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

Abstract. 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 < 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 < 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 < 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.

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Effect of Parathyroid Hormone on cAMP and 1,25-Dihydroxyvitamin D Formation and Renal Handling of Phosphate in Vitamin D-Dependent Rickets

PEDIATRICS ◽

10.1542/peds.71.1.59 ◽

1983 ◽

Vol 71 (1) ◽

pp. 59-63

Author(s):

Dagfinn Aarskog ◽

Lage Aksnes ◽

Trond Markestad

Keyword(s):

Vitamin D ◽

Parathyroid Hormone ◽

Serum Concentration ◽

Urinary Excretion ◽

Serum Levels ◽

Renal Handling ◽

Hydroxyvitamin D ◽

Dihydroxyvitamin D ◽

1,25 Dihydroxyvitamin D ◽

Control Subjects

Studies were carried out to compare the effects of parathyroid extract (PTE) on the serum concentration of 1,25-dihydroxyvitamin D (1,25[OH]2D), 24,25-dihydroxyvitamin D (24,25[OH]2D), 25,26-dihydroxy vitamin D (25,26[OH]2D) and cAMP, and the urinary excretion of calcium, phosphorus, and cAMP in two normal adult subjects, and in a girl with vitamin D-dependent rickets. The concentration of 1,25[OH]2D was markedly decreased even when she was receiving a daily dose of 25,000 IU of ergocalciferol. PTE infusion resulted in a prompt and distinct increase in the serum levels and the urinary excretion of cAMP in the patient and control subjects. In the control subjects the serum concentration of 1,25[OH]2D increased after the PTE infusion, whereas there was no response in the patient with vitamin D-dependent rickets. The two other dihydroxylated metabolites of vitamin D showed no consistent response to the PTE infusion in the control subjects or the patient. The patient showed no phosphaturic response to PTE while she was receiving high-dosage ergocalciferol treatment. By contrast, when the patient was re-studied after therapy with lα-hydroxyvitamin D, PTE infusion resulted in an increase in urinary phosphate excretion. These findings might lend support for the notion that 1,25[OH]2D has an effect on tubular phosphate resorption and has a permissive role in the phosphaturic effect of parathyroid hormone. The present findings also confirm that the formation of 1,25[OH]2D is impaired in vitamin D-dependent rickets and indicate that the renal 25-hydroxyvitamin D-lα-hydroxylase is unresponsive to the stimulatory effect of parathyroid hormone in this condition.

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Renal handling of calcium: influence of parathyroid hormone and 1,25-dihydroxyvitamin D3

AJP Renal Physiology ◽

10.1152/ajprenal.1979.236.4.f349 ◽

1979 ◽

Vol 236 (4) ◽

pp. F349-F356 ◽

Cited By ~ 2

Author(s):

K. Hugi ◽

J. P. Bonjour ◽

H. Fleisch

Keyword(s):

Vitamin D ◽

Parathyroid Hormone ◽

Plasma Concentration ◽

Normal Level ◽

Linear Increase ◽

Renal Handling ◽

Dihydroxyvitamin D3 ◽

1,25 Dihydroxyvitamin D3 ◽

Intestinal Ca Absorption ◽

Filtered Load

The influence of parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on the renal Ca handling was studied in vitamin D-replete rats. The relation between plasma concentration ([Ca]P) and urinary Ca (UCaV/ml GF) was ascertained by clearance techniques over the [Ca]P range of 1.4-3.4 mM varied by infusion of Ca gluconate. Chronic thyroparathyroidectomy (TPTX) decreased the plasma Ca threshold from about 2.3 to 1.5 mM. Between [Ca]P 1.4 and 3.4 mM there was a linear increase in UCaV/ml GF corresponding to 35-50% of the increment in filtered load. In TPTX, PTH (2.5 IU/h i.v.) shifted the Ca threshold from 1.5 to 2.3 mM, without changing the slope of UCaV/ml GF on [Ca]P. The effect of TPTX on the renal Ca handling was not corrected by doses of 1,25(OH)2D3, which increased the intestinal Ca absorption of TPTX rats to normal level. In intact and TPTX rats disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP) given at doses which inhibit the production of 1,25(OH)2D3 did not change the tubular Ca handling. Furthermore, 1,25(OH)2D3 had no effect in EHDP-treated TPTX rats. Therefore, tubular Ca handling does not appear to be altered in response to chronic endogenous variation or physiologic supplementation of 1,25(OH)2D3 in vitamin D-replete rats. This is in contrast to the marked alteration observed after TPTX or PTH administration.

