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.

Fig. 1.

A: anatomical components of Roux-en-Y gastric bypass (RYGB). 1) Isolation of the proximal gastric cardia; 2) nutrient exclusion from the distal stomach; 3) nutrient exclusion from the duodenum; 4) accelerated or enhanced contact of partially digested nutrients with the jejunal mucosa; and 5) partial vagotomy. B: 10-cm endoluminal sleeve (ELS) device mimics two anatomical components of RYGB. 1) Ingested nutrients flow through the ELS lumen and are prohibited from direct contact with the mucosa of the duodenum and proximal jejunum. 2) Undigested or partially digested nutrients contact the distal small intestine, while biliopancratic secretions are distally diverted into the mid-jejunum. A is ELS-anchoring crown; B is highly flexible, nutrient-impermeable tube. C: extent of duodenal exclusion. 1- and 4-cm ELS devices induce more limited nutrient exclusion and rerouting of biliopancreatic secretions than the 10-cm ELS device.

Fig. 2.

Isolated duodenal exclusion increases energy expenditure. A: body weight progression compared with pair-fed shams. B and C: total oxygen consumption, D: resting oxygen consumption, and E: spontaneous locomotor activity over 72 consecutive hours. SO, sham operated; PFS, pair-fed sham; ELS-10, 10-cm ELS; n = 5 per group. *P < 0.05, ***P < 0.001 vs. SO; #P < 0.05 vs. PFS.

Fig. 3.

Isolated duodenal exclusion improves glucose homoestasis independent of weight loss. Fasting blood glucose (A), and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) (B), oral glucose tolerance (C), and glucose-stimulated insulin secretion (GSIS) (D) after oral glucose administration, and glucose-stimulated levels of total GLP-1 20 min after oral glucose administration (50% dextrose, 1 g/kg) (E) are shown. Insets, areas-under-the-curve (AUC) analyses. WMS, weight-matched sham; n = 5 per group. *P < 0.05, **P < 0.01, ***P < 0.001 vs. SO; #P < 0.001 vs. WMS.

Fig. 4.

Partial duodenal exclusion induces weight loss via changes in food intake (FI) but not energy expenditure (EE). A: body weight progression over 8 wk; B: percent calorie absorption; C: cumulative energy intake (EI); D: meal size; E: meal number; F: total oxygen consumption. ELS-10, 10 cm ELS; ELS-4, 4 cm ELS; ELS-1, 1 cm ELS; n = 5 per group. *P < 0.05, ***P < 0.001, vs. SO, +P < 0.05 vs. E.LS-1, ELS-4.

Fig. 5.

Complete duodenal exclusion induces optimal glycemic control. Blood glucose (A) and insulin concentrations (B) after an overnight fast are shown. Oral glucose tolerance (C) and glucose-stimulated insulin secretion (GSIS) (D) after oral glucose administration (50% dextrose, 1 g/kg) are shown. Insets, AUC analyses. E: HOMA-IR. n = 5 per group. *P < 0.05, ***P < 0.001 vs. SO; +++P < 0.001 vs. ELS-1 and ELS-4.