Impaired insulin secretory capacity in mice lacking a functional vitamin D receptor

Zeitz, Ute; Weber, Karin; Soegiarto, Desi W.; Wolf, Eckhard; Balling, Rudi; Erben, Reinhold G.

doi:10.1096/fj.02-0424fje

Cited by 384 publications

(259 citation statements)

References 25 publications

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“…Thus, renal failure as the cause of failure to thrive and early death can largely be excluded. Impaired insulin secretion with reduced insulin mRNA expression has been reported in VDR(Ϫ/Ϫ) mice (35), whereas a greater stimulation of insulin secretion by KCl has been reported in CaBP-D28k(Ϫ/Ϫ) mice (36). We found that pancreatic insulin mRNA levels in the double KO mice are normal in comparison with WT mice (data not shown), which rules out insulin as the cause.…”

Section: Table II Physiological Parameters Of 2-month Old Wt Cabp-d2mentioning

confidence: 54%

Critical Role of Calbindin-D28k in Calcium Homeostasis Revealed by Mice Lacking Both Vitamin D Receptor and Calbindin-D28k

Zheng

Xie

et al. 2004

Journal of Biological Chemistry

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Calbindin (CaBP)-D28k and CaBP-D9k are cytosolic vitamin D-dependent calcium-binding proteins long thought to play an important role in transepithelial calcium transport. However, recent genetic studies suggest that CaBP-D28k is not essential for calcium metabolism. Genetic ablation of this gene in mice leads to no calcemic abnormalities. Genetic inactivation of the vitamin D receptor (VDR) gene leads to hypocalcemia, secondary hyperparathyroidism, rickets, and osteomalacia, accompanied by 90% reduction in renal CaBP-D9k expression but little change in CaBP-D28k. To address whether the role of CaBP-D28k in calcium homeostasis is compensated by CaBP-D9k, we generated VDR/CaBP-D28k double knockout (KO) mice, which expressed no CaBP-D28k and only 10% of CaBP-D9k in the kidney. On a regular diet, the double KO mice were more growth-retarded and 42% smaller in body weight than VDRKO mice and died prematurely at 2.5-3 months of age. Compared with VDRKO mice, the double KO mice had higher urinary calcium excretion and developed more severe secondary hyperparathyroidism and rachitic skeletal phenotype, which were manifested by larger parathyroid glands, higher serum parathyroid hormone levels, much lower bone mineral density, and more distorted growth plate with more osteoid formation in the trabecular region. On high calcium, high lactose diet, blood-ionized calcium levels were normalized in both VDRKO and the double KO mice; however, in contrast to VDRKO mice, the skeletal abnormalities were not completely corrected in the double KO mice. These results directly demonstrate that CaBP-D28k plays a critical role in maintaining calcium homeostasis and skeletal mineralization and suggest that its calcemic role can be mostly compensated by CaBP-D9k.It is well established that calcium homeostasis is primarily maintained by the vitamin D and parathyroid hormone (PTH) 1 endocrine systems. In this regard, the principal role of vitamin D is to regulate calcium transport in the intestine and kidney. Intestinal and renal distal tubular calcium transfer consists of a passive, concentration gradient-dependent paracellular transport and an active, ATP-dependent transcellular transport (1). The latter is largely regulated by vitamin D and is crucial when calcium supply is low. It is believed that the vitamin D-mediated transcellular calcium transport in the duodenum and renal distal tubules involves three sequential steps: entry, intracellular movement, and extrusion. Influx of luminal calcium into the epithelial cells is propelled by a steep electrochemical gradient across the apical membrane, saturable at high levels of luminal calcium, and mediated by apical calcium channels (2-4). Once in the cytosol, calcium binds to the vitamin D-dependent calcium-binding proteins, calbindins (CaBPs), which ferry calcium from the apical to the basolateral portion of the cell, where the Na ϩ /Ca 2ϩ exchanger and Ca 2ϩ -dependent ATPase on the basolateral membrane extrude calcium into extracellular fluids (5-7). It is believed that the apical to b...

