Higher vitamin D status is associated with reduced incidence of insulin resistance and diabetes, but the mechanism has not been clarified. The aim of this study was to investigate the effects of vitamin D on insulin signaling. Because vitamin D status is inversely related to serum parathyroid hormone (PTH) levels, PTH may modulate effects of vitamin D status on insulin sensitivity. In 3T3-L1 adipocytes, PTH (10 nM) treatment for 24 hr decreased insulin-stimulated glucose uptake by 17% (P < 0.01) compared to vehicle, assessed with [3H]-2-deoxyglucose following insulin stimulation. This inhibitory effect was dose-dependent, with a significant reduction noted at 1 nM PTH. The mRNA expression of the insulin receptor (IR), IR substrate-1 (IRS-1), glucose transporter 1 (GLUT1), and glucose transporter 4 (GLUT4) were significantly decreased following 24 hr PTH treatment (10 nM, P < 0.05). There was a significant reduction in insulin-stimulated AKT activity (12%) (phosphorylated/total expression). PTH treatment (24 hr, 10 nM) significantly reduced GLUT4, but not GLUT1 protein expression. In addition, PTH treatment induced increased phosphorylation of IRS-1 at an inhibitory serine site, suggesting that this may be a mechanism by which insulin stimulation is reduced. Therefore, higher vitamin D status may lead to improved insulin sensitivity by suppressing serum PTH. PTH potentially reduces insulin signaling through serine phosphorylation of IRS-1 and decreasing the expression of GLUT4. It was also examined if the active metabolite of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH) 2 D) improves insulin sensitivity in differentiated cells and TNFα-induced insulin resistant adipocytes. However, 1,25(OH) 2 D significantly decreased insulin-stimulated glucose uptake in both cell models. In addition, higher vitamin D intake in rats did not affect insulin sensitivity in rodents fed a diet containing high fructose levels, which induces insulin resistance. The was no signs of altering insulin sensitivity after reversing fructose diet to fructose with high vitamin D (10,000 IU/3904 kcal) and calcium (1.5%) or low vitamin D (400 IU/3904 kcal) and calcium (0.25%) in high fructose induced insulin resistant rats. Taken together, strategies to improve vitamin D status, with subsequent suppression of PTH and improved insulin sensitivity, may significantly contribute to preventing the growing epidemic of Type 2 diabetes.
