Insulinlike Effects of Zinc Ion in Vitro and in Vivo: Preferential Effects on Desensitized Adipocytes and Induction of Normoglycemia in Streptozocin-Induced Rats

The effects of Zn²⁺ in mimicking insulin in vivo and in vitro are further characterized. Like insulin, Zn²⁺ stimulated the conversion of [U-¹⁴C]-, [1-¹⁴C]-, and [6-¹⁴C]glucose to lipids in rat adipocytes. Maximum stimulation of lipogenesis was 55–80% of maximum insulin response after preincubation (30 min at 37 degrees C) of adipocytes with ZnCl₂ (0.4 mM). Under these conditions, the half-maximum effect was achieved at 0.17 ± 0.02 mM of ZnCl₂. Similarly, an insulinlike effect of Zn²⁺ was observed on the oxidation of glucose by both pathways, glycolytic and hexose monophosphate shunt. In contrast, unlike insulin, Zn²⁺ did not inhibit lipolysis but rather exhibited a slight lipolytic activity. Also, the effect of Zn²⁺ on hexose influx did not exceed 14 ± 3% that of insulin. The stimulatory effects of Zn²⁺ were not related to generation of H2O2. Catalase (100 μg/ml) did not inhibit Zn²⁺-stimulated glucose oxidation and its incorporation into lipids. Zn²⁺ had an additive effect on either insulin- or vanadate-stimulated conversion of [1-¹⁴C]glucose to fat, and together, the effect was ∼ 140% of the maximum rate of lipogenesis. Chelation of intracellular Zn²⁺ by the cell-permeable chelator N,N,N′,N′-tetrakis (2-pyridylmethyl)ethylenediamine did not significantly affect the ability of insulin to stimulate lipogenesis. Adipocytes derived from STZ rats were largely refractory to the modulating action of insulin. In contrast, the effect of Zn²⁺ on lipogenesis in these cells was more pronounced. It was more than fivefold that of the hormone, and the dose-response curve shifted to the left (ED₅₀ = 85 ± 10 μM of ZnCI₂).l.p. administration of ZnCI₂ (100 mg/kg body wt) to hyperglycemic STZ rats reduced blood glucose levels within 3 h to normal values. Similarly, ZnCI₂ administered orally to STZ rats (210 mg/kg body wt) reduced blood glucose concentration as much as 50% 2 h after treatment. We conclude that Zn²⁺ mimics several actions of insulin, both in vitro and in vivo, by a mechanism unrelated to insulin. The clinical implication of this study is discussed.