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Section: Table II Physiological Parameters Of 2-month Old Wt Cabp-d2mentioning

confidence: 54%

Critical Role of Calbindin-D28k in Calcium Homeostasis Revealed by Mice Lacking Both Vitamin D Receptor and Calbindin-D28k

Zheng

Xie

et al. 2004

Journal of Biological Chemistry

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“…Their physiological significance at the single-cell level is currently a field of intense study. Typically, rapid 1,25D effects such as transcaltachia in the intestinal epithelium (17) and insulin secretion by ␤-pancreatic cells (18,19) have been studied at the tissue level. In osteoblasts, the bone-forming cells, 1,25D stimulates the production of bone matrix proteins that are constitutively secreted to the extracellular matrix (20,21).…”

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confidence: 99%

Rapid modulation of osteoblast ion channel responses by 1α,25(OH) ₂ -vitamin D ₃ requires the presence of a functional vitamin D nuclear receptor

Zanello

Norman²

2004

Proc. Natl. Acad. Sci. U.S.A.

143

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1␣,25(OH)2-Vitamin D3 (1,25D) modulates osteoblast gene expression of bone matrix proteins via a nuclear vitamin D receptor (VDR) and also modifies the electrical state of the plasma membrane through rapid nongenomic mechanisms still not fully understood. The physiological significance of 1,25D membrane-initiated effects remains unclear. To elucidate whether the VDR is required for 1,25D-promoted electrical responses, we studied 1,25D modulation of ion channel activities in calvarial osteoblasts isolated from VDR knockout (KO) and WT mice. At depolarizing potentials, Cl ؊ currents were significantly potentiated (13.5 ؎ 1.6-fold increase, n ‫؍‬ 12) by 5 nM 1,25D in VDR WT but not in KO (0.96 ؎ 0.3 fold increase, n ‫؍‬ 11) osteoblasts. L-type Ca 2؉ currents significantly shift their peak activation by ؊9.3 ؎ 0.7 mV (n ‫؍‬ 10) in the presence of 5 nM 1,25D in VDR WT but not in KO cells, thus facilitating Ca 2؉ influx. Furthermore, we found that 1,25D significantly increased wholecell capacitance in VDR WT (⌬Cap ‫؍‬ 2.3 ؎ 0.4 pF, n ‫؍‬ 8) but not in KO osteoblasts (⌬Cap ‫؍‬ 0.3 ؎ 0.1 pF, n ‫؍‬ 8); this corresponds to a rapid (1-2 min) fusion in WT of 71 ؎ 33 versus in KO only 9 ؎ 6 individual secretory granules. We conclude that, in calvarial osteoblasts, 1,25D modulates ion channel activities only in cells with a functional VDR and that this effect is coupled to exocytosis. This is a demonstration of the requirement of a functional classic steroid receptor for the rapid hormonal modulation of electric currents linked to secretory activities in a target cell.N ongenomic responses to the steroid 1␣,25(OH) 2 -vitamin D 3 (1,25D) develop at the plasma membrane of various target cells and comprise rapid (seconds to minutes) changes in ion channel activities, activation of second messenger pathways, and elevation of cytosolic calcium concentrations (1-3). At a different level, 1,25D regulates the expression of tissue-specific genes via a nuclear vitamin D receptor (VDR) that functions as a transcription factor (4, 5). Although these two mechanisms of action are known to occur through different signaling pathways, there is no clear consensus yet whether rapid, membrane-related actions of 1,25D are initiated by a unique membrane receptor of unknown molecular identity or whether the classic VDR is involved (6-9).In bone, 1,25D elicits physiological responses at both the genomic and nongenomic levels. Osteoblasts, which are secretory cells, produce a variety of bone matrix proteins and actively participate in the mineralization process under the influence of hormones involved in mineral metabolism, such as 1,25D. Recently, several strains of functional VDR knockout (KO) mice have been created by means of deletion of selected portions of the VDR gene (10-13). They constitute a valuable tool for the study of a vast range of physiological conditions that arise from an impaired 1,25D physiology. Nuclear VDR KO mice, with abrogated 1,25D genomic actions, develop a genotype typical of rickets type II, characterized by decreased...

