digoxin and Insulin-Resistance

The role of hypoxia-inducible factor (HIF)-1 in pancreatic β-cell response to intermittent hypoxia (IH) was examined. Studies were performed on adult wild-type (WT), HIF-1α heterozygous (HET), β-cell-specific

Topics: Animals; Digoxin; Disease Models, Animal; Glucose; Heterozygote; Hydrogen Peroxide; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Insulin; Insulin Resistance; Insulin-Secreting Cells; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; NADPH Oxidase 4; Oxygen; RNA, Small Interfering; Sleep Apnea, Obstructive; Transcriptional Activation

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

Hypertensive obese subjects with glucose intolerance have hyperinsulinaemia, insulin resistance and intracellular cation imbalance resulting in increased sodium content. The aim of our study was to assess in these patients plasma levels of endogenous digoxin-like factor (EDLF), an inhibitor of the sodium-pump mechanism. We studied 14 hypertensive and 12 normotensive subjects with obesity and glucose intolerance for fasting blood glucose, and plasma insulin, C-peptide and EDLF levels: the two groups were matched for age and BMI and were studied after a 2-week wash-out period from hypotensive drugs. Compared with normotensives, hypertensive subjects had higher plasma insulin levels, a greater immunoreactive insulin/C-peptide ratio, a lower glucose/insulin ratio and higher plasma EDLF levels. Our results confirm that among obese people with glucose intolerance, hypertensives are more hyperinsulinaemic and insulin-resistant than normotensives and indicate that the intracellular cation imbalance in these patients may be attributable, at least in part, to EDLF.

Topics: Blood Glucose; Blood Proteins; C-Peptide; Cardenolides; Digoxin; Female; Glucose Tolerance Test; Humans; Hyperglycemia; Hypertension; Insulin; Insulin Resistance; Male; Middle Aged; Obesity; Saponins; Sodium-Potassium-Exchanging ATPase