The relationship among renal injury, changed activity of renal 1-alpha hydroxylase and bone loss in elderly rats with insulin resistance or Type 2 diabetes mellitus.
OBJECTIVE
Chronic kidney disease can lead to a decrease in active vitamin D [1,25-(OH)2D], which may be reversed by 1-alpha hydroxyvitamin D [1-alpha(OH)D]. Renal 1-alpha hydroxylase, expressed in renal tubular epithelial cells, is a key enzyme in the synthesis of 1,25-(OH)2D. 1,25- (OH)2D plays an important role in the regulation of calcium and phosphate metabolism, and its deficiency can result in osteoporosis. Type 2 diabetes mellitus (T2DM) and insulin resistance (IR) are associated with renal injury, decrease in 1,25-(OH)2D and bone loss. The study aimed to explore the relationship among renal injury, decrease in 1,25-(OH)2D and bone loss in the presence of IR or T2DM, as well as the role of renal 1-alpha hydroxylase in the process.


METHODS
Fifty 18-month-old male Wistar rats were randomized into 5 groups: normal control group (Group N), IR group (Group I), T2DM group (Group D), No.1 treatment group (Group T1), and No.2 treatment group (Group T2), 10 in each group. High-fat diet was administered to induce IR, while high-fat diet and low-dose streptozotocin were jointly applied to induce T2DM. Rats in Groups T1 and T2 were treated with vitamin D and 1-alpha(OH)D, respectively. At week 12, IR was determined by the use of euglycemic insulin clamp technique for rats in each group, and then glucose infusion rate (GIR) was calculated. Meanwhile, urinary albumin (UA), serum 25-(OH)D and 1,25-(OH)2D levels were determined by radioimmunoassay. After the rats were sacrificed, bone mineral density (BMD) in femoral bone and lumbar vertebrae was measured by the use of dual energy X-ray absorption.


RESULTS
The GIR in Group N was significantly higher than that of the other 4 groups (p<0.01). Compared with Groups N (p<0.01) or I (p<0.05), the UA levels in Groups D, T1, and T2 were obviously higher. The UA level in Group I was higher than that of Group N, but the difference was not significant (p>0.05). In Groups D and I, the UA levels showed a negative correlation with GIR. No significant difference was observed in the levels of 25-hydroxyvitamin D [25-(OH)D]. The levels of 1,25-(OH)2D in Groups D and T1 were markedly lower than that of Groups N or T2 (p<0.01). The 1,25-(OH)2D level in Group I was lower than that of Group N (p<0.05), but higher than that of Group D (p<0.01). The 1,25-(OH)2D level in Group T2 was nearly equivalent to that of Group N. In Groups D and I, the levels of 1,25-(OH)2D were negatively correlated with UA, and positively correlated with GIR. The BMD levels in lumbar vertebrae or femoral bone in Groups D and T1 were similar, but both were lower than that of Groups T2 (p<0.05) and N (p<0.01). The BMD levels were lower in Groups I and T2 compared with that of Group N (p<0.05), but higher than that of Groups D and T1 (p<0.05). The BMD levels in lumbar vertebrae or femoral bone in Groups I and D were positively correlated with GIR. The BMD level in lumbar vertebrae or femoral bone in Group D showed negative correlation with UA.


CONCLUSIONS
In elderly rats with T2DM or IR, renal injury may cause decreased activity of renal 1-alpha hydroxylase, which may result in bone loss and disturbance in VD metabolism, mainly manifesting as a significant reduction in the 1,25-(OH)2D level.
Huang
C-Q
CQ
Department of Geriatrics, The Third Hospital of Mianyang, Mianyang, PR China. huangshan319@yahoo.com.cn
Ma
G-Z
GZ
Tao
M-D
MD
Ma
X-L
XL
Liu
Q-X
QX
Feng
J
J
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000378:metabolism*; D000375:Aging / Q000378:metabolism / Q000502:physiology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015519:Bone Density / Q000502:physiology; D002112:Calcifediol / Q000097:blood; D002117:Calcitriol / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000150:complications / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications* / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D007668:Kidney / Q000201:enzymology; D008297:Male; D010024:Osteoporosis / Q000097:blood / Q000209:etiology* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000150:complications* / Q000378:metabolism; D013311:Streptozocin; D014808:Vitamin D Deficiency / Q000209:etiology / Q000378:metabolism
D001786:Blood Glucose; D013311:Streptozocin; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol; D002112:Calcifediol