Infusions of parathyroid hormone in ruminants: hypercalcemia and reduced plasma 1,25-dihydroxyvitamin D concentrations

The relationship between infused synthetic bovine PTH-(1-34) and plasma concentrations of minerals and vitamin D metabolites was studied in eight calves (150-230 kg) and two thyroparathyroidectomized goats. Calves were infused iv with saline for 15-20 h. Then, calves were infused with one of three types of solution for an additional 35-h period. Three of the eight calves received 3 ng/kg X min (group H), three received 0.75 ng/kg X min (group L), and the remaining two calves received control saline over a 33-h period (group C). Blood samples were taken every 4-6 h. Plasma calcium, phosphorus, hydroxyproline, and 1,25-dihydroxyvitamin D [1,25-(OH)2D] remained relatively constant in control calves. PTH infusions into calves in group H resulted in an increase in plasma calcium from 2.4 to a plateau of 3.0 mmol/liter. PTH infusion caused no change in plasma phosphorus, but increased urinary excretion of phosphorus. Infusion of PTH caused a moderate increase in urinary calcium excretion, followed by pronounced calciuria after PTH withdrawal. Plasma concentrations of 1,25-(OH)2D decreased from about 30 pg/ml at the start of infusion to undetectable levels (less than 5 pg/ml) at the end of the infusion and for 30 h thereafter. Similar, but less pronounced, changes in plasma calcium and 1,25-(OH)2D concentration were observed in group L. Hypocalcemia and hypophosphatemia developed in the two lactating goats after thyroparathyroidectomy, and plasma 1,25-(OH)2D concentrations were decreased. PTH infusion (3 ng/kg X min) corrected the hypocalcemia and hypophosphatemia and markedly raised plasma 1,25-(OH)2D concentrations. When calcium chloride was infused in addition to PTH, the resulting hypercalcemia (3 mmol/liter) was associated with a marked reduction in plasma 1,25-(OH)2D. We conclude that the concentration of calcium in plasma has the major regulatory role on plasma 1,25-(OH)2D concentrations in ruminant species when potentially conflicting signals, such as hypercalcemia and high PTH concentrations, are present simultaneously.     

Effects of growth hormone replacement therapy on 1,25-dihydroxyvitamin D and calcium metabolism

To elucidate the changes in mineral metabolism and blood concentrations of calciotropic hormones which accompany GH therapy, we studied 12 GH-deficient children for 5 days before and for 1 week after high dose (5 IU/day) GH therapy, and again at 1 month, 3 months, and 1 yr of replacement therapy (0.1 IU/kg to a maximum dose of 2 IU three times weekly). All responded with acceleration of height velocity, and bone ages advanced appropriately. Fasting serum ionized calcium levels did not change: 4.11 +/- 0.06 (SEM) mg/dl before, 4.19 +/- 0.05 for the week of high dose therapy, and 4.20 +/- 0.14 during replacement therapy. Likewise, fasting serum parthormone did not vary: 38.9 +/- 2.6 muleq/ml before to 44.1 +/- 9.2 at 1 yr. Twenty four-hour nephrogenous cyclic AMP (NcAMP) did not vary over the first week (1.2 +/- 0.7 nmol/dl glomerular filtrate before, 1.3 +/- 0.4 after 1 week), but increased to 5.3 +/- 1.9 after 1 yr (alpha less than 0.001). The response of ionized calcium and parathormone to a standardized disodium EDTA infusion of 50 mg/kg also did not change. The mean fasting serum calcitonin level was not different before therapy (29.4 +/- 2.8 pg/ml), after 1 week (21.5 +/- 1.8), or after 1 yr (42.4 +/- 11.0). However, the mean serum 1,25-dihydroxyvitamin D concentration rose from 33.1 +/- 3.3 pg/ml before therapy to 68.3 +/- 12.3 on the seventh day of high dose therapy (alpha less than 0.01), returning to pretherapy values by 1 month. We conclude that high dose GH therapy in GH-deficient children raises 1,25-dihydroxyvitamin D concentration acutely, but that long term, physiological replacement therapy does not cause such an effect. Because NcAMP excretion rose in the absence of an increase in serum parathormone concentration, we conclude that GH sensitizes the kidney to a cAMP-mediated effect of parathormone.     

