Alas! Ileal Interposition Surgery for Diabetes Prevention? See “Ileal interposition surgery improves glu- cose and lipid metabolism and delays diabe- tes onset in the UCD-T2DM rat,” by Cummings BP, Strader AD, Stanhope KL, et al, on page 2437. T he prevalence of diabetes has increased worldwide mainly as a result of the obesity epidemic. 1 In 2007, 23.6 million people in the United States were affected by diabetes, with type 2 diabetes comprising the majority of cases. 2 Another 57 million people had prediabetes, char- acterized by impaired fasting glucose and glucose intol- erance. 2 Worldwide estimates of diabetes are as high as 171 million. 3 The current treatment of type 2 diabetes is aimed at increasing insulin secretion, decreasing glucose absorption from the small intestine or improving insulin sensitivity. Tight glycemic control can reduce some of the complications of diabetes; however, this goal is often unattainable partly because of poor patient compliance, inadequate health care delivery, and the high cost of therapy. 4 Several studies have shown that lifestyle inter- vention can slow the progression of prediabetes to dia- betes, but whether this strategy can be implemented under everyday living conditions is uncertain. 5,6 Given the burgeoning twin epidemics of obesity and diabetes, recent attention has been focused on gastrointestinal surgery as an alternative to behavioral and pharmaco- logic strategies for managing diabetes. 7 Bariatric surgery is undoubtedly the most effective treatment for severe obesity. 7 In addition, studies have shown dramatic improvements in type 2 diabetes and dyslipidemia in severely obese patients after gastric band- ing, roux-en-Y gastric bypass and biliopancreatic diver- sion surgeries. 7 Procedures involving bypass of the upper intestine produce greater normalization of glucose that precedes weight loss. 7 It has been postulated that the entry of nutrients into the distal small intestine after roux-en-Y or other intestinal bypass procedures elicits a neuroendocrine response that reduces glucose and lipid levels, inhibits feeding, and reduces weight and fat. 7 This so-called “ileal break” mechanism is thought to be medi- ated, at least partly, by hormones secreted by L-cells, such as glucagon-like peptide (GLP)-1 and peptide YY (PYY). 7 In this issue of GASTROENTEROLOGY, Cummings et al 8 have performed a comprehensive analysis of ileal inter- position (IT) surgery in a rat model that closely mimics the “metabolic syndrome” in humans. 8 The University of California at Davis Type 2 Diabetes Mellitus (UCD- T2DM) rat was created by crossing obese insulin-resis- tant Sprague-Dawley rats with Zucker diabetic fatty rats, which have a pancreatic -cell defect. In longitudinal studies, UCD-T2DM rats developed obesity, insulin re- sistance, and hyperinsulinemia, followed by reduction of insulin levels and progressive hyperglycemia, indicative of -cell failure. 9 Untreated diabetic UCD-T2DM rats de- velop glycosuria, polyuria, hyperphagia, and weight loss. Cummings et al performed IT surgery as previously de- scribed. 10 A midline incision was made under general anesthesia, and 10 cm of ileum segment located 5–10 cm proximal from the ileocecal valve was transected (Figure 1). 8 The remaining ends of the distal ileum were anasto- mosed. Next, the upper small intestine was transected 5–10 cm distal to the ligament of Treitz, and the ileal segment was then interposed with its vasculature and innervation intact (Figure 1). Sham surgery was per- formed by transecting similar locations as IT surgery and reanastomosing the intestinal segments to their original sites. IT surgery delayed the onset of diabetes compared with sham surgery. After 1 year, 38% of IT rats developed diabetes compared with 78% of sham rats. Food intake was not different between IT and sham groups after 5 months, but the sham group became hyperphagic as diabetes progressed. Body weight was similar in IT and sham rats until 6 months, when the sham group lost weight as a result of diabetes. However, at the prediabetic stage (2 months), body fat, adipocyte size, and ectopic accumulation of triglycerides in liver and muscle were reduced in IT rats. Glucose tolerance was improved in IT rats, and this was associated with enhanced insulin se- cretion, and elevation of plasma GLP 17–36 . Plasma PYY and expression of PYY in the intestine were increased in response to an oral lipid load in IT rats. Plasma bile acids, pancreatic -cell mass, and insulin content were in- creased after 2 months in IT rats. In contrast, gastric inhibitory peptide, ghrelin, and adiponectin levels were not altered substantially by IT surgery. Together, these results demonstrate that IT surgery improves glucose and lipid metabolism, and slows the development of type 2 diabetes. The studies would have benefitted from insulin clamp and tracer techniques to evaluate the effects of IT surgery on insulin sensitivity in liver, muscle, and fat. The mechanisms underlying how IT surgery affects lipid me- tabolism in adipose, muscle, and liver were not deter- mined. Furthermore, the authors proposed that GLP-1, PYY, and bile acids may be involved in the metabolic effects of IT surgery, but did not carry out experiments to prove this hypothesis. Editorials continued 2224