Duodenal-jejunal bypass protects GK rats from β-cell loss and aggravation of hyperglycemia and increases enteroendocrine cells coexpressing GIP and GLP-1

Abstract

Speck M, Cho YM, Asadi A, Rubino F, Kieffer TJ. Duodenaljejunal bypass protects GK rats from ␤-cell loss and aggravation of hyperglycemia and increases enteroendocrine cells coexpressing GIP and GLP-1. Am J Physiol Endocrinol Metab 300: E923-E932, 2011. First published February 8, 2011 doi:10.1152/ajpendo.00422.2010.-Dramatic improvement of type 2 diabetes is commonly observed after bariatric surgery. However, the mechanisms behind the alterations in glucose homeostasis are still elusive. We examined the effect of duodenal-jejunal bypass (DJB), which maintains the gastric volume intact while bypassing the entire duodenum and the proximal jejunum, on glycemic control, ␤-cell mass, islet morphology, and changes in enteroendocrine cell populations in nonobese diabetic Goto-Kakizaki (GK) rats and nondiabetic control Wistar rats. We performed DJB or sham surgery in GK and Wistar rats. Blood glucose levels and glucose tolerance were monitored, and the plasma insulin, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) levels were measured. ␤-Cell area, islet fibrosis, intestinal morphology, and the density of enteroendocrine cells expressing GLP-1 and/or GIP were quantified. Improved postprandial glycemia was observed from 3 mo after DJB in diabetic GK rats, persisting until 12 mo after surgery. Compared with the sham-GK rats, the DJB-GK rats had an increased ␤-cell area and a decreased islet fibrosis, increased insulin secretion with increased GLP-1 secretion in response to a mixed meal, and an increased population of cells coexpressing GIP and GLP-1 in the jejunum anastomosed to the stomach. In contrast, DJB impaired glucose tolerance in nondiabetic Wistar rats. In conclusion, although DJB worsens glucose homeostasis in normal nondiabetic Wistar rats, it can prevent long-term aggravation of glucose homeostasis in diabetic GK rats in association with changes in intestinal enteroendocrine cell populations, increased GLP-1 production, and reduced ␤-cell deterioration. bariatric surgery; Goto-Kakizaki rat; diabetes mellitus; glucose homeostasis; glucagon-like peptide-1; glucose-dependent insulinotropic polypeptide; K cells; L cells; pancreatic and duodenal homoeobox 1; paired box gene 6

Gastric Bypass Improves β-Cell Function and Increases β-Cell Mass in a Porcine Model

“…Occurrence of such cells are, at least in rodents, suggested to be associated with increased islet number and neogenesis (13). Increased b-cell mass is a novel finding and in line with the long-term effects of duodenal-jejunal bypass in GK rats reported by Speck et al (20). Although it has been reported that RYGB increases the incidence of nesidioblastosis (21), attempts to study the effects of bariatric surgery on b-cell mass in humans are few and provide conflicting results.…”

Duodenal-Jejunal Bypass and Jejunectomy Improve Insulin Sensitivity in Goto-Kakizaki Diabetic Rats Without Changes in Incretins or Insulin Secretion

“…However, clinical and experimental data from studies of stomach-sparing procedures, such as duodenal-jejunal bypass (DJB) (3,4,10,(13)(14)(15), endoluminal duodenal sleeve (16,17), ileal-interposition (18,19), jejuno-ileal bypass (20), and jejunectomy (21), show that these approaches can improve type 2 diabetes with relatively minor changes in body weight (22).…”

Phenotype of entero‐endocrine L cells becomes restricted during development

“…A high number of LK cells also differentiate in the small intestine of mice and of humans with metabolic disorders (Theodorakis et al, 2006;Grigoryan et al, 2012) and after anatomical re-arrangement of the small intestine (Speck et al, 2011) suggesting the presence, in these models, of signals that activate LK cell growth. Perhaps similar mechanisms lead to the development of LK cell hyperplasia in embryos.…”

“…Analysis of changes in L and LK cell populations along the small intestine in normal mice (Habib et al, 2012), in ileum of mutant mice lacking the glucagon receptor (GcgrÀ/À) (Grigoryan et al, 2012), and in small intestine of rats following bariatric surgery (Patriti et al, 2007;Kohli et al, 2011;Speck et al, 2011;Woods et al, 2011) suggests an important effect of nutrients and other extrinsic cues on LK, L, and K cell number. Since in embryos, the intestine is not exposed to external cues, we speculated that the proportion of these three cell types could differ from that in adult small intestine.…”