Restoration of Euglycemia After Duodenal Bypass Surgery Is Reliant on Central and Peripheral Inputs in Zucker fa/fa Rats

Abstract

Gastrointestinal bypass surgeries that result in rerouting and subsequent exclusion of nutrients from the duodenum appear to rapidly alleviate hyperglycemia and hyperinsulinemia independent of weight loss. While the mechanism(s) responsible for normalization of glucose homeostasis remains to be fully elucidated, this rapid normalization coupled with the well-known effects of vagal inputs into glucose homeostasis suggests a neurohormonally mediated mechanism. Our results show that duodenal bypass surgery on obese, insulin-resistant Zucker fa/fa rats restored insulin sensitivity in both liver and peripheral tissues independent of body weight. Restoration of normoglycemia was attributable to an enhancement in key insulin-signaling molecules, including insulin receptor substrate-2, and substrate metabolism through a multifaceted mechanism involving activation of AMP-activated protein kinase and downregulation of key regulatory genes involved in both lipid and glucose metabolism. Importantly, while central nervous system–derived vagal nerves were not essential for restoration of insulin sensitivity, rapid normalization in hepatic gluconeogenic capacity and basal hepatic glucose production required intact vagal innervation. Lastly, duodenal bypass surgery selectively altered the tissue concentration of intestinally derived glucoregulatory hormone peptides in a segment-specific manner. The present data highlight and support the significance of vagal inputs and intestinal hormone peptides toward normalization of glucose and lipid homeostasis after duodenal bypass surgery.

Hormonal Signaling in the Gut

“…Contributing to this hypothesis, nutrient-sensing mechanisms also remain intact in this rodent model to lower glucose concentrations after DJB surgery independent of a rise in insulin levels (50). This is consistent with other studies demonstrating that DJB suppresses GP in type 2 diabetic rodents without improving insulin sensitivity (52). These findings suggest that although insulin mediates glucose suppression in some settings, other local intestinal signals are important contributors to the antidiabetic effects of DJB (Fig.…”

“…Despite this, both vertical sleeve gastrectomy and RYGB are effective in normalizing glycemia in several models of models of GLP-1R deficiency (48,49), whereas duodenal-jejunal bypass (DJB) improves glucose levels despite nonelevated postsurgical GLP-1 levels in nonobese type 1 diabetic rats (50). Thus, the role of GLP-1 in mediating the antidiabetic effects of bariatric surgery still remains highly controversial (44,45,(51)(52)(53)(54)(55).…”

Glucoregulatory Relevance of Small Intestinal Nutrient Sensing in Physiology, Bariatric Surgery, and Pharmacology

“…DJB rapidly (in 2 days) lowers plasma glucose concentrations in STZ-induced and BBdp diabetic rodents, and this glucose lowering is independent of changes in insulin concentrations, food intake, and body weight (Breen et al, 2012). This is in line with the fact that most studies demonstrate weight-loss-independent glycemic effects of DJB (Cohen et al, 2012b;Hu et al, 2013) and that DJB rapidly improves glucose tolerance but does not enhance insulin sensitivity (Jiao et al, 2013;Kindel et al, 2009). Importantly, during fastingrefeeding experiments, inhibition of jejunal glucose-and fattyacid-sensing mechanisms via intrajejunal infusion of SGLT-1 inhibitor phlorizin or ACS inhibitor triacsin C, respectively, disrupts glucose homeostasis compared to vehicle infusions (Breen et al, 2012) ( Figure 2).…”

“…Although DJB does not elicit the same weight loss effects as RYGB, it has similar gluco-regulatory effects Jiao et al, 2013;Rubino et al, 2006;Salinari et al, 2014). Non-obese diabetic DJB rats show improved glucose homeostasis, independent of changes in food intake or body weight, as early as 1 week after the procedure and persisting for 9 months (Rubino and Marescaux, 2004;Speck et al, 2011).…”

Diabetes and Cartesian Dualism: what is the evidence for a brain‐centred gluco‐regulatory system?

“…11 More recent work suggests that insulin signalling is required in the ventromedial hypothalamus for the effect of bariatric surgery to inhibit HGP in obese rats. 12,13 There is increasing evidence to suggest that there are strong links between enhanced secretion of FGF-19, the central nervous system and the gut. The potential is therefore to identify how bariatric procedures interfere with the BCGS and perhaps induce diabetes remission through this pathway (without having to resort to surgery).…”