A novel approach to glycemic control in type 2 diabetes mellitus, partial jejunal diversion: pre-clinical to clinical pathway

Abstract

Objective: To explore partial jejunal diversion (PJD) via a side-to-side jejuno-jejunostomy for improved glycemic control in type 2 diabetes mellitus (T2DM). PJD is an anatomy-sparing, technically simple surgery in comparison to the predominate metabolic procedures, Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). Positive results in a rodent model prompted a human proof-of-concept study.

Research design and methods: Pre-clinically, 71 rats were studied in a model of metabolic dysfunction induced by a high-fat diet; 33 animals undergoing one of two lengths of PJD were compared with 18 undergoing sham, 10 RYGB and 10 jejuno-ileal bypass. Clinically, 15 adult subjects with treated but inadequately controlled T2DM (hemoglobin A1c (HbA1c) of 8.0%-11.0%), body mass index of 27.0-40.0 kg/m2, and C peptide ≥3 ng/mL were studied. Follow-up was at 2 weeks, and 3, 6, 9, and 12 months post-PJD.

Results: Pre-clinically, positive impacts with PJD on glucose homeostasis, cholesterol, and body composition versus sham control were demonstrated. Clinically, PJD was performed successfully without serious complications. Twelve months post-surgery, the mean (SD) reduction from baseline in HbA1c was 2.3% (1.3) (p<0.01).

Conclusions: PJD may provide an anatomy sparing, low-risk, intervention for poorly controlled T2DM without significant alteration of the patient's lifestyle. The proof-of-concept study is limited by a small sample size and advanced disease, with 80% of participants on insulin and a mean time since diagnosis of over 10 years. Further study is warranted.

Trial registration number: NCT02283632; Pre-results.

Keywords: Metabolic; Surgery; Type 2 Diabetes.

Conflict of interest statement

Competing interests: MF, KD, APC, and MH have nothing to declare. RJS currently receives funding from Ethicon, Inc. EJF, RS, MLS, and JRW are employed by Ethicon, Inc.

Figures

Figure 1

Body weight and oral glucose tolerance in diet-induced obese rats at 5 weeks post-surgery. Diet-induced obese rats underwent a sham (n=10) operation, 30 cm partial jejunal diversion (PJD) (n=8), 42 cm PJD (n=10), jejuno-ileal bypass (JIB) (n=10), or Roux-en-Y gastric bypass (RYGB) (n=9) surgery. (A) Body weight (g); (B) blood glucose in response to a 2-hour mixed meal tolerance test (MMTT, n=7–11 per group); (C) plasma GLP-1 (pg/mL, 8–10 per group); (D) plasma insulin (ng/mL, n=8–10); (E) 4-week lean mass (g, n=8–10 per group); F) 4-week fat mass (g, n=8–10 per group); (G) liver triglycerides (mg/dL). All data presented as mean±SE. Data were analyzed via one-way independent measures analysis of variance (ANOVA) or two-way ANOVA with time as a repeated measure, followed by Bonferroni multiple comparisons test where appropriate. *p

Figure 2

Key clinical efficacy outcomes for (A) hemoglobin A1c (HbA1c), (B) weight change. Data points are mean change from baseline absolute HbA1c (A) or mean change from baseline absolute body weight (B) and error bars represent SEM for n=15 patients. Data below the charts are absolute mean and median HbA1c (A) or mean and median % body weight reduction (*p