Effects of vitamin D2 or D3 supplementation on glycaemic control and cardiometabolic risk among people at risk of type 2 diabetes: results of a randomized double-blind placebo-controlled trial.

AIMS: To investigate the effect of short-term vitamin D supplementation on cardiometabolic outcomes among individuals with an elevated risk of diabetes. METHODS: In a double-blind placebo-controlled randomized trial, 340 adults who had an elevated risk of type 2 diabetes (non-diabetic hyperglycaemia or positive diabetes risk score) were randomized to either placebo, 100,000 IU vitamin D2 (ergocalciferol) or 100,000 IU vitamin D3 (cholecalciferol), orally administered monthly for 4 months. The primary outcome was change in glycated haemoglobin (HbA1c) between baseline and 4 months, adjusted for baseline. Secondary outcomes included: blood pressure; lipid levels; apolipoprotein levels; C-reactive protein levels; pulse wave velocity (PWV); anthropometric measures; and safety of the supplementation. RESULTS: The mean [standard deviation (s.d.)] 25-hydroxyvitamin D [25(OH)D]2 concentration increased from 5.2 (4.1) to 53.9 (18.5) nmol/l in the D2 group, and the mean (s.d.) 25(OH)D3 concentration increased from 45.8 (22.6) to 83.8 (22.7) nmol/l in the D3 group. There was no effect of vitamin D supplementation on HbA1c: D2 versus placebo: -0.05% [95% confidence interval (CI) -0.11, 0.02] or -0.51 mmol/mol (95% CI -1.16, 0.14; p = 0.13); D3 versus placebo: 0.02% (95% CI -0.04, 0.08) or 0.19 mmol/mol (95% CI -0.46, 0.83; p = 0.57). There were no clinically meaningful effects on secondary outcomes, except PWV [D2 versus placebo: -0.68 m/s (95% CI -1.31, -0.05); D3 versus placebo -0.73 m/s (95% CI -1.42, -0.03)]. No important safety issues were identified. CONCLUSIONS: Short-term supplementation with vitamin D2 or D3 had no effect on HbA1c. The modest reduction in PWV with both D2 and D3 relative to placebo suggests that vitamin D supplementation has a beneficial effect on arterial stiffness.

TNF-alpha downregulates murine hepatic growth hormone receptor expression by inhibiting Sp1 and Sp3 binding.

Children with chronic inflammatory diseases experience growth failure and wasting. This may be due to growth hormone resistance caused by cytokine-induced suppression of growth hormone receptor (GHR) gene expression. However, the factors governing inflammatory regulation of GHR are not known. We have reported that Sp1 and Sp3 regulate hepatic GHR expression. We hypothesized that TNF-alpha suppresses GHR expression by inhibiting Sp1/Sp3 transactivators. LPS administration significantly reduced murine hepatic GHR expression, as well as Sp1 and Sp3 binding to GHR promoter cis elements. TNF-alpha was integral to this response, as LPS did not affect hepatic Sp1/Sp3 binding or GHR expression in TNF receptor 1-deficient mice. TNF-alpha treatment of BNL CL.2 mouse liver cells reduced Sp1 and Sp3 binding to a GHR promoter cis element and downregulated activity of a GHR promoter-driven luciferase reporter. Combined mutations within adjacent Sp elements eliminated GHR promoter suppression by TNF-alpha without affecting overall nuclear levels of Sp1 or Sp3 proteins. These studies demonstrate that murine GHR transcription is downregulated by LPS, primarily via TNF-alpha-dependent signaling. Evidence suggests that inhibition of Sp transactivator binding is involved. Further investigation of these mechanisms may identify novel strategies for preventing inflammatory suppression of growth.

Induction of mRNAs for the growth hormone receptor gene during mouse 3T3-L1 preadipocyte differentiation.

