How the hindgut can cure type 2 diabetes. Ileal transposition improves glucose metabolism and beta-cell function in Goto-kakizaki rats through an enhanced Proglucagon gene expression and L-cell number.
BACKGROUND
It has been hypothesized that glucagon-like peptide-1 (GLP-1), secreted by ileal L cells, plays a key-role in the resolution of type 2 diabetes after bariatric operations whose common feature is an expedite nutrient delivery to the hindgut. Ileal transposition (IT), an operation that permits L-cell stimulation by undigested food, was employed to verify this theory.


METHODS
IT was carried out in Goto-Kakizaki (GK) type 2 diabetic rats and in euglycemic Sprague-Dawley (SD) rats. Glucose tolerance, insulin resistance, food-intake, body weight, pancreas morphology, and function were evaluated to track the effects of IT on diabetes. Intact GLP-1 secretion and gene expression pattern of the transposed ileum were investigated to verify the molecular bases of the hindgut action.


RESULTS
In GK rats, IT significantly improved glucose tolerance, insulin sensitivity, and acute insulin response without affecting body weight and food intake. Immunohistochemistry revealed remodeled islets strictly resembling that of euglycemic rats and signs of beta-cell neogenesis starting with exocrine structures. GLP-1 secretion in GK transposed rats was characterized by a more sustained response to oral glucose compared with nontreated rats. Gene expression of Proglucagon, Proconvertase 1/3 (PC1/3), and Chromogranin A in the transposed ileum significantly enhanced. Effects on glucose metabolism and pancreas morphology were not observed in the euglycemic rats as a consequence of the glucose-dependent action of GLP-1.


CONCLUSIONS
This study gives strong evidences for the crucial role of the hindgut in the resolution of diabetes after Roux-en-Y gastric bypass (GBP) and biliopancreatic diversion (BPD). Moreover, these findings confirm at the preclinical level that IT is a surgical procedure of possible relevance in the therapy of type 2 diabetes in non-overweight and mildly obese patients.
Patriti
Alberto
A
Department of Surgery, Section of General and Emergency Surgery, University of Perugia, Perugia, Italy. albertopatriti@gmail.com
Aisa
Maria Cristina
MC
Annetti
Claudia
C
Sidoni
Angelo
A
Galli
Francesco
F
Ferri
Ivana
I
Gullà
Nino
N
Donini
Annibale
A
D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D053379:Chromogranin A / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000378:metabolism* / Q000473:pathology / Q000601:surgery*; D004435:Eating; D019858:Enteroendocrine Cells / Q000473:pathology*; D015870:Gene Expression; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D005947:Glucose / Q000008:administration & dosage / Q000494:pharmacology; D005951:Glucose Tolerance Test; D007082:Ileum / Q000601:surgery*; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D052336:Proglucagon / Q000235:genetics / Q000378:metabolism*; D045664:Proprotein Convertase 1 / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D017207:Rats, Sprague-Dawley; D015430:Weight Gain
D001786:Blood Glucose; D053379:Chromogranin A; D012333:RNA, Messenger; D052336:Proglucagon; D052216:Glucagon-Like Peptide 1; D045664:Proprotein Convertase 1; D005947:Glucose