies have also examined the effect of bariatric surgery on gastrointestinal peptide hormones18
and have shown that GLP-1 secretion is enhanced after RYGB17, 19
although to a much lesser degree (less than three-fold over baseline) than the nearly ten-fold increase we observed. After biliopancreatic diversion, a malabsorptive bariatric procedure that bypasses the foregut and part of the hindgut, fasting GLP-1 levels were shown to increase compared to pre-surgical values, however, circulating levels after an OGTT were nearly flat-line20
. Postprandial GLP-1 and enteroglucagon levels also increase after jejunoileal bypass, whereas results of this procedure on GIP concentrations are inconsistent18
. We are not aware of other studies that examine the effect of RYGB on GIP in non-diabetic subjects. Animal models such as ileal transposition in rodents also show that expedited delivery of nutrients to a segment of foregut increases levels of hormones synthesized in the hindgut, such as GLP-1, enteroglucagon and PYY21, 22
Bariatric surgery, particularly RYGB, confers long-term maintenance of a reduced body weight and improvement in glucose homeostasis. GLP-1 analogues and methods to decrease the inactivation of GLP-1 by dipeptidyl peptidase IV (DPP IV) are now in clinical use and are being extensively studied for the treatment of type 2 diabetes23
. Manipulation of incretin hormone concentrations may also affect body weight. For example, the use in humans of the GLP-1 receptor agonist, exenatide, is associated with weight loss23
, and mice lacking the GIP receptor are resistant to diet-induced obesity24
. Our results suggest that enhancement of postprandial GLP-1 concentrations after RYGB and suppression of GIP secretion may contribute to increased weight loss and improved glucoregulation.