Adipose tissue is a growth hormone (GH)-responsive tissue in which GH regulates energy metabolism. GH exerts its effect by interacting with its specific GH receptor (GHR). In rodents, alternative splicing of the nascent transcript from the GHR gene produces two major transcripts: GHR mRNA and GHR binding protein (GHBP) mRNA. These two transcripts share the common extracellular ligand-binding domain, but differ in the C-terminal sequence. Since GHR plays an important role in mediating the actions of GH in adipose metabolism, we initiated these studies to examine GHR gene expression in the course of mouse 3T3-L1 preadipocyte-adipocyte conversion. GHR and GHBP transcripts were detected by RNase protection assay (RPA) using the antisense riboprobes complementary either to the specific sequence of the GHR or to the sequence shared by both GHR and GHBP mRNAs. After stimulation of differentiation, mRNA abundance increased 28-fold and reached a maximal level by day 7 of adipogenesis. The GHR mRNA:GHBP mRNA ratio was 1.1 +/- 0.12 and remained unchanged during differentiation. The decay rate for both mRNAs, estimated by treating the cells with actinomycin D, was approximately 24 hours and showed no significant difference between preadipocytes and adipocytes. Thus, GHR gene expression is dramatically upregulated during preadipocyte-adipocyte differentiations.

Hyperparathyroidism and low serum osteocalcin despite vitamin D replacement in primary biliary cirrhosis.

Thirty-six patients with primary biliary cirrhosis (PBC) receiving calcium and calciferol supplements (100,000 IU monthly by im injection) were investigated for their calcium, vitamin D, PTH, and osteocalcin status. The corrected plasma calcium concentrations in PBC patients were significantly greater than those in normal subjects. While the mean serum 25-hydroxycholecalciferol and 1,25-dihydroxyvitamin D concentrations in these patients were similar to those in normal subjects, the mean serum PTH concentration was significantly greater, and it was supranormal in 11 patients. Three patients had elevated corrected calcium concentrations; 1 of them had a concomitant increase in ionized calcium and a supranormal PTH level, and another had a high normal PTH. Ionized calcium concentrations were normal in the rest. Serum osteocalcin concentrations were significantly lower in the patients compared with those in normal subjects. These results indicate that PTH concentrations are frequently elevated in PBC patients despite adequate vitamin D supplementation and normal or even supranormal plasma calcium concentrations. Nonsuppression of PTH concentrations and autonomy of PTH secretion suggest that vitamin D deficiency and secondary hyperparathyroidism in such patients probably occur much earlier in the natural history of this disease than is currently realized. Persistent nonsuppressible hypersecretion of PTH probably contributes to the bone disease of primary biliary cirrhosis. The low osteocalcin concentrations probably reflect diminished osteoblastic activity, which may also contribute to osteopenia in these patients.

Calcium, vitamin D and parathyroid hormone relationships in pregnant Caucasian and Asian women and their neonates.

Plasma calcium, serum 25 hydroxyvitamin D [25(OH)D], 1,25 dihydroxyvitamin D[1,25(OH)2D] and parathyroid hormone (PTH) have been measured in pregnant and newborn Caucasians and Asians. Calcium and 25(OH)D concentrations were lower in Caucasian than in Asian women at all four stages (three trimesters and during labour) of pregnancy. PTH concentrations were greater in Asian than in Caucasian women during the three trimesters, but not at labour, and increased in both groups through pregnancy, without a concomitant change in plasma calcium concentrations. There was a significant inverse correlation between calcium and PTH, as well as 25(OH)D and PTH, concentrations. These data demonstrate the presence of progressive 'hyperparathyroidism' during pregnancy in Caucasian and Asian women. The higher PTH concentrations in Asian women may reflect the necessity of maintaining adequate plasma calcium concentrations through PTH-induced osteolysis in the face of vitamin D deficiency. Relative hyperparathyroidism in Asians may contribute to net loss of calcium from the skeleton and osteopenia in Asian women. Calcium, 25(OH)D and 1,25(OH)2D concentrations were lower, and those of PTH higher, in Asian newborns compared with Caucasian newborns. Serum 1,25(OH)2D concentrations in the Asian newborn, though lower than respective maternal levels, were comparable with normal adult levels, indicating that 1,25(OH)2D biosynthesis is stimulated in the Asian newborn to compensate for the low serum 25(OH)D concentrations.