Leptin receptor deficiency causes intestinal hyperplasia and altered membrane abundance of glucose transporters

Abstract

Increasing evidence supports an important role for the small intestine in the control of glucose homeostasis and the pathogenesis of type 2 diabetes. We studied morphological changes in the small intestine and expression of the Na+/glucose transporter 1 (SLC5A1 or SGLT1) and glucose transporter 2 (SLC2A2 or GLUT2) in leptin receptor deficient (db/db; n=6) and control (db/con; n=10) mice. db/db mice were obese (47±1 vs 25±1 g; P<0.01), hyperglycemic (499±43 vs 126±5 mg/dl; P<0.01) and exhibited small intestinal hyperplasia vs db/con as determined by measuring total intestinal length (36.8±1.5 vs 30.0±0.7 cm; P<0.01). Moreover, db/db mice showed increased mucosal mass, including longer villi (673.0±14.3 vs 483.3±19.9 μm; P<0.01) and deeper crypts (112.0±1.7 vs 97.7±3.1 μm; P<0.01). Intestinal proliferation was quantified by staining for proliferating cell nuclear antigen (PCNA). Proliferation was higher in db/db vs db/con (1760±93 vs 1037±28 PCNA‐positive cells/100 crypts; P<0.01). Immunohistochemistry revealed decreased apical membrane abundance of SGLT1, but, in contrast, increased apical membrane abundance of GLUT2 in db/db vs. db/con. These findings suggest that changes in SGLT1 and GLUT2 are present under type 2 diabetic conditions and might contribute to a dysbalance in intestinal homeostasis ultimately leading to intestinal hyperplasia, a situation comparable to diabetic renal hypertrophy.