Effect of experimental human magnesium depletion on parathyroid hormone secretion and 1,25-dihydroxyvitamin D metabolism

Magnesium (Mg) deficiency in man may result in hypocalcemia, impaired PTH secretion, and low serum concentrations of 1,25-dihydroxyvitamin D [1,25-(OH)2D]. To determine whether these changes are due to selective Mg depletion, we studied 26 normal subjects before and after a 3-week low Mg (less than 1 meq/day) diet. This diet induced Mg deficiency, as demonstrated by a fall in pre- to postdiet serum Mg levels from 0.80 +/- 0.01 to 0.61 +/- 0.02 mmol/L (P less than 0.001), an increase in Mg retention from 11 +/- 4% to 62 +/- 4% (P less than 0.001), and a fall in red blood cell free Mg2+ from 205 +/- 10 to 162 +/- 7 microM (P less than 0.001). Serum calcium (Ca) fell significantly from 2.36 +/- 0.02 to 2.31 +/- 0.03 mmol/L (P less than 0.05), and serum 1,25-(OH)2D fell from 55 +/- 4 to 43 +/- 3 pmol/L (P less than 0.05). PTH secretion was impaired, as demonstrated by a fall or no change in serum PTH in 20 of 26 subjects despite a fall in the serum Ca and Mg. In addition, an iv injection of Mg in eight subjects after the diet resulted in a significant rise in PTH from 15 +/- 2 to 19 +/- 2 ng/L (P less than 0.01), whereas a similar injection given to six of the subjects before the diet resulted in a significant fall from 28 +/- 5 to 13 +/- 3 ng/L (P less than 0.001). The fall in serum 1,25-(OH)2D may be due to both the decrease in PTH secretion and a renal resistance to PTH. PTH resistance was suggested, as no increase in serum 1,25-(OH)2D was observed in the six subjects in which the PTH concentration rose by mean of 68% after the diet. Also, the rise in serum 1,25-(OH)2D after a 6-h human PTH-(1-34) infusion was significantly less after Mg deprivation. The results demonstrate that mild Mg depletion can impair mineral homeostasis and may be implicated as risk factor for osteoporosis in disorders such as chronic alcoholism and diabetes mellitus, in which Mg deficiency and osteoporosis are both common.     

Effects of parathyroid hormone and 1,25-dihydroxyvitamin D3 on tubular handling of phosphate in hypophosphatemic rickets

A controlled metabolic study to examine the effects of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) treatment on the renal handling of phosphate was conducted in nine patients with X-linked dominant hypophosphatemic rickets, including one with autonomous secondary hyperparathyroidism. Administration of 1,25(OH)2D3 resulted in uniform reduction in serum PTH from 63.6 +/- 14.7 (SD) to 49.3 +/- 14.8 muleq/ml (P less than 0.01), elevation of the tubular threshold for phosphate (TmP/GFR) from 1.41 +/- 0.30 to 1.90 +/- 0.31 mg/dl (P less than 0.01) and increase in serum phosphate from 2.6 +/- 0.7 to 3.4 +/- 1.1 mg/dl (P less than 0.01) in eight PTH-suppressible patients. Four patients treated with phosphate before and during the study (group A) excreted significantly more phosphate than those not treated with phosphate (group B) (P less than 0.001). In the control period, group A also had depressed TmP/GFR and higher concentrations of serum phosphate and PTH. With 1,25(OH)2D3 treatment, serum phosphate in group A became remarkably higher than in group B, 4.28 +/- 0.99 vs. 2.55 +/- 0.31 mg/dl (P less than 0.02), whereas serum PTH and TmP/GFR were similar in both groups. A good inverse linear correlation was found between mean serum PTH and mean TmP/GFR of the groups before and after treatment (r = 0.947); whereas, no correlation was found between TmP/GFR and serum calcium. The patient with autonomous secondary hyperparathyroidism, who was also treated with phosphate, had the lowest TmP/GFR. Administration of 1,25(OH)2D3 had no effect on the serum PTH and phosphate concentrations or on TmP/GFR. We conclude that in patients with X-linked dominant hypophosphatemic rickets PTH modulates to some extent the tubular handling of phosphate, and that the importance of this mechanism increases with therapeutic phosphate supplementation. Simultaneous administration of 1,25(OH)2D3 suppressed PTH activity, raised serum phosphate concentrations, and elevated TmP/GFR.     

1,25-dihydroxyvitamin D3: a kidney-produced steroid hormone essential to calcium homeostasis

Principal among the many relationships involving the metabolism and function of vitamin D is the central role of the kidney in the production of the biologically active steroid, 1,25-dihydroxychole-calciferol. Three important topics under intensive investigation in many laboratories are (1) the role of the kidney as an endocrine organ producing the biologically active form of vitamin D, (2) the regulation of the endocrine organ and its integration in the process of calcium homeostasis, and (3) reevaluation of the wide variety of vitamin D-related disease states as they relate to the central role of the kidney in vitamin D action.     

