Incretins or Anti-Incretins? A New Model for the “Entero-Pancreatic Axis”

Abstract

The role of incretins in glucose homeostasis is well known. Yet, in recent years, the sustained weight loss and rapid glycemic control following bariatric surgery has challenged our understanding of the intestinal-pancreatic interaction. This in turn led to the introduction of metabolic surgery, an innovative medical discipline in which a surgical manipulation of the gastrointestinal tract (e.?g., through a Roux-en-Y gastric bypass, RYGB, or Bilio-Pancreatic-Diversion, BPD) yields a sustained remission of diabetes mellitus. The pathophysiological background of this metabolic effect is, amongst other things, based on the anti-incretin theory. This theory postulates that in addition to the well-known incretin effect, nutrient passage through the GI-tract could also activate negative feedback mechanisms (anti-incretins) to balance the effects of incretins and other postprandial glucose-lowering mechanisms (i.?e., suppression of ghrelin, glucagon, and hepatic glucose production via activation of nutrient sensing). This in turn prevents postprandial hyperinsulinemic hypoglycemia. The bypass of the duodenum, the entire jejunum and the first portion of the ileum by BPD induce normalization of peripheral insulin sensitivity, while the bypass of a shorter intestinal tract by RYGB mainly improves the hepatic insulin sensitivity. In addition, RYGB greatly increases insulin secretion. Therefore, metabolic surgery highlights the important role of the small intestine in glucose homeostasis, while until few years ago, it was only the pancreas and the liver that were thought to represent the regulatory organs for glucose disposal.

Assessment of glucose regulation in pregnancy after gastric bypass surgery

“…One prominent theory suggests that enhanced GLP-1 release is mainly caused by direct stimulation of the intestinal mucosa following accelerated delivery of undigested nutrients (hindgut hypothesis) [30,31]. However, the exact mechanisms underlying how the specific gastrointestinal anatomy after RYGB surgery leads to alteration of insulin response are not fully understood; the loss of inhibitory feedback mechanisms owing to bypassing the upper part of the duodenum might be involved (foregut hypothesis) [32][33][34]. It is not the scope of this report to further investigate this complex interaction between gut and pancreas.…”

Recent advances in the modification of taste and food preferences following bariatric surgery

“…Of note, the supraphysiologic increase in GLP-1 after RYGB is important for reduction in caloric intake, weight loss, and diabetes remission, but may not be the dominant factor in achieving these goals as injectable long-acting GLP-1 analogs achieving similar plasma concentrations show changes in these parameters of a much smaller magnitude than RYGB [30]. When food stops flowing through the duodenum and the proximal jejunum after RYGB, factors, called Banti-incretins,^are inhibited [64]. For example, GIP appears to have a dual function concerning glycemic control: it is able to reduce glycemia (insulinotropic effect) but is also able to increase glycemia (glucagonotropic effect).…”

Weight Loss Interventions and Progression of Diabetic Kidney Disease

“…Prior to the onset of significant weight loss and even later when weight loss is comparable between gastric banding and RYGB, the latter is more efficacious as a means of restoring glycaemic control in patients with diabetes [21]. This phenomenon has been proposed in part to depend upon the exaggerated release of enteroendocrine incretin hormones such as glucagon-like peptide 1 as a consequence of early distal nutrient delivery and potentially also via the removal of proximal anti-incretin(s) due to duodenal exclusion from nutrient flow [21,22].…”