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Gut Hormones and Bariatric Surgery

Human subjects with severe obesity are increasingly treated with bariatric surgery to promote weight loss via procedures that reduce the capacity of the stomach and/or the absorptive surface area of the small bowel, resulting in reduced food intake and/or energy malabsorption. Some of these surgical procedures may also be associated with changes in plasma levels of one or more gut hormones, due to anatomical alterations in gut motility, incomplete nutrient digestion, and disruption of neural innervation. Changes in the levels of circulating gut hormones have been commonly observed after gut surgery, and in some instances, relative changes in the numbers of specific enteroendocrine cell subsets have also been described. Diversion of nutrients away from the proximal gut and consequent exposure of the distal gut to a greater load of incompletely digested nutrients is often associated with a reductions in levels of circulating peptides derived from the proximal gut, and an increase in levels of peptide hormones derived from the distal gut, such as neurotensin, PYY and enteroglucagon (a surrogate for levels of glicentin, oxyntomodulin, GLP-1 and GLP-2)1,2,3….

As many human subjects experience significant weight loss, and even more remarkable improvement or complete resolution of their diabetes within days of the surgical procedure, there is great interest in understanding the potential roles of gut hormones in the improvement of beta-cell function, the amelioration of the diabetic state, and in the factors contributing to weight loss. An increase in the levels of anorectic hormones such as PYY or GLP-1, or a decrease in levels of orexigenic hormones such as ghrelin4 are associated with changes in appetite and body weight in subsets of patients following bypass surgery.5 Indeed, in some cross-sectional studies, a restored GLP-1 response is a key variable redictive of diabetes remission.6

As outlined below, ascertaining the precise individual contributions of specific hormones and metabolites in the gluco-regulatory and weight loss responses after bariatric surgery is more challenging.

Gastric bypass surgery, GLP-1, weight loss, and improvement in glycemia

Many patients with obesity experience rapid weight loss together with striking amelioration of their diabetes often within days of gastric bypass surgery. As marked amelioration or complete resolution of the associated diabetes frequently precedes weight loss, a role for GI hormones secreted from the distal GI tract, such as GLP-1 has been invoked to explain these impressive clinical improvements. As different surgical procedures result in distinct anatomical rearrangement of the normal proximal-distal gut orientation and integrity, it is important to distinguish between the various surgical procures and associated changes in levels of gut hormones. Much of the published data correlates changes in gut hormone levels with improvements in glycemia and weight loss after GBS. Some studies use transient administration of antagonists to probe the role of specific gut hormones. It seems clear that a subset of patients develop hyperinsulinemic hypoglycemia secondary to a brisk exaggerated rise in GLP-1 secretion and in many patients, increased GLP-1 levels contribute to improved insulin secretion after meal ingestion post bariatric surgery. It is less clear how much GLP-1 contributes to the overall improvement in fasting glycemia, improvement in insulin sensitivity, complete resolution of diabetes, and weight loss in the majority of subjects undergoing bariatric surgery.

Clinical Data

Jimenez and colleagues examined the importance of endogenous GLP-1 for glucose control and insulin secretion by studying 8 female subjects (mean age 54) who had experienced complete remission of their diabetes; patients were studied at least 2 years after their GBS. Subjects were studied on two different days with or without the GLP-1R antagonist exendin(9-39) administered as an iv bolus followed by a continuous infusion prior to and following a standardized liquid test meal. Glucose levels rose more rapidly and peaked at higher levels in the post GBS subjects. Ex(9-39) produced a small but significant increase in glycemic excursions in control subjects from 30-70 minutes. In contrast, the increased glycemic profile in post GBS patients was comparatively delayed at ~ 80-120 minutes after Ex(9-39). Notably, Ex(9-39) did not shift the glycemic profile of the GBS patients into the diabetic range. Ex(9-39) had no significant effect on fasting insulin/C-peptide levels in control or post GBS groups. Plasma GLP-1, C-peptide and insulin responses were significantly greater post test meal in the GBS groups and Ex(9-39) significantly decreased insulin and C-peptide excursions to a much greater extent in the GBS group compared to control, without comparable large increases in plasma glucose levels. Glucagon levels were also higher post GBS, and rose modestly but were not significantly different after Ex(9-39). GIP levels were also much greater post GBS and not different after Ex(9-39). The authors conclude that elevated GLP-1 levels post GBS do not contribute significantly to the major improvements in glycemic control in the majority of subjects.7

In contrast, Jorgensen and colleagues studied 9 patients with type 2 diabetes, mean age 50, BMI 39, duration of diabetes ~ 5 yrs, before and 1 week and 3 months after RYGB surgery. Acute administration of exendin(9-39) reversed the improvements in beta-cell glucose sensitivity and glucose tolerance, and further increased already elevated levels of glucagon, leading the authors to conclude that the ~8-fold increase in GLP-1 levels was very important for the observed improvements in beta-cell function and reduction of glycemia.8