Stimulation of 1,25-dihydroxyvitamin D production by parathyroid hormone and hypocalcemia in man

The serum levels of 1.25-dihydroxycholecalciferol [1,25(OH)2D3] were increased in five patients with primary hyperparathyroidism [60 +/- 13 (SD) pg/ml; normal value, 33 +/- 15 (SD) pg/ml] but fell rapidly after parathyroidectomy to values of 23 +/- 9 (SD) pg/ml. This was accompanied by parallel decreases in the serum concentrations of calcium and immunoreactive parathyroid hormone. Over the following 5--35 days, the serum 1,25(OH)2D3 concentrations increased markedly to levels of 59 +/- 17 (SD) pg/ml, which could most likely be explained by a stimulatory effect of the hypocalcemia per se on the renal production of 1,25(OH)2D3.     

Effects of gonadal suppression on the regulation of parathyroid hormone and 1,25-dihydroxyvitamin D secretion in women.

Although a causal association between estrogen deficiency and bone loss has been established for many years, the mechanism by which estrogen deficiency leads to bone loss is unclear. Estrogen deficiency could induce bone loss either by a direct effect on bone cells to modify the production of bone-resorbing cytokines or by altering the production or response to calcium regulatory hormones such as PTH and 1,25-dihydroxyvitamin D. To assess the effects of ovarian hormones on calcium regulatory hormones, we evaluated the ability of calcium to suppress PTH secretion and the ability of PTH to increase serum 1,25-dihydroxyvitamin D and whole blood ionic calcium levels in women before and after GnRH analog-induced ovarian suppression. Sixteen women with endometriosis underwent i.v. infusion of calcium (1.1 mg calcium gluconate/cc in 5% dextrose) at a rate of 4 cc/kg x h (n = 7) or human PTH-(1-34) (Parathar) at a dose of 0.55 U/kg x h (n = 9) before and after 6 months of suppression of ovarian function with the GnRH analog nafarelin acetate (200 microg, intranasally, twice daily). Initial infusions were performed between days 6-10 of the menstrual cycle. Serum PTH and whole blood ionic calcium levels were measured at -20, -10, and 0 min and then every 10 min for 2 h during i.v. calcium infusions. Whole blood ionic calcium and 1,25-dihydroxyvitamin D levels were measured every 6 h for 24 h during i.v. human PTH-(1-34) infusions. Serum estradiol levels were markedly suppressed by nafarelin therapy in both groups of women. The relationship between whole blood ionic calcium and serum PTH levels was similar before and during nafarelin-induced ovarian suppression. The net change and rate of rise in serum 1,25-dihydroxyvitamin D levels in response to PTH infusion were similar before and during nafarelin therapy. Peak whole blood ionic calcium and incremental increases in ionic calcium in response to PTH were similar before and during nafarelin therapy. Our data suggest that ovarian suppression does not alter the regulation of PTH secretion in response to calcium, the ability of PTH to stimulate 1,25-dihydroxyvitamin D formation, or the skeletal sensitivity to PTH. These findings suggest that alterations in calcium regulatory hormones by estrogen deficiency are unlikely to play a major role in the pathogenesis of estrogen deficiency bone loss.     

1,25-Dihydroxyvitamin D and vitamin D-binding protein are both decreased in streptozotocin-diabetic rats

Calcium and vitamin D metabolism were studied in streptozotocin-treated rats up to 10 days after the induction of diabetes. Proteinuria, hypercalciuria, and hyperphosphaturia appeared as early as 3 days after diabetes induction and were reversed by insulin. The serum proteins and fasting calcium concentrations were decreased in untreated diabetic rats. The concentration of serum vitamin D binding protein (DBP) was higher in male than in female control rats (mean +/- SD; 555 +/- 73 vs. 348 +/- 28 mg/liter, P less than 0.001). When sequentially measured in male untreated diabetic rats, DBP concentration steadily decreased. Compared with control values, DBP was reduced 19%, 28%, and 32% on days 3, 6, and 10, respectively, after induction of diabetes in male rats. In female animals, DBP was reduced 22% on day 10 of diabetes. DBP concentration was corrected by insulin treatment of diabetic rats and remained normal in streptozotocin-treated animals that did not develop diabetes. The serum concentration of 25-hydroxyvitamin D3 was similar in both sexes and was not affected by diabetes. Like DBP, the concentration of total 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] was higher in male than in female control rats (120 +/- 24 vs. 96 +/- 17 ng/liter, P less than 0.001), but 10 days after induction of diabetes this concentration decreased by 37% and 29% in male and female rats, respectively. The free 1,25-(OH)2D3 concentration, estimated from the molar 1,25-(OH)2D3/DBP ratio, was similar in both sexes and was not decreased by diabetes. We conclude that experimental diabetes in the rat induces a decrease in DBP concentration and a concomitant decrease in total but not in free 1,25-(OH)2D3 concentrations. This may indicate that diabetes decreases circulating 1,25-(OH)2D3 concentrations through alterations in DBP levels.     

