The jejunum is the key factor in insulin resistance

BACKGROUND: Biliopancreatic diversion (BPD) is more effective than Roux-en-Y gastric bypass (RYGB) on both insulin resistance and diabetes. OBJECTIVES: Because the major difference between the 2 procedures resides in the length of jejunal bypass, we investigated the role of the jejunum in insulin resistance. SETTING: University hospital in Italy. METHODS: Insulin sensitivity (IS) and secretion were measured before and 4 weeks after RYGB or BPD in 16 patients. A translational study was also conducted in 6 pigs, by isolating a jejunal loop with its vascular and nerve supply (Thiry-Vella loop [TVL]). TVL was doubly stomatized and bowel continuity restored by a side-to-side jejuno-jejunostomy. At baseline and 4 weeks postoperatively a glucose bolus was injected either in the stomach or in the TVL. Whole-body IS and jejunal heat shock proteins (HSPs) were measured. Primary porcine hepatocyte cultures were incubated with plasma or individual HSPs. RESULTS: Whole-body IS increased from 353.5 ± 26.7 to 442.0 ± 37.4 (P < .05) after RYGB and from 312.4 ± 14.9 to 441.2 ± 15.9 mL/m-2/min-1 (P < .001) after BPD. Hepatic IS was unchanged after RYGB, while it increased from .3 ± .01 to .4 ± .1 (μM/pM) - 1 (P < .01) after BPD. Total insulin secretion rate remained unchanged after RYGB but decreased (from 58.3 ± 23.6 to 33.1 ± 7.8 nmol/m-2, P < .05) after BPD. Jejunectomy in pigs enhanced IS (.3 ± .01 versus .2 ± .01 mM/pM, P < .001), while injection of glucose into TVL reduced it (.1 ± .01 versus .3 ± .01 mM/pM, P < .0001). The jejunum secreted HSPs, Hsp70, and GRP78, which impaired insulin signaling in hepatocyte cultures. CONCLUSIONS: This study shows that jejunal bypass in both humans and pigs improves IS. Injection of glucose into the TVL in pigs determines insulin resistance. In response to glucose, the jejunum secretes HSPs that impair insulin signaling.