The study aimed to explore the relationship among renal injury, abnormal vitamin D metabolism, and bone homeostasis in insulin resistance (IR) or type 2 diabetes mellitus (T2DM).
Design and Methods
The animal models of IR, T2DM, and T2DM treated with 1-alpha hydroxyvitamin D (1-α(OH)D) were established on 18-month-old male Wistar rats. Glucose infusion rates (GIR) and levels of urinary albumin (UA), serum 25-hydroxyvitamin D (25-(OH)D), serum 1,25-dihydroxyvitamin D (1,25-(OH)2D), and bone mineral density (BMD) in lumbar vertebrae and femoral bone were measured.
Results
Urinary albumin level in the rats with T2DM significantly increased, and there existed a significant and negative correlation between GIR and UA level in the rats with T2DM or IR. The levels of serum 25-(OH)D in all models were similar. The levels of serum 1,25-(OH)2D and BMD in the rats with IR were significantly higher than those in the rats with T2DM and were lower than those in normal control rats. In the aged rats with T2DM, administration of 1-α(OH)D had no effect on serum 25-(OH)D level although significantly increased the levels of serum 1,25-(OH)2D and BMD. There existed a negative correlation between the levels of serum 1,25-(OH)2D and UA in the rats with T2DM or IR.
Conclusions
In IR or T2DM, abnormal vitamin D metabolism is characterized by 1,25-(OH)2D deficiency and is related to renal injury, and there also existed bone loss. In T2DM, both 1,25-(OH)2D deficiency and bone loss can be reversed by 1-α(OH)D.
TakeyamaK, KitanakaS, SatoT, . 25-Hydroxyvitamin D3 1alpha-hydroxylase and vitamin D synthesis. Science1997;277:1827–1830.
2.
OhyamaY, YamasakiT.Eight cytochrome P450s catalyze vitamin D metabolism. Front Biosci2004;9:3007–3018.
3.
BlandR, ZehnderD, HewisonM.Expression of 25-hydroxyvitamin D3-1alpha-hydroxylase along the nephron: new insights into renal vitamin D metabolism. Curr Opin Nephrol Hypertens2000;9:17–22.
4.
AndressDL.Vitamin D in chronic kidney disease: a systemic role for selective vitamin D receptor activation. Kidney Int2006;69:33–43.
5.
DussoAS, BrownAJ, SlatopolskyE.Vitamin D. Am J Physiol Renal Physiol2005;289:F8–F28.
6.
MillerWL, PortaleAA.Vitamin D biosynthesis and vitamin D 1 alpha-hydroxylase deficiency. Endocr Dev2003;6:156–174.
7.
OkanoT.Vitamin D, K and bone mineral density. Clin Calcium2005;15:1489–1494.
8.
IshimuraE, TsuchidaT, HirowatariK, . Annual change in bone mineral density in predialysis patients with chronic renal failure: significance of a decrease in serum 1,25-dihydroxy-vitamin D. J Bone Miner Metab2007;25:74–79.
9.
FournierA, MorinièrePH, OprisiuR, . 1-alpha-Hydroxyvitamin D3 derivatives in the treatment of renal bone diseases: justification and optimal modalities of administration. Nephron1995;71:254–283.
Toto RobertD.Appropriate drug therapy for improving outcomes in diabetic nephropathy. Curr Diab Rep2002;2:545–552.
12.
Whaley-ConnellA, PaveyBS, . Obesity and insulin resistance as risk factors for chronic kidney disease. J Cardiometab Syndr2006;1(3):209–214; >quiz 215–6>.
13.
SitD, KadirogluAK, KayabasiH, . The prevalence of insulin resistance in nondiabetic nonobese patients with chronic kidney disease. Adv Ther2006Nov-Dec;23:988–998.
14.
AbrassCK. Overview: obesity: what does it have to do with kidney disease?J Am Soc Nephrol2004;15(11):2768–2772.
15.
FliserD, PaciniG, EngelleiterR, . Insulin resistance and hyperinsulinemia are already present in patients with incipient renal disease. Kidney Int1998;53:1343–1347.
16.
ScraggR, HoldawayI, SinghV, . Serum 25-hydroxyvitamin D3 levels decreased in impaired glucose tolerance and diabetes mellitus. Diabetes Res Clin Pract1995;27:181–188.
17.
PietschmannP, SchernthanerG, WoloszczukW.Serum osteocalcin levels in diabetes mellitus: analysis of the type of diabetes and microvascular complications. Diabetologia1988;31:892–895.
18.
IsaiaG, GiorginoR, AdamiS.High prevalence of hypovitaminosis D in female type 2 diabetic population. Diabetes Care2001;24:1496.
19.
