Ever since its discovery by Windhaus, the importance of the active metabolite of vitamin D (1,25-dihydroxyvitamin D3; 1,25-(OH)2D3) has been ever expanding. In this review, the attention is shifted towards the importance of the extra-skeletal effects of vitamin D, with special emphasis on the immune system. The first hint of the significant role of vitamin D on the immune system was made by the discovery of the presence of the vitamin D receptor on almost all cells of the immune system. In vitro, the overwhelming effect of supra-physiological doses of vitamin D on the individual components of the immune system is very clear. Despite these promising pre-clinical results, the translation of the in vitro observations to solid clinical effects has mostly failed. Nevertheless, the evidence of a link between vitamin D deficiency and adverse outcomes is overwhelming and clearly points towards avoidance of vitamin D deficiency especially in early life.

The microRNA-29 (miR-29) family is among the most abundantly expressed microRNA in the pancreas and liver. Here, we investigated the function of miR-29 in glucose regulation using miR-29a/b-1 (miR-29a)-deficient mice and newly generated miR-29b-2/c (miR-29c)-deficient mice. We observed multiple independent functions of the miR-29 family, which can be segregated into a hierarchical physiologic regulation of glucose handling. miR-29a, and not miR-29c, was observed to be a positive regulator of insulin secretion in vivo, with dysregulation of the exocytotic machinery sensitizing β-cells to overt diabetes after unfolded protein stress. By contrast, in the liver both miR-29a and miR-29c were important negative regulators of insulin signaling via phosphatidylinositol 3-kinase regulation. Global or hepatic insufficiency of miR-29 potently inhibited obesity and prevented the onset of diet-induced insulin resistance. These results demonstrate strong regulatory functions for the miR-29 family in obesity and diabetes, culminating in a hierarchical and dose-dependent effect on premature lethality.

systemic glucose levels by increasing glucose utilization by the skeleton. This simple yet unexpected concept brings a potential new angle to the sophisticated integration of the skeleton in global nutrient homeostasis, and may have broad clinical impact with regard to bone and metabolic disorders, as well as in cancer pathology and therapy.

Hepatic fat accumulation is associated with diabetes and hepatocellular carcinoma (HCC). Here we characterize the metabolic response that high fat availability elicits in livers prior to disease development. After a short term on a high fat diet, otherwise healthy mice showed elevated hepatic glucose uptake and increased glucose contribution to serine and pyruvate carboxylase activity compared to control diet mice. This glucose phenotype occurred independently from transcriptional or proteomic programming, which identifies increased peroxisomal and lipid metabolism pathways. High fat diet-fed mice exhibited increased lactate production when challenged with glucose. Consistently, administration of an oral glucose bolus to healthy individuals revealed a correlation between waist circumference and lactate secretion in a human cohort. In vitro, palmitate exposure stimulated production of reactive oxygen species and subsequent glucose uptake and lactate secretion in hepatocytes and liver cancer cells.Furthermore, high fat diet enhanced the formation of HCC compared to control diet in mice exposed to a hepatic carcinogen. Regardless of the dietary background, all murine tumors showed similar alterations in glucose metabolism to those identified in fat exposed non-transformed mouse livers; however, particular lipid species were elevated in high fat diet tumor and nontumor-bearing high fat diet liver tissue. These findings suggest that fat can induce glucosemediated metabolic changes in non-transformed liver cells similar to those found in HCC.Significance: With obesity-induced hepatocellular carcinoma on a rising trend, this study shows in normal, non-transformed livers that fat induces glucose metabolism similar to an oncogenic transformation.