digoxin and Hyperinsulinism

Insulin resistance is strongly associated with hypertension and is postulated to participate in the elevation of blood pressure, although the mechanisms involved are not understood. Recently, we reported that acute increases in plasma insulin levels in normal subjects resulted in increased serum levels of a sodium pump inhibitor, termed the digitalis-like factor (DLF), which has been implicated in both experimental and essential human hypertension. This study looked at the DLF response to hyperinsulinemia, achieved by an oral glucose tolerance test (OGTT), in the setting of a naturally occurring and self-resolving state of human insulin resistance, during third-trimester pregnancy. This model allowed us the further opportunity to compare the DLF response to insulin in the same subjects postpartum, after resolution of their insulin resistance. Administration of an OGTT during pregnancy and postpartum in the same subjects elicited a comparable serum glucose response but a significantly greater insulin response during third-trimester pregnancy, consistent with diminished insulin sensitivity (integrated insulin response during pregnancy: 1611+/-236 vs postpartum: 685+/-101 pmol/l, P=0.004). The time courses of the glucose and insulin responses were identical whether women were pregnant or not. Plasma free fatty acids fell significantly and to a comparable degree during pregnancy and postpartum, but the response was slower during pregnancy. DLF levels increased in response to oral glucose in both pregnant and nonpregnant states. The response was more rapid during pregnancy than after. These findings showed that the increment of insulin induced by oral glucose during pregnancy caused a more rapid rise in circulating DLF levels than it did during the nonpregnant state. At the same time, the response of circulating fatty acids to glucose is retarded during pregnancy. This suggests that the insulin resistance of pregnancy impairs insulin's influence on intermediary metabolism but not its influence on DLF. As a vasoactive substance, DLF might contribute to the hypertension characteristic of insulin-resistant states.

Topics: Adult; Biomarkers; Blood Glucose; Cardenolides; Digoxin; Enzyme Inhibitors; Fatty Acids, Nonesterified; Female; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Maternal Welfare; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy Outcome; Pregnancy Trimester, Third; Saponins; Statistics as Topic; Time Factors; Utah

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.

Topics: Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Digoxin; Glucose; Humans; Hyperinsulinism; Hypertension; Immunoassay; Insulin; Insulin Secretion; Models, Biological; Ouabain