Duodenal-jejunal exclusion improves glucose tolerance in the diabetic, Goto-Kakizaki rat by a GLP-1 receptor-mediated mechanism.
BACKGROUND
Gastric bypass results in the rapid resolution of type 2 diabetes. No causal evidence exists to link specific gut hormone changes with improvements in glucose homeostasis post-operatively. We hypothesized that surgical augmentation of the glucoregulatory factor GLP-1 would improve glucose tolerance in diabetic GK rats. We compared two procedures that increase distal small bowel stimulation, ileal interposition (IT), and duodenal-jejunal exclusion (DJE).


METHODS
DJE, IT, DJE Sham, or IT Sham were performed in GK rats. Glucose tolerance was tested at 4 and 6 weeks, the latter with and without Exendin-[9-39], a GLP-1 receptor antagonist. Small bowel segments were harvested for GLP-1 protein content 2 weeks after DJE or Sham surgery.


RESULTS
Despite similar weight profiles, a significant improvement in the OGTT was noted at 4 weeks after DJE and IT. Plasma GLP-1 levels were significantly elevated after DJE and IT. Intestinal GLP-1 was increased in the mid-jejunum and ileum after DJE. Exendin-[9-39] abolished the improvement in glucose tolerance after DJE.


CONCLUSIONS
DJE increased GLP-1 secretion and improved glucose tolerance, an effect that was reversed by GLP-1 receptor antagonism. This study provides direct evidence that improvement of glucose tolerance following a gastric bypass-like surgery is mediated by enhanced GLP-1 action.
Kindel
Tammy L
TL
Department of Pathology and Laboratory Medicine, Genome Research Institute, University of Cincinnati, 2180 E. Galbraith Road, Cincinnati, OH, USA. venematl@email.uc.edu
Yoder
Stephanie M
SM
Seeley
Randy J
RJ
D'Alessio
David A
DA
Tso
Patrick
P
D000818:Animals; D050110:Bariatric Surgery / Q000379:methods*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000601:surgery; D004195:Disease Models, Animal; D004386:Duodenum / Q000601:surgery*; D015390:Gastric Bypass; D000067757:Glucagon-Like Peptide-1 Receptor; D018149:Glucose Intolerance / Q000378:metabolism* / Q000601:surgery; D007082:Ileum / Q000601:surgery; D007583:Jejunum / Q000601:surgery*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D018027:Receptors, Glucagon / Q000378:metabolism*
C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D018027:Receptors, Glucagon