Did the Gradual Loss of GLUT2 Cause a Shift to Diabetic Disorders in the New Zealand Obese Mouse (NZO/Hl)?

Abstract

The New Zealand obese mouse (NZO/Hl) is characterised by hereditary obesity and type-2 diabetes, including insulin resistance, hyperinsulinaemia, and glucose intolerance. In other diabetic models, it has been revealed that the proper functioning of the glucose transporter isoform 2 (GLUT2) is essential for adequate secretion of insulin. The aim of this study was to compare the distribution of islet cells and GLUT2, as well as the expression of Glut2-mRNA, in the pancreas of NZO mice and metabolically unimpaired NMRI (Naval Medical Research Institute) mice. Pancreas tissue was obtained from different stages of development. For molecular determination of the expression level of Glut2-mRNA, total-RNA was extracted from the pancreas and analysed by quantitative real-time RT-PCR. All investigated NZO mice displayed increased weight, elevated hyperinsulinaemia, and slightly enhanced blood glucose levels compared with the NMRI control mice. By means of immunofluorescence microscopy drastically reduced insulin levels were detected, which might be compensated by the observed islet cell hyperplasia and hypertrophy. Furthermore, the normally peripheral localisation of the α-cells within islets was disturbed. By contrast, there were no changes in somatostatin cell distribution. However, considerable differences appeared with regard to GLUT2: whereas the β-cells of NMRI mice showed dense immunostaining of the GLUT2 transporter on the cell surface, in all age groups of NZO mice, GLUT2 on the plasma membranes was reduced and dispersed in the cytoplasm. These findings agree with the molecular biological results, which displayed decreased mRNA-expression of Glut2. In summary, the observed alteration of islet morphology and of Glut2 expression in diabetic mice complements our previous results from a superfusion protocol and further clarifies the mechanisms of diabetogenesis in NZO mice.

Key words

GLUT2 - diabetes - New Zealand obese mouse - β-cells - hyperinsulinaemia

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