Abstract
Recent evidence has identified a role of micronutrients, such as magnesium (Mg2+) and calcium (Ca2+), in glycemic control. 4-Phenylbutyric acid (PBA) and tauroursodeoxycholic acid (TUDCA) are molecular chaperones that can improve protein folding and alleviate endoplasmic reticulum (ER) stress. Increasingly, research is focusing on the association between molecular chaperones and micronutrients. This study established and characterized a mouse model of type 1 diabetes (T1D) and investigated the effect of PBA and TUDCA on Mg2+ and Ca2+ metabolism in these mice. T1D was established in Friend virus B-type mice using multiple low doses of streptozotocin. Mice were administered chaperones. Mg2+and Ca2+ levels in tissues and serum were detected using acid digestion and ICP-MS. At 2 weeks and 2 months after chaperone administration was initiated, Mg2+ levels in the heart, liver, kidney, and serum and Ca2+ levels in spleen and serum of T1D mice were significantly decreased compared with controls; Ca2+ levels in the kidney and muscle of T1D mice were significantly increased; Mg2+ and Ca2+ levels in the heart, liver, kidney, muscle, spleen, and serum were positively correlated in control and T1D mice; and PBA restored renal Mg2+ levels to normal values and TUDCA restored hepatic, renal, and serum Mg2+ levels and renal and serum Ca2+ levels to normal values in T1D mice. PBA restored muscular Ca2+ levels to normal values in T1D mice at 2 months after chaperone or vehicle administration was initiated. Further research is required to investigate the underlying mechanisms by which chaperones regulate micronutrients in diabetes.
Highlights
Non-communicable diseases (NCDs), including cardiovascular disease, diabetes mellitus, cancer, and chronic respiratory diseases [1], are associated with substantial morbidity and mortality
Mice were randomly divided into six groups: non-diabetic control mice (CON); diabetic mice (DM); diabetic mice treated with phenylbutyric acid (PBA) (PBA + DM); diabetic mice treated with tauroursodeoxycholic acid (TUDCA) (TUDCA + DM); non-diabetic control mice treated with PBA (PBA); and non-diabetic control mice treated with TUDCA (TUDCA)
At 2 weeks and 2 months, PBA + DM or TUDCA + DM mice had significantly higher body weight (2 weeks, PBA + DM 28.8 ± 0.49 g, TUDCA + DM 26.0 ± 0.35 g; 2 months, PBA + DM 25.8 ± 0.28 g, TUDCA + DM 26.1 ± 0.20 g; P < 0.05 vs. DM mice) and significantly lower blood glucose (2 weeks, PBA + DM 26.4 ± 0.47 mmol/L, TUDCA + DM 21.4 ± 0.84 mmol/L; 2 months, PBA + DM 28.5 ± 0.76 mmol/L, TUDCA + DM 23.1 ± 0.71 mmol/L; P < 0.05 vs. DM mice) than the DM mice, most values did not return to control levels
Summary
Non-communicable diseases (NCDs), including cardiovascular disease, diabetes mellitus, cancer, and chronic respiratory diseases [1], are associated with substantial morbidity and mortality. Mg2+ is the most abundant divalent intracellular cation, the second most abundant intracellular ion, and the fourth most abundant mineral in the human body [7]. Ca2+ is the most abundant ion in the body. Alterations in Ca2+ homeostasis are associated with organelle dysfunction and stress responses in metabolic organs such as liver and adipose tissue [6]. Both T1D and T2D are characterized by changes in Ca2+ and bone metabolism, in part due to impaired Ca2+ absorption from intestine [10]. According to our previous studies [11, 12], diabetes induces endoplasmic reticulum stress (ERS) and vice versa; the effect on trace elements, especially on Ca2+, is quite clear
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