Serum calcium,vitamin D and parathyroid hormone relationship among diabetic and non-diabetic pregnant women and their neonates

AimsThe purpose of the study was to determine the prevalence of osteomalacia and hypovitaminosis D among diabetic and non-diabetic pregnant women and in their neonates.MethodsSerum calcium, phosphorus, heat labile alkaline phosphatase, 25(OH) vitamin D and PTH were measured in 32 non-diabetic, 16 gestational diabetic and 8 Type 1 diabetic pregnant women and in cord blood of their newborn.ResultsAmong 32 non-diabetic subjects, 4 subjects (12.5%) had biochemical osteomalacia. 4 out of 16 gestational diabetic subjects (25%) had biochemical osteomalacia whereas 5 out of 8 Type 1 diabetic subjects (62.5%) had biochemical osteomalacia. Mean concentration of 25(OH) vitamin D in the non-diabetic group was 17.18 ± 9.88 ng/ml. Mean concentration of 25(OH) vitamin D in the Gestational diabetic group was 14.75 ± 6.90 ng/ml, while in Type 1 diabetic group, it was 7.81 ± 3.79 ng/ml. 50% of neonates of normal pregnant women had vitamin D deficiency whereas, 50% had vitamin D insufficiency. 40% of neonates of Gestational diabetic pregnant women had vitamin D deficiency whereas, 40% had vitamin D insufficiency.ConclusionVitamin D deficiency and biochemical osteomalacia was present in significant percentage of normal pregnant women and their neonates. Gestational diabetes and Type 1 diabetic women were more prone to develop vitamin D deficiency and biochemical osteomalacia.     

Binding and metabolism of 1,25-dihydroxyvitamin D3 in cultured bovine parathyroid cells.

Several laboratories, including ours, have reported that receptors for 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] are decreased in parathyroid glands of uremic animals and patients. To elucidate the factors involved in receptor regulation in this tissue, we have characterized the receptor in primary cultures of bovine parathyroid cells. Extracts from these cells contain a single binding component that binds 1,25-(OH)2D3 with a Kd of 58 pM and sediments in sucrose density gradients at 3.4S, indicating the continued expression of the vitamin D receptor in these cells. Labeling of the intact parathyroid cells with tritiated 1,25-(OH)2D3 was maximal by 2 h, and binding affinity by this method was estimated to be 22 pM. Longer incubation of the cells with tritiated 1,25-(OH)2D3 resulted in a loss of specific binding to 10% maximal by 12 h. The decrease in binding correlated temporally with degradation of 1,25-(OH)2D3 in the medium. This metabolic activity was absent in vitamin D-deficient cells and was first detectable 3-4 h after the addition of 1,25-(OH)2D3, indicating that 1,25-(OH)2D3 induces its own metabolism in parathyroid cells. Replenishment of the cultures after 12 h with fresh tritiated 1,25-(OH)2D3 restored maximal binding, demonstrating that the loss of binding was not due to down-regulation of receptor. Inclusion of the cytochrome P450 inhibitor ketoconazole did not alter maximal binding at 2 h, but blocked both the metabolism of 1,25-(OH)2D3 and the decrease in binding after 3 h. In contrast to other cell types, such as osteosarcoma cells, no homologous up-regulation was seen in cultured parathyroid cells even after 12 h in the presence of 0.5 nM 1,25-(OH)2D3. Furthermore, receptor levels in preparations from cells treated for 20 h with unlabeled 1,25-(OH)2D3 at concentrations of 0.1, 1.0, and 10 nM were not different from controls. Thus, it appears that the vitamin D receptors in parathyroid cell cultures are not up-regulated by their ligand.     

Intestinal calcium-binding protein and calcium absorption in cortisol-treated chicks: effects of vitamin D3 and 1,25-dihydroxyvitamin D3.

