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Rapid normalization/stimulation by 1,25-dihydroxyvitamin D3 of insulin secretion and glucose tolerance in the vitamin
Abstract:
It has been previously demonstrated in this laboratory that vitamin D3 is essential for normal insulin secretion from the perfused rat pancreas. More recently we have shown, consistent with a physiological role for the vitamin in this process, that vitamin D-deficient rats exhibit impaired glucose clearance and insulin secretion, as monitored during iv glucose tolerance tests. Both of these parameters are significantly improved after vitamin D repletion independently of nutritional factors and the prevailing plasma calcium and phosphorus concentrations. In this present study the dose response and time course of effect of a single sc injection of the active metabolite 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] on glucose tolerance and insulin secretion were investigated. The impaired glucose clearance of vitamin D-deficient rats (KG = 912 +/- 37, where KG is a function of glucose tolerance) was markedly improved as early as 3 h after acute 1,25(OH)2D3 (1.3 nmol; 20 U) administration (KG = 676 +/- 13), and this clearance was maintained for up to 20 h (KG = 688 +/- 24). This improvement corresponded to enhanced glucose-induced insulin secretion. By 3 h after 1,25-(OH)2D3 substitution, the peak of insulin secretion was elevated by 170% of control values, independently of a significant increase in plasma phosphorus or plasma calcium concentrations. The hypoglycemic propensity of 1,25-(OH)2D3 was also dose dependent. Glucose tolerance was significantly improved (KG = 573 +/- 33), and insulin secretion was maximal (250% of control) after administration of only 0.26 nmol (4 U) 1,25-(OH)2D3. Higher concentrations of seco-steroid, although stimulatory, proved less effective. This study demonstrates a rapid response (within 3 h) to the potentiating action of 1,25-(OH)2D3 on in vivo insulin secretion and glucose clearance in the vitamin D-deficient rat. A dose dependence of this hypoglycemic action is also established.