Impaired pancreatic growth, β cell mass, and β cell function in E2F1 –/– mice
Lluis Fajas, … , Mitsuhiro Watanabe, Johan Auwerx
Lluis Fajas, … , Mitsuhiro Watanabe, Johan Auwerx
Published May 1, 2004
Citation Information: J Clin Invest. 2004;113(9):1288-1295. https://doi.org/10.1172/JCI18555.
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Article Metabolism

Impaired pancreatic growth, β cell mass, and β cell function in E2F1 –/– mice

Abstract

We evaluated the effects of E2F1 on glucose homeostasis using E2F1–/– mice. E2F1–/– mice show an overall reduction in pancreatic size as the result of impaired postnatal pancreatic growth. Furthermore, these animals have dysfunctional β cells, linked to impaired PDX-1 activity. Because of the disproportionate small pancreas and dysfunctional islets, E2F1–/– mice secrete insufficient amounts of insulin in response to a glucose load, resulting in glucose intolerance. Despite this glucose intolerance, E2F1–/– mice do not develop overt diabetes mellitus because they have insulin hypersensitivity, which is secondary to a diminished adipose tissue mass and altered adipocytokine levels, which compensates for the defect in insulin secretion. These data demonstrate that factors controlling cell proliferation, such as E2F1, determine pancreatic growth and function, subsequently affecting metabolic homeostasis.

Authors

Lluis Fajas, Jean-Sébastien Annicotte, Stéphanie Miard, David Sarruf, Mitsuhiro Watanabe, Johan Auwerx

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PDX-1 expression and insulin secretion of islets of E2F1_/_ and E2F1+/+ ...
PDX-1 expression and insulin secretion of islets of E2F1_/_ and E2F1+/+ mice. (A) In situ hybridization of E2F1 or PDX-1 in sections of 12.5 or 16.5 dpc embryos. Location of liver (liv), stomach, skin, lung, pancreas (panc), intestine (int), and dorsal root ganglion (rg) in the embryo is indicated. (B) Immunofluorescence analysis of PDX-1 expression (green) in insulin-producing cells (red) of pancreatic sections of E2F1+/+ or E2F1_/_ 16-week-old mice. (C) Quantification (500 cells) of insulin-producing cells, which also expressed PDX-1. Results are relative to total number of insulin-producing cells. (D) Cellular localization of PDX-1 expression (green) in pancreatic β cells. Hoechst staining of nuclei is in blue. (E) Quantification of the expression by real-time RT-PCR of relevant genes for pancreatic islet development or function. Results were normalized by the expression of the 18S ribosomal subunit RNA. (F) Insulin secretion of isolated islets of E2F1+/+ or E2F1_/_ mice in the absence or presence of 5, 10, or 15 mM glucose. Islets were isolated from 16-week-old male mice. Results are relative to total DNA and insulin content. tot ins, total insulin.