Vitamin D3 in rachitic chicks stimulates calcium absorption and induces the synthesis of two pools of intestinal calcium-binding protein (CaBP), one soluble and the other membrane bound. Cortisol acetate caused a decrease in calcium absorption which was accompanied by a decrease in soluble CaBP. Cortisol was similarly effective in 1,25-dihydroxyvitamin D3-dosed chicks, suggesting that the glucocorticoid effect was not entirely due to the defective synthesis of this metabolite. Ca absorption was directly correlated with soluble CaBP and alkaline phosphatase and inversely related to the ratio of bound to soluble CaBP. It was further observed that the slope of the Ca absorption vs. soluble CaBP regression line was greater in chicks given 1,25-dihyroxyvitamin D3 compared to those given vitamin D3, and this is interpreted to mean that another factor or condition, in addition to assayed concentrations of soluble CaBP, determines the degree of calcium absorption.     

Evidence of an age-related decrease in intestinal responsiveness to vitamin D: relationship between serum 1,25-dihydroxyvitamin D3 and intestinal vitamin D receptor concentrations in normal women.

Although aged rats reportedly have reduced intestinal vitamin D receptor (VDR) concentrations, it is unclear whether an analogous age-related defect occurs in man. Thus, we assessed the interrelationship among serum 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3], calcium absorption and intestinal VDR in 44 healthy, ambulatory women, ages 20-87 yr. Fractional calcium absorption was measured after oral administration of 45Ca (20 mg CaCl2 as carrier); serum 1,25-(OH)2D3, by the calf thymus binding assay; and serum intact PTH, by a two-site immunochemiluminometric assay. Vitamin D receptor concentration was measured, by a new immunoradiometric assay, in biopsy specimens taken from the second part of the duodenum during gastroduodenoscopy in 35 of the women. Despite an age-related increase in serum PTH (r = 0.48; P less than 0.001) and in serum 1,25-(OH)2D3 concentration (r = 0.32; P less than 0.05), intestinal VDR concentration decreased with age (r = -0.38; P = 0.03) and fractional calcium absorption did not change with age. Although a contribution of decreased 25-hydroxyvitamin D 1 alpha-hydroxylase activity to the blunting of the increase in serum 1,25-(OH)2D3 concentration late in life is not excluded, the data are far more consistent with impaired intestinal responsiveness to 1,25-(OH)2D3 action. This defect could lead to compensatory increases in PTH secretion and 1,25-(OH)2D3 production which maintain calcium absorption and serum ionic calcium, but at the expense of increased bone loss.     

Combined effects of dexamethasone and 1,25-dihydroxyvitamin D3 on parathyroid hormone secretion in cultured bovine parathyroid cells

The present studies investigate the effects of glucocorticoids on the function of the parathyroid glands using primary cultures of bovine parathyroid cells. Treatment of parathyroid cell cultures with dexamethasone for 48 h caused a dose-dependent stimulation of PTH secretion. The minimal concentration of dexamethasone required for a significant stimulation of PTH secretion was 0.1 nM. The stimulatory effect of dexamethasone on the secretion of PTH was found within 12 h of treatment with 100 nM dexamethasone. The steroids deoxycorticosterone and cortexolone, which do not have glucocorticoid activity were without effect of PTH secretion. Since glucocorticoids may modulate the effects of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] in other tissues, additional studies were performed to evaluate the interactions of glucocorticoids and 1,25-(OH)2D3. Addition of 1,25-(OH)2D3 to parathyroid cell cultures for 48 h significantly suppressed PTH secretion. In the presence of dexamethasone, however, 1,25-(OH)2D3 also significantly decreased PTH secretion, although it did not reduce PTH secretion to control levels. The treatment of parathyroid cell cultures with 100 nM dexamethasone did not affect the parathyroid cell content of 1,25-(OH)2D3 receptors. In summary, these studies indicate that glucocorticoids significantly increase the secretion of PTH in vitro. This stimulatory effect can be inhibited by 1,25-(OH)2D3. The parathyroid gland is an additional site of physiological antagonism of glucocorticoids and 1,25-(OH)2D3.     

