Elimination of Vitamin D Signaling Causes Increased Mortality in a Model of Overactivation of the Insulin Receptor: Role of Lipid Metabolism.

Vitamin D (VD) deficiency has been associated with cancer and diabetes. Insulin signaling through the insulin receptor (IR) stimulates cellular responses by activating the PI3K/AKT pathway. PTEN is a tumor suppressor and a negative regulator of the pathway. Its absence enhances insulin signaling leading to hypoglycemia, a dangerous complication found after insulin overdose. We analyzed the effect of VD signaling in a model of overactivation of the IR. We generated inducible double KO (DKO) mice for the VD receptor (VDR) and PTEN. DKO mice showed severe hypoglycemia, lower total cholesterol and increased mortality. No macroscopic tumors were detected. Analysis of the glucose metabolism did not show clear differences that would explain the increased mortality. Glucose supplementation, either systemically or directly into the brain, did not enhance DKO survival. Lipidic liver metabolism was altered as there was a delay in the activation of genes related to ß-oxidation and a decrease in lipogenesis in DKO mice. High-fat diet administration in DKO significantly improved its life span. Lack of vitamin D signaling increases mortality in a model of overactivation of the IR by impairing lipid metabolism. Clinically, these results reveal the importance of adequate Vitamin D levels in T1D patients.

The Role of Disturbed Mg Homeostasis in Chronic Kidney Disease Comorbidities.

Some of the critical mechanisms that mediate chronic kidney disease (CKD) progression are associated with vascular calcifications, disbalance of mineral metabolism, increased oxidative and metabolic stress, inflammation, coagulation abnormalities, endothelial dysfunction, or accumulation of uremic toxins. Also, it is widely accepted that pathologies with a strong influence in CKD progression are diabetes, hypertension, and cardiovascular disease (CVD). A disbalance in magnesium (Mg) homeostasis, more specifically hypomagnesemia, is associated with the development and progression of the comorbidities mentioned above, and some mechanisms might explain why low serum Mg is associated with negative clinical outcomes such as major adverse cardiovascular and renal events. Furthermore, it is likely that hypomagnesemia causes the release of inflammatory cytokines and C-reactive protein and promotes insulin resistance. Animal models have shown that Mg supplementation reverses vascular calcifications; thus, clinicians have focused on the potential benefits that Mg supplementation may have in humans. Recent evidence suggests that Mg reduces coronary artery calcifications and facilitates peripheral vasodilation. Mg may reduce vascular calcification by direct inhibition of the Wnt/ß-catenin signaling pathway. Furthermore, Mg deficiency worsens kidney injury induced by an increased tubular load of phosphate. One important consequence of excessive tubular load of phosphate is the reduction of renal tubule expression of α-Klotho in moderate CKD. Low Mg levels worsen the reduction of Klotho induced by the tubular load of phosphate. Evidence to support clinical translation is yet insufficient, and more clinical studies are required to claim enough evidence for decision-making in daily practice. Meanwhile, it seems reasonable to prevent and treat Mg deficiency. This review aims to summarize the current understanding of Mg homeostasis, the potential mechanisms that may mediate the effect of Mg deficiency on CKD progression, CVD, and mortality.