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“…[20] Vitamin D 3 facilitates the secretion of insulin from pancreatic beta cells, thus appearing to regulate insulin secretion and therefore vitamin D 3 deficiency may be related to impaired insulin secretion in the diabetes mellitus type 2. [21] Osei et al studies recommend vitamin D 3 supplementation to improve glucose control in type 2 diabetes mellitus patients. [22] In a randomized controlled trial, the administration of 2000 international units (IU) cholecalciferol daily for 16 weeks was found to improve beta cell function in adults at high risk for diabetes, and there was a trend toward attenuating the rise in HbA1c.…”

Section: Discussionmentioning

confidence: 99%

Study of vitamin D3 level in patients with diabetes mellitus

Makadia¹,

Patel²,

Patel³

et al. 2016

Int J of Biomed & Adv Res

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Introduction: Glycated hemoglobin (HbA1c) is primarily measured to identify glycemic control in diabetic patients. According to The American Diabetes Association (ADA), and World Health Organization (WHO), HbA1c concentrations 6.5% or more is diagnostic of diabetes. Vitamin D 3 deficiency has high prevalence all over the India. It has been proposed that mild to moderate vitamin D 3 deficiency is a risk factor for type 2 diabetes and higher plasma vitamin D 3 is related to a lower risk for the development of diabetes mellitus in high-risk patients. Aim and Objectives: The aim was to study the levels of vitamin D 3 and relationship between the levels of vitamin D 3 and HbA1c in diabetic patients. Material and Method: HbA1c and vitamin D 3 were measured in 100 diabetic patients, and another 100 age and sex matched normal healthy individuals. HbA1c was measured by Immunoturbidimetry and vitamin D 3 was measured by Electrochemiluminescence. Results: The mean vitamin D 3 level in diabetic patients (27.19 ± 6.03 nmol/L) was significantly lower than healthy individuals (61.13 ± 10.85 nmol/L) (P <0.001). There was an inverse correlation between the levels of vitamin D 3 and HbA1c (Pearson's correlation coefficient, r = -0.63, P <0.001). Conclusion: Vitamin D 3 levels are deficient in diabetic patients, and there is an inverse correlation between the levels of vitamin D 3 and HbA1c. So, the level of vitamin D 3 is inversely associated with glycemic control in diabetic patients. Therefore, vitamin D 3 supplementation may be helpful in the treatment of Diabetes Mellitus.

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Impaired insulin secretory capacity in mice lacking a functional vitamin D receptor

Cited by 384 publications

References 25 publications

Critical Role of Calbindin-D28k in Calcium Homeostasis Revealed by Mice Lacking Both Vitamin D Receptor and Calbindin-D28k

Critical Role of Calbindin-D28k in Calcium Homeostasis Revealed by Mice Lacking Both Vitamin D Receptor and Calbindin-D28k

Rapid modulation of osteoblast ion channel responses by 1α,25(OH) ₂ -vitamin D ₃ requires the presence of a functional vitamin D nuclear receptor

Study of vitamin D3 level in patients with diabetes mellitus

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Impaired insulin secretory capacity in mice lacking a functional vitamin D receptor

Cited by 384 publications

References 25 publications

Critical Role of Calbindin-D28k in Calcium Homeostasis Revealed by Mice Lacking Both Vitamin D Receptor and Calbindin-D28k

Critical Role of Calbindin-D28k in Calcium Homeostasis Revealed by Mice Lacking Both Vitamin D Receptor and Calbindin-D28k

Rapid modulation of osteoblast ion channel responses by 1α,25(OH) 2 -vitamin D 3 requires the presence of a functional vitamin D nuclear receptor

Study of vitamin D3 level in patients with diabetes mellitus

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Rapid modulation of osteoblast ion channel responses by 1α,25(OH) ₂ -vitamin D ₃ requires the presence of a functional vitamin D nuclear receptor