Effect of Duodenal-Jejunal Exclusion in a Non-Obese Animal Model of Type 2 Diabetes: A New Perspective for an Old Disease

To the Editor:

I found the article by Rubino and Marescaux¹ very interesting. The author investigated the effect of surgery on type 2 diabetes observed in cases of obese patients with type 2 diabetes who underwent Roux-en-Y gastric bypass (GBP) and biliopancreatic diversion (BPD).^2–6

To determine if long-term control of blood glucose following surgery was due to the treatment of obesity or to alterations in the enteroinsular axis induced by duodenal-jejunal exclusion, a gastrojejunal bypass (GJB) was performed on non-obese rats with type 2 diabetes. After treatment, reduced fasting glycemia was observed at an even higher level with respect to a control group treated with Rosiglitazone, with increased glucose tolerance, better insulin sensitivity, and lower levels of FFA and cholesterol. More importantly, blood glucose control was achieved in non-obese rats without any postoperative weight loss. This experimental model definitively demonstrates that reduced fasting glycemia and insulin resistance, as well as improved glucose tolerance are attributable to surgery rather than solely to weight loss.¹

We would like to point out that this concept has already been demonstrated in a series published by Noya et al in 1998, presenting a case study of 10 moderately obese patients (mean BMI of 33.20 kg/m²) who underwent biliopancreatic diversion preserving the stomach and pylorus, a duodenal-jejunal switch without the restrictive gastric surgery as that proposed by Rubino in his paper, to treat hypercholesterolemia, hypertriglyceridemia and type 2 diabetes mellitus. In all treated patients, cholesterol and triglyceride levels normalized and blood glucose stabilized within normal range in 9 patients during the first few weeks postoperatively, despite the fact that no dietary restrictions were applied and before a significant weight loss was gained.⁷

Rubino attributed the result of diabetes control to duodenal-jejunal exclusion, suggesting a potential role of the proximal gut in the pathogenesis of the disease and putting forward the possibility of alternative therapeutic approaches for the management of type 2 diabetes.¹ In fact, he has focused attention on glucose-dependent-insulinotropic peptide (GIP) a secretin produced by the duodenal K-cells that presents a marked decrease in its insulinotropic effect in type 2 diabetic patients.^1,8

Though GJB has not produced significant changes on its secretion, the author proposes that the deficit of the enteroinsular system corrected by surgery lies in the bypassed duodenal-jejunal tract. Instead, we believe that the physiopathology of Glucagon-like Peptide 1 (GLP- 1), a secretin produced by the l-cells of the terminal ileum in patients with type 2 diabetes mellitus, and its alterations following surgery can provide a more likely explanation for the resolution of diabetes observed by Rubino.

GLP-1 is a peptide secreted by the l-cells of the terminal ileum in response to nutrients and neural stimuli. It exerts a powerful insulinotropic action, the so-called incretin effect, delays gastric emptying, increases satiety and fullness, and has anabolic, glycogenic and lipogenic actions on liver, fatty and muscle tissues.⁹

In type 2 diabetic patients, the incretin effect of GLP-1 is diminished or disappears entirely, as occurs with GIP, therefore the deficit of entero-insular axis theorized by Rubino has been already demonstrated.¹⁰

Radioimmunoassay of GLP-1 has shown that this event can be attributed to its reduced secretion in both basal conditions and postprandially. Oral glucose load during a euglycemic hyperinsulinemic clamp has demonstrated that there is a lower rate of GLP-1_7-36amide in obese patients with type 2 diabetes both before and after load.¹¹

A reduced GLP-1 response was also observed following a mixed meal in obese patients with type 2 diabetes, as compared with a control group of normoglycemic obese patients.^12,13 The secretion of GIP, on the other hand, is normal in type 2 diabetic patients, but its effect is lost.¹⁰ The reduced incretin effect of GLP-1 can in fact be attributable to impaired secretion, whereas with GIP the reduced effect can be attributed to a defect of its receptors and this makes GIP useless as a hormone for treating type 2 diabetes.⁸

Moreover, each surgical procedure (jejunoileal bypass, GBP, BPD) that produces the early arrival of food at the terminal ileum triggers the hypersecretion of GLP-1 and accompanies the resolution of type 2 diabetes mellitus, as noted in animal models and in humans.^14–18 Therefore, it is our opinion that GJB has had such an effect on diabetes, as reported by Rubino, because of early arrival of indigested food in the terminal ileum and the consequent stimulation of GLP-1 secretion.

In accordance with Mason, new research prospects are open for surgical methods that can increase GLP-1 secretion even in normal-weight or moderately obese patients:¹⁷ GJB, as proposed by Rubino in animal models and by Noya in humans, may represent one of these methods. This becomes particularly important due to the fact that pharmacological research is trying to develop GLP-1 synthetic analogs with a clinical application for the treatment of type 2 diabetes mellitus. However, their therapeutic utility is still limited by their short half-life (1–2 minutes).¹⁹

Alberto Patriti, MD
Enrico Facchiano, MD
Annibale Donini, MD
University of Perugia
Perugia, Italy
a.donini@ospedale.perugia.it