Similarly, Jorgensen and colleagues used exendin(9-39) infusion in 9 patients at 1 week and 3 months after RYGB to implicate a role for GLP-1R signaling in changes in insulin, glucagon, and beta cell glucose sensing after bypass surgery. β-GS decreased to preoperative levels, glucagon secretion increased, and glucose tolerance was impaired by Ex-9 infusion.9 In contrast, similar studies by different investigators in 8 subjects with sustained remission of diabetes after RYGP surgery demonstrated detectable but modest effects of exendin(9-39) on parameters of glucose tolerance, leading these investigators to conclude that, “The limited deterioration of glucose tolerance on blockade of GLP-1 action in our study suggests the resolution of T2DM after RYGBP may be explained by mechanisms beyond enhancement of GLP-1 action.”10

Shah and colleagues infused exendin(9-39) into human subjects after gastric bypass to probe the role of GLP-1R signaling. Although exendin(9-39) did increase glucose and reduce insulin levels, exendin(9-39) did not alter meal appearance, suppression of glucose production or stimulation of glucose disappearance after RYGB subjects. Hence, GLP-1 may contribute to but does not explain the complex metabolic improvements observed after RYGB.11

Le Roux and colleagues examined changes in plasma levels of gut hormones and glucose tolerance following different gastric bypass procedures in rats and human subjects. Patients with Roux-en-Y gastric bypass (RYGB) had increased postprandial levels of plasma PYY and GLP-1 together with early and exaggerated insulin responses, and improved glycemic control. In contrast, these hormonal changes were not seen in subjects after gastric banding.12

Sequential changes in glucose tolerance, gastric emptying and levels of gut hormones in response to a liquid test meal were also assessed by Falken and colleagues in 12 obese subjects at 3 days, 2 months, and one year after gastric bypass. Change in body mass was highly significant (from 45 to 30 over one year). Plasma levels of several gut hormones, including GLP-1 increased progressively over time, glucose tolerance and beta-cell function improved, coincident with satiety and weight loss. However, significant improvements in plasma levels of GLP-1 were also noted as early as day 3. Transit through the GI tract was rapidly improved as early as day 3.13

Gastric bypass surgery and postprandial hypoglycemia

Six patients with hyperinsulinemic hypoglycemia following meal ingestion were detected 0.5-8 years following Roux-en-Y gastric bypass surgery were found to have histological evidence for nesidioblastosis following resection of pancreatic tissue-one patient was found to have multiple insulinomas as described in the July 21 2005 New England Journal of Medicine. The authors speculated, as further discussed in an accompanying editorial, that excessive secretion of gut hormones such as GLP-1 may have contributed to the development of islet proliferation in these human subjects. Indeed, many of the patients presenting with hypoglycemia post bypass have increased GLP-1 levels and enhanced beta cell sensitivity to GLP-1 action.14,15

References:
  1. Gut hormone changes after jejunoileal (JIB) or biliopancreatic (BPB) bypass surgery for morbid obesity. Int J Obes 1981; 5:471-80.
  2. Plasma enteroglucagon after jejunoileal bypass with 3:1 or 1:3 jejunoileal ratio. Scand J Gastroenterol 1979; 14:205-7.
  3. Morphological and functional alterations to a sub-group of regulatory peptides in human pancreas and intestine after jejuno-ileal bypass. Int J Obes Relat Metab Disord 1993 17:109-113.
  4. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med 2002: 346:1623-1630.
  5. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med 2002: 346:1623-1630
  6. Roux-en-Y Gastric Bypass and Sleeve Gastrectomy: Mechanisms of Diabetes Remission and Role of Gut Hormones J Clin Endocrinol Metab. 2013 Nov;98(11):4391-9.
  7. GLP-1 Action and Glucose Tolerance in Subjects With Remission of Type 2 Diabetes Mellitus After Gastric Bypass Surgery Diabetes Care. 2013 Jan 28.
  8. Exaggerated glucagon-like peptide 1 response is important for improved β-cell function and glucose tolerance after Roux-en-Y gastric bypass in patients with type 2 diabetes Diabetes. 2013 Sep;62(9):3044-52
  9. Exaggerated glucagon-like peptide 1 response is important for improved β-cell function and glucose tolerance after Roux-en-Y gastric bypass in patients with type 2 diabetes Diabetes. 2013 Sep;62(9):3044-52
  10. GLP-1 action and glucose tolerance in subjects with remission of type 2 diabetes after gastric bypass surgery Diabetes Care. 2013 Jul;36(7):2062-9.
  11. Contribution of endogenous glucagon-like peptide 1 to glucose metabolism after Roux-en-Y gastric bypass Diabetes. 2014 Feb;63(2):483-93.
  12. Gut hormone profiles following bariatric surgery favor an anorectic state, facilitate weight loss, and improve metabolic parameters. Ann Surg. 2006 Jan;243(1):108-14.
  13. Changes in Glucose Homeostasis after Roux-en-Y Gastric Bypass Surgery for Obesity at Day Three, Two Months, and One Year after Surgery: Role of Gut Peptides. J Clin Endocrinol Metab. 2011 May 4. [Epub ahead of print].
  14. Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery. N Engl J Med. 2005 Jul 21;353(3):249-54.
  15. Exaggerated release and preserved insulinotropic action of glucagon-like peptide-1 underlie insulin hypersecretion in glucose-tolerant individuals after Roux-en-Y gastric bypass Diabetologia. 2013 Dec;56(12):2679-87.