Calmodulin overexpression causes Ca(2+)-dependent apoptosis of pancreatic beta cells, which can be prevented by inhibition of nitric oxide synthase.
We investigated the mechanism of beta-cell loss in transgenic mice with elevated levels of beta cell calmodulin. The transgenic mice experienced a sudden rise in blood glucose levels between 21 and 28 days of age. This change was associated with development of severe hypoinsulinemia and loss of beta cells from the islets. Ultrastructural analysis revealed that compromised granule formation and apoptotic changes in the transgenic beta cells preceded the onset of hyperglycemia. Intraperitoneal injection of tolbutamide, an antidiabetic sulfonylurea, decreased blood glucose levels but increased the number of apoptotic beta cells. Finally, injection of transgenic mice with N(omega)-nitro-L-arginine methyl ester, which inhibits nitric oxide synthase activity, prevented hyperglycemia and lessened the changes in number and size of beta cells. Because immunofluorescent staining revealed preferential distribution of neural nitric oxide synthase in pancreatic beta cells, we speculate that overexpression of calmodulin sensitizes the beta cells to Ca(2+)-dependent activation of neural nitric oxide synthase, which mediates apoptosis.
Yu
Wei
W
Department of Anatomy, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan.
Niwa
Tae
T
Miura
Yoshitaka
Y
Horio
Fumihiko
F
Teradaira
Shin
S
Ribar
Thomas J
TJ
Means
Anthony R
AR
Hasegawa
Yoshimi
Y
Senda
Takao
T
Niki
Ichiro
I
D000818:Animals; D017209:Apoptosis; D001786:Blood Glucose / Q000032:analysis; D002118:Calcium / Q000378:metabolism*; D002147:Calmodulin / Q000032:analysis / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D007515:Islets of Langerhans / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D051379:Mice; D008856:Microscopy, Fluorescence; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000032:analysis / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D011863:Radioimmunoassay
D001786:Blood Glucose; D002147:Calmodulin; D004791:Enzyme Inhibitors; D007328:Insulin; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D002118:Calcium; D019331:NG-Nitroarginine Methyl Ester