Endogenous digoxin-like immunoactivity and diabetes mellitus: facts and hypotheses

Substances with digoxin- and ouabain-like immunoactivity (DLIA) are specific inhibitors of Na(+)-K(+)-ATPase which increase the total amount of intracellular stored calcium (Ca2+i). In diabetic patients, DLIA levels have been reported to be increased. Although this increase is probably secondary to sodium retention and volume expansion (included in diabetic subjects by hyperinsulinemia and/or diabetic nephropathy), the question arises of whether it has pathophysiological consequences: namely, whether substances with DLIA, via their effect on Na(+)-K(+)-ATPase activity and Ca2+i stores, could in diabetic subjects facilitate development of hypertension and/or modulate insulin sensitivity or insulin secretion. Clinical findings of correlations of DLIA to blood pressure, insulin levels and to degree of insulin resistance, together with experimental findings of decreased Na(+)-K(+)-ATPase activity, increased Ca2+i and decreased Mg2+i in both diabetic and hypertensive subjects, support these hypotheses. However, the issue of whether or not these relations are causative and whether or not defects in intracellular milieu are primary or secondary to non-insulin-dependent diabetes mellitus has not been resolved yet. Moreover, pathogenesis of both diabetes mellitus and hypertension is multifactorial and includes many other factors. Therefore, further efforts should be made to elucidate the exact role of substances with DLIA in diabetes mellitus.