Successful modulation of type 2 diabetes in db/db mice with intra-bone marrow--bone marrow transplantation plus concurrent thymic transplantation.
There is increasing evidence that both autoimmune and autoinflammatory mechanisms are involved in the development of not only type 1 diabetes mellitus (T1 DM), but also type 2 diabetes mellitus (T2 DM). Our laboratory has focused on this concept, and in earlier efforts replaced the bone marrow cells (BMCs) of leptin receptor-deficient (db/db) mice, an animal model of T2DM, with those of normal C57BL/6 (B6) mice by IBM-BMT. However, the outcome was poor due to incomplete recovery of T cell function. Therefore, we hypothesized that intra-bone marrow-bone marrow transplantation plus thymus transplantation (IBM-BMT + TT) could be used to treat T2 DM by normalizing the T cell imbalance. Hence we addressed this issue by using such dual transplantation and demonstrate herein that seven weeks later, recipient db/db mice manifested improved body weight, reduced levels of blood glucose, and a reduction of plasma IL-6 and IL-1β. More importantly, this treatment regimen showed normal CD4/CD8 ratios, and increased plasma adiponectin levels, insulin sensitivity, and the number of insulin-producing cells. Furthermore, the expression of pancreatic pAKT, pLKB1, pAMPK and HO-1 was increased in the mice treated with IBM-BMT + TT. Our data show that IBM-BMT + TT treatment normalizes T cell subsets, cytokine imbalance and insulin sensitivity in the db/db mouse, suggesting that IBM-BMT + TT is a viable therapeutic option in the treatment of T2 DM.
Li
Ming
M
Department of Stem Cell Disorders, Kansai Medical University, Moriguchi City, Osaka 570-8506, Japan.
Abraham
Nader G
NG
Vanella
Luca
L
Zhang
Yuming
Y
Inaba
Muneo
M
Hosaka
Naoki
N
Hoshino
Sho-Ichi
S
Shi
Ming
M
Ambrosini
Yoko Miyamoto
YM
Gershwin
M Eric
ME
Ikehara
Susumu
S
D052242:Adiponectin / Q000097:blood; D000818:Animals; D001786:Blood Glucose / Q000096:biosynthesis / Q000235:genetics; D016026:Bone Marrow Transplantation; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000276:immunology* / Q000628:therapy*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D007167:Immunotherapy; D050417:Insulin-Secreting Cells / Q000473:pathology; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D054411:Receptors, Leptin / Q000172:deficiency; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D013950:Thymus Gland / Q000637:transplantation*
D052242:Adiponectin; C499919:Adipoq protein, mouse; D001786:Blood Glucose; D053583:Interleukin-1beta; D015850:Interleukin-6; D054411:Receptors, Leptin