| First Author | Kato I | Year | 2008 |
| Journal | Diabetes Metab Res Rev | Volume | 24 |
| Issue | 6 | Pages | 486-97 |
| PubMed ID | 18551708 | Mgi Jnum | J:146048 |
| Mgi Id | MGI:3836545 | Doi | 10.1002/dmrr.864 |
| Citation | Kato I, et al. (2008) A novel model of insulin-dependent diabetes with renal and retinal lesions by transgenic expression of CaMKIIalpha (Thr286Asp) in pancreatic beta-cells. Diabetes Metab Res Rev 24(6):486-97 |
| abstractText | BACKGROUND: The activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in pancreatic beta-cells has been thought to play a central role in Ca2+-mediated insulin secretion. However, the physiological and pathological significance of CaMKII activation in pancreatic beta-cells has never been investigated in vivo. METHODS: We generated transgenic (TG) mice overexpressing the constitutively active-type CaMKIIalpha (Thr286Asp) in beta-cells. The mice were extensively examined histologically and biochemically. Time-course changes of blood glucose, haemoglobin A1C and insulin were also determined. RESULTS: Western blot and immunohistochemical analyses showed overexpression of CaMKIIalpha proteins in pancreatic beta-cells of TG mice. All TG mice developed severe hypoinsulinaemic diabetes by P28. In vivo BrdU labelling analysis revealed that cell proliferation in TG islets is severely impaired. Immunohistochemical examination revealed accumulations of NF-kappaB in nuclei of TG beta-cells at P21, which are associated with DNA laddering, a hallmark of apoptosis. At P28, pancreatic and serum insulin levels were both significantly (p < 0.05) lower in TG mice (0.037 +/- 0.005 ng/microg and 0.50 +/- 0.01 ng/mL) than in wild-type mice (0.997 +/- 0.093 ng/microg and 2.50 +/- 0.22 ng/mL). TG mice at P140 showed enlargement of kidney, mesangial expansion and glomerulosclerosis, which are associated with urinary albumin excretion. TG mice at P140-P168 developed severe retinal lesions such as disrupted ganglion cells and showed a flat pattern in electroretinography. CONCLUSIONS: The TG mice established herein will be valuable as a novel model of severe insulin-dependent diabetes accompanied by an early progression of diabetic micro-vascular complications. |
