Abstract
The aim of this study was to examine postnatal islet and beta-cell expansion in healthy female control mice and its disturbances in diabetic GIPRdn transgenic mice, which exhibit an early reduction of beta-cell mass. Pancreata of female control and GIPRdn transgenic mice, aged 10, 45, 90 and 180 days were examined, using state-of-the-art quantitative-stereological methods. Total islet and beta-cell volumes, as well as their absolute numbers increased significantly until 90 days in control mice, and remained stable thereafter. The mean islet volumes of controls also increased slightly but significantly between 10 and 45 days of age, and then remained stable until 180 days. The total volume of isolated beta-cells, an indicator of islet neogenesis, and the number of proliferating (BrdU-positive) islet cells were highest in 10-day-old controls and declined significantly between 10 and 45 days. In GIPRdn transgenic mice, the numbers of islets and beta-cells were significantly reduced from 10 days of age onwards vs. controls, and no postnatal expansion of total islet and beta-cell volumes occurred due to a reduction in islet neogenesis whereas early islet-cell proliferation and apoptosis were unchanged as compared to control mice. Insulin secretion in response to pharmacological doses of GIP was preserved in GIPRdn transgenic mice, and serum insulin to pancreatic insulin content in response to GLP-1 and arginine was significantly higher in GIPRdn transgenic mice vs. controls. We could show that the increase in islet number is mainly responsible for expansion of islet and beta-cell mass in healthy control mice. GIPRdn transgenic mice show a disturbed expansion of the endocrine pancreas, due to perturbed islet neogenesis.
Highlights
The functional pancreatic beta-cell mass is critical for adequate insulin secretion, and maintenance of glucose homeostasis
The aims of this study were to analyze the postnatal development of total numbers and mean volumes of islets and beta-cells of female control mice (CD1 outbred genetic background), and to determine the morphological features of disrupted postnatal beta-cell mass expansion of diabetic mice, expressing a dominant negative glucose-dependent insulinotropic polypeptide receptor (GIPRdn), using unbiased quantitative-stereological methods
Since our previous investigations [12] revealed no difference in the development of total islet and beta-cell volumes between male and female control mice and since the phenotype of GIPRdn transgenic mice is not influenced by gender, one gender was chosen for analyses
Summary
The functional pancreatic beta-cell mass is critical for adequate insulin secretion, and maintenance of glucose homeostasis. Beta-cell mass is dynamic throughout life and may adapt to meet the actual demand [1]. There are some conflicting data in literature about the dynamics of numbers and mean volumes of islets and beta-cells, but it seems generally believed that islet number is fixed in postnatal life, whereas mean islet size is thought to increase (islet hypertrophy) with age or increasing demand [2,3,4,5]. The aims of this study were to analyze the postnatal development of total numbers and mean volumes of islets and beta-cells of female control mice (CD1 outbred genetic background), and to determine the morphological features of disrupted postnatal beta-cell mass expansion of diabetic mice, expressing a dominant negative glucose-dependent insulinotropic polypeptide receptor (GIPRdn), using unbiased quantitative-stereological methods
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