BoucherBJ, MannanN, NoonanK, . Glucose intolerance and impairment of insulin secretion in relation to vitamin D deficiency in east London Asians. Diabetologia1995;38:1239–1245.
20.
GlothFM, GundbergCM, HollisBW, . Vitamin D deficiency in homebound elderly persons. JAMA1995;274:1683–1686.
21.
ChungYS, LeeMD, LeeSK, . HMG-CoA reductase inhibitors increase BMD in type 2 diabetes mellitus patients. J Clin Endocrinol Metab2000;85:1137–1142.
22.
GregorioF, CristalliniS, SanteusanioF, . Osteopenia associated with non-insulin-dependent diabetes mellitus: what are the causes?Diabetes Res Clin Pract1994;23:43–54.
23.
NakashimaA, NakashimaR, ItoT, . Title HMG-CoA reductase inhibitors prevent bone loss in patients with Type 2 diabetes mellitus. Diabet Med2004;21:1020–1024.
24.
TakizawaM, KameyamaK, MaruyamaM, . Loss in type 2 diabetes mellitus-diabetic osteopenia. Nippon Rinsho2003;61:287–291.
25.
BlaedelWJ, UhlJM.Nature of materials in serum that interfere in the glucose oxidase-peroxidase-O-dianisidine method for glucose, and their mode of action. Clin Chem1975;21:119–124.
26.
StraczkowskiM, StepieńA, KowalskaI, . Comparison of simple indices of insulin sensitivity using the euglycemic hyperinsulinemic clamp technique. Med Sci Monit2004;10:CR480–CR484.
27.
WattsGF, AlbanoJD, BennettJE, . Assessment of new radioimmunoassay kit for determining urinary albumin at low concentrations: comparison with radial immunodiffusion. J Clin Patho1986;39:1151–1154.
28.
LilleyJ, WaltersBG, HeathDA, . In vivo and in vitro precision for bone density measured by dual-energy X-ray absorption. Osteoporos Int1991;1:141–146.
29.
BroholmB, PodenphantJ, Biering-SorensenF.The course of bone mineral density and biochemical markers of bone turnover in early postmenopausal spinal cord-lesioned females. Spinal Cord2005;43:674–677.
30.
SpencerEM, KhalilM, TobiassenO.Experimental diabetes in the rat causes an insulin-reversible decrease in renal 25-hydroxyvitamin D3-1 alpha-hydroxylase activity. Endocrinology1980;107:300–305
31.
HoughS, FaustoA, SonnY, . Vitamin D metabolism in the chronic streptozotocin-induced diabetic rat. Endocrinology1983;113:790–796.
32.
HülyaA, FatihA, NaciyeK, . Serum 1,25 dihydroxy vitamin D (1,25(OH)2D3), 25 hydroxy vitamin D (25(OH)D) and parathormone levels in diabetic retinopathy. Clin Biochem2000;33:47–51.
33.
ParvanovaAI, TrevisanR, IlievIP, . Insulin resistance and microalbuminuria: a cross-sectional, case-control study of 158 patients with type 2 diabetes and different degrees of urinary albumin excretionDiabetes2006;55:1456–1462.
34.
HoehnerCM, GreenlundKJ, Rith-NajarianS, . Association of the insulin resistance syndrome and microalbuminuria among nondiabetic native Americans. The Inter-Tribal Heart Project. J Am Soc Nephrol2002;13:1626–1634.
35.
KawanoK, HirashimaT, MoriS, . Spontaneous long-term hyperglycemic rat with diabetic complications: Otsuka Long-Evans Tokushima Fatty (OLETF) strain. Diabetes1992;41:1422–1428.
36.
De CosmoS, MinennaA, LudovicoO, . Increased urinary albumin excretion, insulin resistance and related cardiovascular risk factors in patients with type 2 diabetes: evidence of a sex-specific association. Diabetes Care2005;28:910–915.
37.
CooperME.Pathogenesis, prevention, and treatment of diabetic nephropathy. Lancet1998;352:213–219.
38.
YaqoobM, McClellandP, PatrickAW, . Tubulopathy with macroalbuminuria due to diabetic nephropathy and primary glomerulonephritis. Kidney Int Suppl1994;47:101–104.
39.
YaqoobM, McClellandP, PatrickAW, . Evidence of oxidant injury and tubular damage in early diabetic nephropathy. QJM1994;87:601–607.
40.
KarkkainenM, TahtelaR, LaitinenK, . Bone mass and markers of bone and calcium metabolism in postmenopausal women treated with 1,25-dihydroxyvitamin D (Calcitriol) for four years. Calcif Tissue Int2000;67:122–127.
41.
TsuruokaS, WakaumiM, YamamotoH, . Chronopharmacology of oxacalcitriol in rat model of osteoporosis. Eur J Pharmacol2004;19;488:239–245.
