A novel model of insulin-dependent diabetes with renal and retinal lesions by transgenic expression of CaMKIIα (Thr286Asp) in pancreatic β-cells

Ichiro Kato, Takeshi Oya, Hikari Suzuki, Kumi Takasawa, Andi M. Ichsan, Shinji Nakada, Yoko Ishii, Yutaka Shimada, Masakiyo Sasahara, Kazuyuki Tobe, Shin Takasawa, Hiroshi Okamoto, Koichi Hiraga

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

Abstract

Background: The activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in pancreatic β-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 β-cells has never been investigated in vivo. Methods: We generated transgenic (TG) mice overexpressing the constitutively active-type CaMKIIα (Thr286Asp) in β-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 CaMKIIα proteins in pancreatic β-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-κB in nuclei of TG β-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/μg and 0.50 ± 0.01 ng/mL) than in wild-type mice (0-997 ± 0.093 ng/μg 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.

Original languageEnglish
Pages (from-to)486-497
Number of pages12
JournalDiabetes/Metabolism Research and Reviews
Volume24
Issue number6
DOIs
Publication statusPublished - 2008 Sep

Keywords

  • Animal model
  • Ca/calmodulin-dependent protein kinase II
  • Insulin
  • Insulin-dependent diabetes
  • Transgenic mice

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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