Vitamin D homeostasis is compromised due to increased urinary excretion of the 25-hydroxycholecalciferol-vitamin D-binding protein complex in the Zucker diabetic fatty rat.
Altered serum concentrations of the major circulating form of vitamin D [25-hydroxycholecalciferol (25D(3))] and its active hormone derivative [1,25-dihydroxycholecalciferol (1,25D(3))] have been linked to non-insulin-dependent diabetes mellitus (NIDDM). However, a mechanistic basis for this occurrence has not been fully elucidated. Normally, renal reabsorption of vitamin D-binding protein-bound 25D(3) absolutely requires receptor-mediated endocytosis via a receptor complex containing megalin, cubilin, and disabled-2 (Dab2), whereas an absence of megalin or its endocytic partners can lead to a marked urinary loss of 25D and severe vitamin D deficiency. Therefore, we hypothesized that reduced serum vitamin D status in NIDDM may be due to reduced expression of megalin and/or its endocytic partners and increased urinary excretion of protein-complexed 25D(3). In the present study, we utilized Zucker diabetic fatty Rats (ZDF) to demonstrate that renal reuptake of the 25D(3)-DBP complex was compromised in ZDF animals, which was reflected by a reduction in expression of megalin and Dab2. Moreover, serum levels of both 25D(3) and 1,25D(3) were reduced, and urinary 25D(3), 1,25D(3), and DBP excretion were elevated in the ZDF animals compared with their lean controls regardless of vitamin D levels in the diet. Taken together, these are the first reports to our knowledge that associate compromised renal reabsorption of the 25D(3)-DBP complex with expression of megalin and its endocytic partners in NIDDM, which in turn can lead to compromised vitamin D status.
Anderson
R L
RL
Dept. of Food Science and Human Nutrition, Iowa State University, Ames, IA 50011, USA.
Ternes
S B
SB
Strand
K A
KA
Rowling
M J
MJ
D000704:Analysis of Variance; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002112:Calcifediol / Q000378:metabolism*; D002118:Calcium / Q000097:blood; D003404:Creatinine / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006706:Homeostasis / Q000502:physiology*; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood; D007668:Kidney / Q000378:metabolism*; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000378:metabolism; D008297:Male; D010281:Parathyroid Hormone / Q000097:blood; D051381:Rats; D011924:Rats, Zucker; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D014807:Vitamin D / Q000378:metabolism*
D001786:Blood Glucose; D007328:Insulin; D026561:Low Density Lipoprotein Receptor-Related Protein-2; D010281:Parathyroid Hormone; D014807:Vitamin D; D003404:Creatinine; D002112:Calcifediol; D002118:Calcium