Plasma vitamin D-binding protein and free 1,25-dihydroxyvitamin D3 index in pregnant ewes and their fetuses in the last month of gestation

A radioimmunoassay for ovine vitamin D-binding protein (DBP) has been developed. This assay can also effectively measure DBP in goat plasma. A suitable ovine DBP antiserum raised in a rabbit produced a single monospecific line of precipitation when reacted against purified sheep DBP and sheep plasma. The preliminary purification of 125I-labelled ovine DBP was carried out using adsorption chromatography, and the final purification immediately before addition to the assay tubes was achieved by high-pressure liquid chromatography. Displacement of 125I-labelled ovine DBP by dilutions of sheep and goat plasma or standard DBP gave parallel curves, and only weak competition was observed with calf and pig plasma. The assay detected as little as 26 pmol DBP/l with intra- and interassay coefficients of variation of 3 and 14% respectively. The mean plasma concentration of DBP in nine pregnant sheep (110-120 days of gestation) was 8.7 +/- 0.3 (S.E.M.) mumol/l. These levels were significantly (P less than 0.02; paired t-test) higher than those in matched fetal plasma (6.7 +/- 0.4 mumol/l) obtained in utero through a catheter in a carotid artery. Plasma DBP concentrations in pregnant sheep were also significantly (P less than 0.02) higher than in five normal non-pregnant sheep (6.8 +/- 0.5 mumol/l). The mean concentrations of total 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) in maternal and fetal plasma were 92.0 +/- 8.7 pmol/l and 152.5 +/- 18.0 pmol/l respectively (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Regulation of the murine renal vitamin D receptor by 1,25-dihydroxyvitamin D3 and calcium

Renal vitamin D receptor (VDR) is required for 1,25-dihydroxyvitamin D3-[1,25(OH)2D3]-induced renal reabsorption of calcium and for 1,25(OH)2D3-induced 1,25(OH)2D3 24-hydroxylase. The long-term effect of vitamin D and dietary calcium on the expression of renal VDR was examined in the nonobese diabetic mouse. Vitamin D-deficient and vitamin D-replete mice were maintained on diets containing 0.02%, 0.25%, 0.47%, and 1.20% calcium with or without 50 ng of 1,25(OH)2D3 per day. Vitamin D-replete mice on a 1.20% calcium diet had renal VDR levels of 165 fmol/mg protein. Calcium restriction caused renal VDR levels to decrease to <30 fmol/mg protein in vitamin D-deficient mice and to approximately 80 fmol/mg protein in vitamin D-replete mice. When dietary calcium was present, 50 ng of 1,25(OH)2D3 elevated the VDR levels 2- to 10-fold, depending on vitamin D status and the level of calcium. In the absence of either vitamin D or calcium, the VDR mRNA was expressed at a basal level. 1,25(OH)2D3 supplementation caused relative VDR mRNA to increase 8- to 10-fold in the vitamin D-deficient mouse when dietary calcium was available. This increase was completely absent in the calcium-restricted mice. This in vivo study demonstrates that 1,25(OH)2D3 and calcium are both required for renal VDR mRNA expression above a basal level, furthering our understanding of the complex regulation of renal VDR by 1,25(OH)2D3 and calcium.     

Insulin modulates the stimulation of renal 1,25-dihydroxyvitamin D3 production by parathyroid hormone

Previous studies have shown that there is an impairment in renal production of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the major biologically active metabolite of vitamin D3, in diabetes. This impairment is not due to a deficiency in the parathyroid hormone (PTH), a major stimulator of renal 1,25(OH)2D3 production. Therefore, we have investigated the capacity of PTH to stimulate 1,25(OH)2D3 production in insulin deficiency and with insulin replacement. Experiments were performed in rats fed a 0.6% calcium, vitamin D sufficient diet for 2 weeks. Thyroparathyroidectomy was performed on all rats. Rats to be rendered diabetic were injected with streptozotocin immediately after surgery. In non-diabetic rats, PTH administration significantly increased renal 1,25(OH)2D3 production (11 +/- 2 vs 46 +/- 5 pg/min/g; P less than 0.05). In diabetic rats, however, PTH caused only a modest increase in 1,25(OH)2D3 production (11 +/- 1 vs 19 +/- 4 pg/min/g; P less than 0.05). With insulin replacement, PTH stimulation of 1,25(OH)2D3 production was markedly increased over that seen in diabetic rats (48 +/- 12 vs 19 +/- 4 pg/min/g; P less than 0.05). PTH was equally effective in raising serum calcium, depressing serum phosphorus and tubular reabsorption of phosphate in non-diabetic as well as in diabetic rats. These results demonstrate that insulin is necessary for the maximal stimulation of renal 1,25(OH)2D3 production by PTH. However, insulin is not necessary for PTH action in terms of renal handling of phosphate and inducing hypercalcaemia. These results suggest multiple pathways for the action of PTH, only some of which are insulin requiring.