Isolated duodenal exclusion increases energy expenditure and improves glucose homeostasis in diet-induced obese rats

Abstract

Roux-en-Y gastric bypass (RYGB) in rodent models reduces food intake (FI), increases resting energy expenditure (EE), and improves glycemic control. We have shown that mimicking the duodenal component of RYGB by implantation of a 10-cm endoluminal sleeve device (ELS-10) induces weight loss and improves glycemic control in diet-induced obese (DIO) rats. We sought to determine the mechanisms and structural requirements of these effects. We examined the effects of ELS-10 devices implanted in male DIO rats on body weight, food intake (FI), meal patterns, total and resting EE, and multiple parameters of glucose homeostasis, comparing them with sham-operated (SO) rats and with SO rats weight matched to the ELS-10-treated group. To determine the extent of duodenal exclusion required to influence metabolic outcomes, we compared the effects of implanting 10-, 4-, or 1-cm ELS devices. ELS-10 rats exhibited 13% higher total and 9% higher resting EE than SO controls. ELS-10 rats also exhibited enhanced postprandial GLP-1 secretion and improved glucose tolerance and insulin sensitivity out of proportion to the effects of weight loss alone. Implantation of 4- or 1-cm ELS devices had no effect on EE and limited effects on glucose homeostasis. Complete duodenal exclusion with ELS-10 induces weight loss by decreasing FI and increasing EE and improves glycemic control through weight loss-independent mechanisms. Thus signals originating in the proximal small intestine appear to exert a direct influence on the physiological regulation of EE and glucose homeostasis. Their selective manipulation could provide effective new therapies for obesity and diabetes that mimic the benefits of RYGB.

Endoscopic Duodenal Mucosal Resurfacing for the Treatment of Type 2 Diabetes: 6-Month Interim Analysis From the First-in-Human Proof-of-Concept Study

“…In addition, an as yet unidentified factor isolated from proximal intestinal cells may directly impact systemic insulin sensitivity, as myocytes become insulin resistant when exposed in vitro to proteins produced by duodenal/jejunal mucosa from subjects with diabetes (28). Moreover, studies in animals and humans show that duodenal exclusion ameliorates the metabolic disturbance (9,29,30) of type 2 diabetes, and in humans and rats, an intestinal device that prevents nutrient contact with the duodenal mucosa also leads to improvement in metabolic measures (31)(32)(33).…”

Bariatric and metabolic surgery: a shift in eligibility and success criteria

“…27 Interestingly, duodenal exclusion alone is reportedly sufficient to reduce fasting blood levels of glucose in patients with T2DM independently of weight loss. 68,69,[86][87][88][89] This finding is further backed by experimental models of lean animals with T2DM, such as nonobese diabetic Goto-Kakizaki rats. [90][91][92] Thus, signals originating in the proximal small intestine seem to exert a direct effect on the physiological regulation of glucose homeostasis.…”

Intestinal sweet-sensing pathways and metabolic changes after Roux-en-Y gastric bypass surgery

“…The surgical isolation of duodenum and proximal jejunum appear to be critical in mediating resolution of T2D, supported by outcomes following endoluminal sleeve device insertion and surgical procedures (e.g., RYGB, biliopancreatic diversion), which exclude a similar region of the intestine from the digestive process (9,19,20,21). Further highlighting the importance of proximal bowel isolation are studies in RYGB models showing that the reintroduction of mixed nutrients into the excluded bowel reverses the beneficial effects of surgery on glucose tolerance (7,8,22).…”