Effect of dietary minerals and diabetes on renal vitamin D hydroxylation and calcium homeostasis.

Abstract

Mg deficiency is associated with profound changes in Ca homeostasis which may involve complex interactions between PTH and vitamin D. To examine the aetiology of the aberrant Ca homeostasis in Mg deficiency a series of studies were conducted in chicks to assess indices of vitamin D metabolism and PTH target tissue effects. Mg deficient chicks fed adequate Ca had normal circulating 1,25(OH)2D3, 1alphahydroxylase activity and retention of Ca in bone, despite hypocalcaemia. In contrast chicks consuming diets low in Ca concomitant with or subsequent to Mg depletion exhibited elevated circulating 1,25(OH)2D3, decreased bone Ca and normocalcaemia. Mg deficient chicks which received 1,25(OH)2D3 supplementation maintained normal extracellular Ca. Collectively these results suggest alterations in vitamin D metabolism are pivotal to the genesis of hypomagnesaemic hypocalcaemia. The inappropriate 1alphahydroxylase responsiveness to the prevailing hypocalcaemia in Mg deficiency was not associated with decreased circulating 25(OH)D3, elevated circulating 24,25(OH)2D3, increased metabolic clearance of 1,25(OH)2D3 or alterations in renal tubule viability; nor was renal resistance to PTH indicated. Since neither vitamin D resistance nor renal or skeletal PTH resistance were consistently observed in Mg deficiency, it is possible that alterations in cell Ca, induced by Mg deficiency, are involved in the aetiology of hypomagnesaemic hypocalcaemia. Alterations in vitamin D metabolism and Ca homeostasis are consistently observed in insulin dependent diabetes. The aetiology of the aberrant vitamin D metabolism in diabetes was investigated in experimental spontaneous (BB) and chemically induced (STZ) diabetes. Circulating and net synthesis of 1,25(OH) 2D3 were reduced in both models of diabetes. These reductions were observed 72 hours after insulin deficiency in STZ diabetes. In vivo insulin therapy normalized circulating 1,25(OH)2D3 and 1alphahydroxylase activity in diabetes, however 1alphahydroxylase activity was not increased in diabetic renal tubules exposed to insulin in vitro. Thus insulin does not directly alter basal 1,25(OH)2D3 synthesis or acutely influence vitamin D metabolism. Renal resistance to in vitro PTH was not observed in diabetes. 1,25(OH)2D3 production was enhanced in renal tubules from diabetic rats on low dietary Ca. PKC activity was elevated in STZ diabetic rat renal tubule membranes 24 hours prior to the onset of decreased circulating and net synthesis of 1,25(OH)2D3. PKC activity correlated with renal hypertrophy in diabetes, and PKC activation was associated with decreased 1alphahydroxylase activity in isolated renal tubules. Therefore the alterations in vitamin D metabolism associated with insulin dependent diabetes, may be related to elevated renal PKC activity and renal hypertrophy.