How the hindgut can cure type 2 diabetes. Ileal transposition improves glucose metabolism and beta-cell function in Goto-kakizaki rats through an enhanced Proglucagon gene expression and L-cell number Alberto Patriti, MD, a * Maria Cristina Aisa, PhD, b * Claudia Annetti, MS, b Angelo Sidoni, MD, c Francesco Galli, PhD, b Ivana Ferri, MS, c Nino Gullà, MD, a and Annibale Donini, MD, a Perugia, Italy Background: It has been hypothesized that glucagon-like peptide-1 (GLP-1), secreted by ileal L cells, plays a key-role in the resolution of type 2 diabetes after bariatric operations whose common feature is an expedite nutrient delivery to the hindgut. Ileal transposition (IT), an operation that permits L-cell stimulation by undigested food, was employed to verify this theory. Methods: IT was carried out in Goto-Kakizaki (GK) type 2 diabetic rats and in euglycemic Sprague-Dawley (SD) rats. Glucose tolerance, insulin resistance, food-intake, body weight, pancreas morphology, and function were evaluated to track the effects of IT on diabetes. Intact GLP-1 secretion and gene expression pattern of the transposed ileum were investigated to verify the molecular bases of the hindgut action. Results: In GK rats, IT significantly improved glucose tolerance, insulin sensitivity, and acute insulin response without affecting body weight and food intake. Immunohistochemistry revealed remodeled islets strictly resembling that of euglycemic rats and signs of -cell neogenesis starting with exocrine structures. GLP-1 secretion in GK transposed rats was characterized by a more sustained response to oral glucose compared with nontreated rats. Gene expression of Proglucagon, Proconvertase 1/3 (PC1/ 3), and Chromogranin A in the transposed ileum significantly enhanced. Effects on glucose metabolism and pancreas morphology were not observed in the euglycemic rats as a consequence of the glucose- dependent action of GLP-1. Conclusions: This study gives strong evidences for the crucial role of the hindgut in the resolution of diabetes after Roux-en-Y gastric bypass (GBP) and biliopancreatic diversion (BPD). Moreover, these findings confirm at the preclinical level that IT is a surgical procedure of possible relevance in the therapy of type 2 diabetes in non– overweight and mildly obese patients. (Surgery 2007;142:74-85.) From the Department of Surgery, Section of General and Emergency Surgery, a the Department of Internal Medicine, Section of Applied Biochemistry and Nutritional Sciences, b and the Department of Experimental Medicine and Biochemistry, Section of Pathology, c University of Perugia, Perugia, Italy bariatric procedures, including bypass of the foregut such as Roux-en-Y gastric bypass (GBP) and biliopancreatic diversion (BPD), can lead to nor- mal concentrations of plasma glucose, insulin, and glycosylated hemoglobin in the majority of mor- bidly obese diabetic patients, with an observed im- provement in glucose metabolism long before weight loss occur. 1-4 In animal models of type 2 diabetes, it has been confirmed that ileal transposition can represent a specific procedure to improve glucose tolerance. 5 These findings strongly suggest the existence of an underlying hormonal mechanism for the postoper- *A.P. and M.C.A. contributed equally to this article. (The first two authors are joint first authors.) Supported by Fondazione Cassa di Risparmio di Perugia, Fonda- zione Todini. Accepted for publication March 2, 2007. Reprint requests: Alberto Patriti, MD, Department of Surgery, Uni- versity of Perugia, Ospedale Santa Maria della Misericordia, San Sisto, 06156 Perugia, Italy. E-mail: albertopatriti@gmail.com. 0039-6060/$ - see front matter © 2007 Mosby, Inc. All rights reserved. doi:10.1016/j.surg.2007.03.001 74 SURGERY