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Interaction between amrinone and parathyroid hormone on bone in culture

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1982.243.6.e499 ◽

1982 ◽

Vol 243 (6) ◽

pp. E499-E504

Author(s):

N. S. Krieger ◽

P. H. Stern

Keyword(s):

Parathyroid Hormone ◽

Bone Resorption ◽

Direct Interaction ◽

Inhibitory Effects ◽

Dihydroxyvitamin D3 ◽

Basal Bone ◽

Cardiotonic Agent ◽

Neonatal Mouse Calvaria ◽

Dose Dependent ◽

Stimulation Of

The cardiotonic agent amrinone has been postulated to directly affect Na-Ca exchange. Because stimulated bone resorption has been proposed to require Na-Ca exchange, we examined the effects of amrinone on bone. Amrinone inhibited release of Ca from neonatal mouse calvaria in organ culture stimulated by parathyroid hormone (PTH), 1,25-dihydroxyvitamin d3, or prostaglandin E2. Inhibition was dose dependent and maximal at 2 X 10(-4) M. The effect of amrinone differed from the inhibitory effects of calcitonin, ouabain, or nigericin in that 1) 6-h exposure to amrinone alone prevented the effect of subsequently added PTH; 2) amrinone was only partially effective if added after resorption was initiated by 24-h treatment with PTH; 3) coincubation with amrinone and PTH during the first 48 h of culture allowed for a response to PTH after amrinone was removed; no such protection by a stimulator occurred with ouabain or nigericin. Also submaximal concentrations of amrinone plus calcitonin, ouabain, or nigericin gave greater than additive inhibition of Ca release. Amrinone had no effect on basal bone cAMP or on the acute stimulation of cAMP by PTH. The results suggest that amrinone could have a more direct interaction with the pathway involved in stimulated bone resorption than the other inhibitors.

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Renal Handling of Calcium in Rats: Influence of Parathyroid Hormone and 1,25-Dihydroxyvitamin D3

Vitamin D - Biochemical, Chemical and Clinical Aspects Related to Calcium Metabolism ◽

10.1515/9783112327203-075 ◽

1977 ◽

pp. 433-436

Keyword(s):

Parathyroid Hormone ◽

Renal Handling ◽

Dihydroxyvitamin D3 ◽

1,25 Dihydroxyvitamin D3

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Vitamin D Status among Thai School Children and the Association with 1,25-Dihydroxyvitamin D and Parathyroid Hormone Levels

PLoS ONE ◽

10.1371/journal.pone.0104825 ◽

2014 ◽

Vol 9 (8) ◽

pp. e104825 ◽

Cited By ~ 5

Author(s):

Lisa A. Houghton ◽

Andrew R. Gray ◽

Michelle J. Harper ◽

Pattanee Winichagoon ◽

Tippawan Pongcharoen ◽

...

Keyword(s):

Vitamin D ◽

Parathyroid Hormone ◽

School Children ◽

Vitamin D Status ◽

Hormone Levels ◽

Dihydroxyvitamin D ◽

1,25 Dihydroxyvitamin D

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1,25-Dihydroxyvitamin D3 and Development of Tuberculosis in Cattle

Clinical and Diagnostic Laboratory Immunology ◽

10.1128/cdli.10.6.1129-1135.2003 ◽

2003 ◽

Vol 10 (6) ◽

pp. 1129-1135 ◽

Cited By ~ 18

Author(s):

S. G. Rhodes ◽

L. A. Terry ◽

J. Hope ◽

R. G. Hewinson ◽

H. M. Vordermeier

Keyword(s):

Vitamin D ◽

T Cell ◽

Mononuclear Cells ◽

T Cell Proliferation ◽

Accessory Cell ◽

Dihydroxyvitamin D3 ◽

Dihydroxyvitamin D ◽

Cell Responses ◽

1,25 Dihydroxyvitamin D ◽

Accessory Cells

ABSTRACT This report describes the presence and activity of 1,25-dihydroxyvitamin D3 (1,25-D3) in experimental bovine tuberculosis. Animals that went on to develop tuberculous lesions exhibited a rapid transient increase in serum 1,25-D3 within the first 2 weeks following infection with Mycobacterium bovis. 1,25-D3-positive mononuclear cells were later identified in all tuberculous granulomas by immunohistochemical staining of postmortem lymph node tissue. These results suggest a role for 1,25-D3 both at the onset of infection and in the development of the granuloma in these infected animals. Using a monoclonal antibody to the vitamin D receptor (VDR) as a VDR agonist, we confirmed that activation of the vitamin D pathway profoundly depresses antigen-specific, but not mitogenic, bovine peripheral blood T-cell responses (proliferation and gamma interferon production). Investigation of the mechanism of this suppression showed that the VDR antibody modified the expression of CD80 by accessory cells, such that a significant positive correlation between T-cell proliferation and accessory cell CD80 emerged.

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Abnormal parathyroid hormone stimulation of 25-hydroxyvitamin D-1 alpha-hydroxylase activity in the hypophosphatemic mouse. Evidence for a generalized defect of vitamin D metabolism.

