Rapid normalization/stimulation by 1,25-dihydroxyvitamin D3 of insulin secretion and glucose tolerance in the vitamin D-deficient rat

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.