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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Figure 5

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In vivo proliferation and apoptosis rates and expression of E2F1. (A) Re...
In vivo proliferation and apoptosis rates and expression of E2F1. (A) Representative micrograph showing BrdU immunostaining of pancreatic sections from E2F1_/_ and E2F1+/+ 2-week-old mice. The percentage of BrdU-positive cells is indicated. Results are the mean of the summed numbers from ten sections of each pancreas from five mice per genotype. (B and C) Phosphohistone H3 (PH3) immunofluorescent labeling in pancreatic sections of either E2F1+/+ or E2F1_/_ mice. Nuclei are stained by Hoechst. Percentage of phosphohistone H3_positive cells is indicated (B). (D) Quantification of the expression by real-time RT-PCR of relevant E2F target genes in isolated islets. Results were normalized by the expression of the 18S ribosomal subunit RNA. Cyc E, cyclin E; cycD1, cyclin D; TK, thymidin kinase. (E) Percentage of apoptotic cells as measured by TUNEL assay in pancreatic sections of E2F1_/_ and E2F1+/+ 16-week-old mice. (F) Insulin (Ins) (red: β cells) and glucagon (Gluc) (green: α cells) immunostaining of pancreatic islets in E2F1_/_ and E2F1+/+ 16-week-old mice. (G) Quantification of the β cell area in arbitrary (arb.) units (left panel) and the α/β cell ratio (right panel) in pancreatic sections of E2F1_/_ and E2F1+/+ mice. At least 50 pancreatic sections from different mice were analyzed after immunostaining for insulin and glucagon. Areas were calculated using the Canvas 9 software in arbitrary units. (H) Quantification of the glucagon/insulin ratio in the serum of E2F1_/_ and E2F1+/+ male 16-week-old mice. *Statistically significant differences (ANOVA, P < 0.005).