| First Author | Sasaki H | Year | 2011 |
| Journal | Biochem Biophys Res Commun | Volume | 408 |
| Issue | 2 | Pages | 306-11 |
| PubMed ID | 21513702 | Mgi Jnum | J:172202 |
| Mgi Id | MGI:5004993 | Doi | 10.1016/j.bbrc.2011.04.026 |
| Citation | Sasaki H, et al. (2011) Acceleration of autoimmune diabetes in Rheb-congenic NOD mice with beta-cell-specific mTORC1 activation. Biochem Biophys Res Commun 408(2):306-11 |
| abstractText | The protein Ras homolog enriched in brain (Rheb) is a Ras-like small GTPase that activates the mechanistic target of rapamycin complex 1 (mTORC1), which promotes cell growth. We previously generated transgenic C57BL/6 mice overexpressing Rheb in beta-cells (B6(Rheb)), which exhibited increased beta-cell size and improved glucose tolerance with higher insulin secretion than wild type C57BL/6 mice. The mice also showed resistance to obesity-induced hyperglycemia, a model of type 2 diabetes, and to multiple low-dose-streptozotocin (MLDS)-induced hyperglycemia, a model of type 1 diabetes (T1D). To investigate whether the effects of mTORC1 activation by Rheb in B6(Rheb) mice would also be evident in NOD mice, a spontaneous autoimmune T1D model, we created two NOD mouse lines overexpressing Rheb in their beta-cells (NOD(Rheb); R3 and R20). We verified Rheb overexpression in beta-cells, the relative activation of mTORC1 and beta-cell enlargement. By 35weeks of age, diabetes incidence was significantly greater in the R3 line and tended to be greater in the R20 line than in NOD mice. Histological analysis demonstrated that insulitis was significantly accelerated in 12-week-old R3 NOD(Rheb) mice compared with NOD mice. Furthermore, serum insulin autoantibody (IAA) expression was significantly higher than that of NOD mice. We also examined whether complete Freund's adjuvant (CFA) treatment alone or with glucagon-like peptide-1 (GLP-1) analog would reverse the hyperglycemia of NOD(Rheb) mice; unexpectedly, almost none achieved normoglycemia. In summary, diabetes progression was significantly accelerated rather than prevented in NOD(Rheb) mice. Our results suggest that the beta-cell enlargement might merely enhance the autoimmunity of pathogenic T-cells against islets, leading to acceleration of autoimmune diabetes. We conclude that not only enlargement but also regeneration of beta-cells in addition to the prevention of beta-cell destruction will be required for the ideal therapy of autoimmune T1D. |
