Kubosaki Atsutaka, Nakamura Shinichiro, Notkins Abner Louis
Experimental Medicine Section, Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Building 30/Room 106, 30 Convent Dr., MSC 4322, Bethesda, Maryland 20892-4322, USA.
Diabetes. 2005 Dec;54 Suppl 2:S46-51. doi: 10.2337/diabetes.54.suppl_2.s46.
IA-2 and IA-2beta are members of the transmembrane protein tyrosine phosphatase family located in dense core vesicles of neuroendocrine cells, including the beta-cells of pancreatic islets. In the present study, by mating C57BL/6Nci IA-2(+/-) with IA-2beta(+/-) mice, we generated double knockout mice (IA-2(-/-)/IA-2beta(-/-)) to study the effect of the combined deletion of these two proteins on insulin secretion and blood glucose levels. The double knockout mice appeared healthy at birth and showed normal growth and development. Histological examination and immunostaining for insulin, glucagon, somatostatin, and pancreatic polypeptide revealed no difference between the double knockout and wild-type mice. Nonfasting blood glucose and insulin levels also were within the normal range. However, compared with the wild-type mice, the double knockout mice showed glucose intolerance and an absent first-phase insulin release curve. No evidence of insulin resistance was observed nor were there alterations in fasting blood glucose, insulin, or leptin levels in the double knockout mice maintained on a high-fat diet compared with the wild-type mice maintained on the same diet. In addition, to determine whether the combined deletion of IA-2 and IA-2beta played any role in the development of diabetes in NOD mice, we generated double knockout mice on the NOD/LtJ background. The incidence of diabetes in these mice was not significantly different than that in the wild-type mice. Taken together, our experiments show that the dense core vesicle proteins IA-2 and IA-2beta, alone or in combination, are involved in insulin secretion, but neither alone nor in combination are they required for the development of diabetes in NOD mice.
IA-2和IA-2β是跨膜蛋白酪氨酸磷酸酶家族的成员，位于神经内分泌细胞的致密核心囊泡中，包括胰岛的β细胞。在本研究中，通过将C57BL/6Nci IA-2(+/-)与IA-2β(+/-)小鼠交配，我们培育出了双敲除小鼠（IA-2(-/-)/IA-2β(-/-)），以研究这两种蛋白的联合缺失对胰岛素分泌和血糖水平的影响。双敲除小鼠出生时看起来健康，生长发育正常。对胰岛素、胰高血糖素、生长抑素和胰多肽进行组织学检查和免疫染色发现，双敲除小鼠与野生型小鼠之间没有差异。非空腹血糖和胰岛素水平也在正常范围内。然而，与野生型小鼠相比，双敲除小鼠表现出葡萄糖不耐受且缺乏第一阶段胰岛素释放曲线。未观察到胰岛素抵抗的证据，与食用相同高脂饮食的野生型小鼠相比，双敲除小鼠空腹血糖、胰岛素或瘦素水平也没有改变。此外，为了确定IA-2和IA-2β的联合缺失是否在非肥胖糖尿病（NOD）小鼠的糖尿病发展中起任何作用，我们培育了NOD/LtJ背景的双敲除小鼠。这些小鼠的糖尿病发病率与野生型小鼠没有显著差异。综上所述，我们的实验表明，致密核心囊泡蛋白IA-2和IA-2β单独或联合参与胰岛素分泌，但它们单独或联合都不是NOD小鼠糖尿病发展所必需的。
