Prevention of type I diabetes in NOD mice by nonhypercalcemic doses of a new structural analog of 1,25-dihydroxyvitamin D3, KH1060.
Pharmacological amounts of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] have potent immunoregulatory activity, but with marked effects on calcium and bone metabolism. In this study we demonstrate that nonhypercalcemia-inducing nondemineralizing doses of an analog of 1,25-(OH)2D3, 1 alpha,25-(OH)2-20-epi-22-oxa-24,26,27-trishomo-vitamin D (KH1060), can prevent type I diabetes. Female NOD mice received 1,25-(OH)2D3 (5 micrograms/kg), KH1060 (0.4 or 0.2 micrograms/kg), or the treatment vehicle ip every 2 days from 21-200 days of age. The incidence of diabetes in controls was 17 of 31 (55%), whereas 7 of 38 (18%) 1,25-(OH)2D3-treated mice, 3 of 27 (11%) KH1060 (0.4 micrograms/kg)-treated mice, and 6 of 27 (22%) KH1060 (0.2 micrograms/kg)-treated mice developed diabetes (P < 0.025 vs. controls). Protection was achieved with the low KH1060 dose without effects on calcium or bone metabolism, as evaluated by serum calcium (9.5 +/- 0.4 vs. 9.4 +/- 0.3 mg/dl in controls; P = NS), serum osteocalcin (82 +/- 17 vs. 83 +/- 20 ng/ml; P = NS), bone calcium content (6.8 +/- 0.7 vs. 6.4 +/- 0.5 mg/tibia; P = NS), urinary calcium (21 +/- 4 vs. 21 +/- 4 mg/dl; P = NS), pyridinoline excretion, and duodenal calbindin-D9K concentration. The proposed mechanism of action is a restoration of suppressor cell activity, as demonstrated in vitro (suppressor cell assay) and in vivo (cell transfer experiments). This study demonstrates that an analog of 1,25-(OH)2D3 prevents type I diabetes in NOD mice without significant effects on calcium or bone metabolism.
Mathieu
C
C
Laboratory for Experimental Medicine and Endocrinology, Catholic University of Leuven, Belgium.
Waer
M
M
Casteels
K
K
Laureys
J
J
Bouillon
R
R
D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology; D002452:Cell Count; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control*; D005260:Female; D006934:Hypercalcemia / Q000139:chemically induced; D007116:Immunization, Passive; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007515:Islets of Langerhans / Q000187:drug effects; D051379:Mice; D016688:Mice, Inbred NOD; D010195:Pancreatitis / Q000517:prevention & control; D050378:T-Lymphocytes, Regulatory / Q000473:pathology
D007166:Immunosuppressive Agents; C074279:KH 1060; D002117:Calcitriol