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Excessive cholecalciferol supplementation increases kidney dysfunction associated with intrarenal artery calcification in obese insulin-resistant mice.

ABSTRACT: Diabetes mellitus accelerates vascular calcification (VC) and increases the risk of end-stage renal disease (ESRD). Nevertheless, the impact of VC in renal disease progression in type 2 diabetes mellitus (T2DM) is poorly understood. We addressed the effect of VC and mechanisms involved in renal dysfunction in a murine model of insulin resistance and obesity (ob/ob), comparing with their healthy littermates (C57BL/6). We analyzed VC and renal function in both mouse strains after challenging them with Vitamin D₃ (VitD₃). Although VitD₃ similarly increased serum calcium and induced bone disease in both strains, 24-hour urine volume and creatinine pronouncedly decreased only in ob/ob mice. Moreover, ob/ob increased urinary albumin/creatinine ratio (ACR), indicating kidney dysfunction. In parallel, ob/ob developed extensive intrarenal VC after VitD₃. Coincidently with increased intrarenal vascular mineralization, our results demonstrated that Bone Morphogenetic Protein-2 (BMP-2) was highly expressed in these arteries exclusively in ob/ob. These data depict a greater susceptibility of ob/ob mice to develop renal disease after VitD₃ in comparison to paired C57BL/6. In conclusion, this study unfolds novel mechanisms of progressive renal dysfunction in diabetes mellitus (DM) after VitD₃ in vivo associated with increased intrarenal VC and highlights possible harmful effects of long-term supplementation of VitD₃ in this population.

SUBMITTER: Almeida YE

PROVIDER: S-EPMC6952360 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Excessive cholecalciferol supplementation increases kidney dysfunction associated with intrarenal artery calcification in obese insulin-resistant mice.

Almeida Youri E YE Fessel Melissa R MR do Carmo Luciana Simão LS Jorgetti Vanda V Farias-Silva Elisângela E Pescatore Luciana Alves LA Gamarra Lionel F LF Andrade Maria Claudina MC Simplicio-Filho Antonio A Mangueira Cristóvão Luis Pitangueiras CLP Rangel Érika B ÉB Liberman Marcel M

Scientific reports 20200109 1

Diabetes mellitus accelerates vascular calcification (VC) and increases the risk of end-stage renal disease (ESRD). Nevertheless, the impact of VC in renal disease progression in type 2 diabetes mellitus (T2DM) is poorly understood. We addressed the effect of VC and mechanisms involved in renal dysfunction in a murine model of insulin resistance and obesity (ob/ob), comparing with their healthy littermates (C57BL/6). We analyzed VC and renal function in both mouse strains after challenging them ...[more]

PMID: 31919470

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Project description:BackgroundThere is increasing interest in the extraskeletal effects of vitamin D, particularly in the obese state with regard to the development of insulin resistance and diabetes.ObjectiveThe objective of the study was to determine the effect of 2 doses of cholecalciferol (vitamin D3) supplementation on insulin action (Si) and pancreatic β-cell function in obese adolescents.MethodsWe performed a 12-wk double-blind, randomized comparison of the effect of vitamin D3 supplementation on Si and β-cell function in obese Caucasian adolescents (body mass index > 95(th) percentile). The subjects were randomly assigned to receive either 400 IU/d (n = 25) or 2000 IU/d (n = 26) of vitamin D3. Each subject underwent a 7-sample 75 g oral glucose tolerance test, with glucose, insulin, and C-peptide measurements, to calculate Si and β-cell function as assessed by the disposition index (DI), with use of the oral minimal model before and after supplementation. A total of 51 subjects aged 15.0 ± 1.9 y were enrolled. Included for analysis at follow-up were a total of 46 subjects (20 male and 26 female adolescents), 23 in each group.ResultsInitial serum 25-hydroxyvitamin D [25(OH)D] was 24.0 ± 8.1 μg/L. There was no correlation between 25(OH)D concentrations and Si or DI. There was a modest but significant increase in 25(OH)D concentration in the 2000 IU/d group (3.1 ± 6.5 μg/L, P = 0.04) but not in the 400 IU/d group (P = 0.39). There was no change in Si or DI following vitamin D3 supplementation in either of the treatment groups (all P > 0.10).ConclusionsThe current study shows no effect from vitamin D3 supplementation, irrespective of its dose, on β-cell function or insulin action in obese nondiabetic adolescents with relatively good vitamin D status. Whether obese adolescents with vitamin D deficiency and impaired glucose metabolism would respond differently to vitamin D3 supplementation remains unclear and warrants further studies. This trial was registered at clinicaltrials.gov as NCT00858247.

Dataset Information

Excessive cholecalciferol supplementation increases kidney dysfunction associated with intrarenal artery calcification in obese insulin-resistant mice.

Publications

Excessive cholecalciferol supplementation increases kidney dysfunction associated with intrarenal artery calcification in obese insulin-resistant mice.

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