ROLE OF METALLOTHIONEIN AND CYSTEINE-RICH INTESTINAL PROTEIN IN THE REGULATION OF ZINC-ABSORPTION BY DIABETIC RATS

Hyperzincuria and low Zn absorption in diabetic animals and humans have prompted speculation that diabetics are more susceptible to Zn deficiency. There is little information, however, describing the effects of diabetes on the biochemical mechanisms of intestinal Zn transport. We evaluated Zn absorption in streptozotocin-induced diabetic rats based on a model of Zn transport in which cysteine-rich intestinal protein serves as an intracellular carrier that is inhibited by metallothionein (MT). Apparent absorption and retention of Zn and Cu in rats fed a purified diet were measured in a balance study 15-17 d after induction of diabetes. The rate of Zn-65 absorption from isolated intestinal segments, molecular distribution of Zn-65 in mucosal cytosol, and tissue MT levels were measured on d 20-22. Food consumption, and thus Zn and Cu intake, by diabetic rats was twice that of controls. Although fractional absorption (percent) of Zn and Cu was lower in the diabetic rats, net absorption (mu g/100 g body weight/d) was higher. The higher net absorption in the diabetic group was offset, however, by higher urinary excretion, so that Zn and Cu retention was similar in both groups of animals. Low fractional absorption is attributable to the down-regulation of intestinal Zn transport, as indicated by the lower rate of Zn-65 absorption from isolated intestinal segments in the diabetic rats. Down-regulation of intestinal transport is in turn attributable to higher concentrations of intestinal MT, which resulted in more Zn-65 in the mucosal cytosol bound to MT, an inhibitor of Zn transport, and less to cysteine-rich intestinal protein. These observations are similar to those previously described in rats consuming normal amounts of a diet containing excess Zn and are consistent with an antagonistic relationship between cysteine-rich intestinal protein and MT in Zn transport. The results suggest that decreased Zn absorption in diabetic rats is not a disease-related defect in Zn transport but instead is a homeostatic response to high Zn intake caused by overconsumption of a diet with a moderate Zn content.