Dense Core Vesicle Proteins IA-2 and IA-2β

Metabolic Alterations in Double Knockout Mice

  1. Atsutaka Kubosaki,
  2. Shinichiro Nakamura and
  3. Abner Louis Notkins
  1. From the Experimental Medicine Section, Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland
  1. Address correspondence and reprint requests to Abner L. Notkins, MD, National Institutes of Health, Building 30/Room 106, 30 Convent Dr., MSC 4322, Bethesda, MD 20892-4322. E-mail: anotkins{at}mail.nih.gov

Abstract

IA-2 and IA-2β are members of the transmembrane protein tyrosine phosphatase family located in dense core vesicles of neuroendocrine cells, including the β-cells of pancreatic islets. In the present study, by mating C57BL/6Nci IA-2+/− with IA-2β+/− mice, we generated double knockout mice (IA-2−/−/IA-2β−/−) 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-2β 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-2β, 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.

Footnotes

  • This article is based on a presentation at a symposium. The symposium and the publication of this article were made possible by an unrestricted educational grant from Servier.

    DCV, dense core vesicle; DKO, double knockout.

    • Accepted May 11, 2005.
    • Received March 3, 2005.
| Table of Contents