Journal of Clinical Investigation ◽

10.1172/jci112274 ◽

1986 ◽

Vol 77 (1) ◽

pp. 181-187 ◽

Cited By ~ 51

Author(s):

T Nesbitt ◽

M K Drezner ◽

B Lobaugh

Keyword(s):

Vitamin D ◽

Parathyroid Hormone ◽

Hydroxylase Activity ◽

Vitamin D Metabolism ◽

Hormone Stimulation ◽

Hydroxyvitamin D ◽

25 Hydroxyvitamin D ◽

Stimulation Of

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Vitamin D3 and glucose-6-phosphate dehydrogenase in rat duodenal epithelial cells

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1989.257.5.g760 ◽

1989 ◽

Vol 257 (5) ◽

pp. G760-G765

Author(s):

L. B. Nasr ◽

J. D. Monet ◽

P. Lucas ◽

C. A. Bader

Keyword(s):

Vitamin D ◽

Intraperitoneal Administration ◽

Middle Part ◽

G6pd Activity ◽

Dihydroxyvitamin D3 ◽

Rat Duodenum ◽

High Level ◽

Glucose 6 Phosphate Dehydrogenase ◽

Stimulation Of

A microdensitometric method was employed to determine enzyme activities in situ in undisrupted tissue rat duodenum. The effect of 1 alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3] on glucose-6-phosphate dehydrogenase (G6PD) activity and on the two utilization pathways of synthesized NADPH, H1 (mixed function oxidation) and H2 (biosynthesis), was studied. In normal animals, a crypt-to-villus gradient of G6PD activity and of both NADPH utilization pathways was observed. A high level of NADPH utilization occurred predominantly via the H2 pathway. In vitamin D-deficient rat animals, G6PD activity in the middle part of the villus was approximately 60% lower than in normal animals [10.05 +/- 0.35 vs. 3.95 +/- 0.26 (means +/- SE) A585.min-1.micron-3 X 10(5), P less than 0.001] with reduced NADPH utilization via the H2 pathway (8.39 +/- 0.49 vs. 2.73 +/- 0.43 A585.min-1.micron-3 X 10(5), P less than 0.001) but not the H1 pathway (1.65 +/- 0.17 vs. 1.22 +/- 0.19 A585.min-1.micron-3 X 10(5), P = NS). Intraperitoneal administration of 1,25(OH)2D3 (500 pmol) to vitamin D-deficient animals resulted in increased G6PD activity within 30 min (4.09 +/- 0.38 vs. 5.51 +/- 0.39 A585.min-1.micron-3 X 10(5), P less than 0.05), attaining normal levels within 2 h. The H2 but not the H1 pathway of NADPH utilization increased significantly in response to 1,25(OH)2D3. This increase is essentially located in the basal and middle parts of the villus. Thus 1,25(OH)2D3 may influence biosynthesis in the duodenum via stimulation of G6PD activity and the H2 pathway of NADPH utilization.

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Stimulation of 24R,25-dihydroxyvitamin D3 synthesis by metabolites of vitamin D3

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1983.245.4.e359 ◽

1983 ◽

Vol 245 (4) ◽

pp. E359-E364 ◽

Cited By ~ 1

Author(s):

G. S. Reddy ◽

G. Jones ◽

S. W. Kooh ◽

D. Fraser ◽

H. F. DeLuca

Keyword(s):

Vitamin D ◽

Vitamin D3 ◽

The Other ◽

Hydroxyl Group ◽

Vitamin D Metabolites ◽

Structural Requirements ◽

Dihydroxyvitamin D3 ◽

Hydroxylated Metabolites ◽

Perfusion Period ◽

Stimulation Of

Previously we have shown that the isolated perfused kidney from vitamin D-deficient rats converts [3H]25(OH)D3 into [3H]1 alpha,25(OH)2D3. When certain vitamin D metabolites were added to perfusate the same kidney began to synthesize [3H]24R,25(OH)2D3. In this study we investigated the structural requirements of the vitamin D molecule necessary to stimulate synthesis of [3H]24R,25(OH)2D3 in a 1-hydroxylating kidney. Kidneys were perfused with tracer [3H]25(OH)D3 (450 pM) alone and in the presence of a variety of hydroxylated metabolites and fluorinated analogues of vitamin D3 at concentrations of 450 pM to 25 microM. Tracer [3H]25(OH)D3 alone resulted in synthesis of only [3H]1 alpha,25(OH)2D3 during the 6-h perfusion period. 25-Hydroxylated metabolites [25(OH)D3, 25 nM; 1 alpha,25(OH)2D3, 25 nM; 24R,25(OH)2D3, 25 nM; 24(F)2,25(OH)D3, 50 nM] stimulated [3H]24R,25(OH)2D3 production at 2 h of perfusion. On the other hand, analogues without the 25-hydroxyl group [D3; 1 alpha(OH)D3; 25(F)D3; 1 alpha(OH),25(F)D3; 1 alpha(F)D3; 1 beta(F)D3]; did not stimulate [3H]24R,25(OH)2D3 synthesis. We conclude that the 25-hydroxyl group is an essential determinant of 24-hydroxylation.

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