Effects of Ouabain on Insulin Secretion in the Dog

Abstract

The mechanism of the previously reported hypoglycemic effect of ouabain was studied in dogs. Ouabain (1.0 /xg/kg/min infused intravenously for 60 minutes) combined with insulin or propranolol caused a greater and more prolonged decrease in blood glucose than either of the drugs administered separately. In intact dogs, ouabain changed significantly portohepatic venous differences in plasma glucose from +6.6 to -13.6 mg/100 ml and in K + from -0.03 to -0.4 mEq/liter. In pancreatectomized animals, ouabain did not cause any significant decrease in peripheral glucose level, and the portohepatic differences in plasma glucose changed from +5.3 to +30.2 mg/100 ml and the differences in K + from -0.01 to +0.2 mEq/liter. These changes, indicating an increased release of glucose and K + by the liver in the pancreatectomized dog, were also observed in isolated rat liver perfused with ouabain 10~6M. Glucose uptake of the hindlimb increased significantly during the infusion of ouabain in normal dogs, but did not change in pancreatectomized dogs. Ouabain caused a significant increase in plasma insulin in portal blood ( + 155%). These results demonstrate that the observed metabolic effects of ouabain in the dog are mainly mediated by insulin and that ouabain increases the secretion of insulin in intact dogs.ADDITIONAL KEY WORDS hypoglycemia potassium cardiac glycosides glucose uptake insulin levels• The metabolic effects of ouabain in different tissues have been extensively studied in vitro. It has been observed that ouabain decreases the formation of lactate and oxidation of glucose and increases glycogen content in the muscle (1-6). Other investigators showed that in adipose tissue hormoneinduced lipolysis was inhibited by ouabain (7-9). The effect of ouabain on epinephrinestimulated glycogenolysis and lipolysis was further studied in this laboratory, and it was Dr. Triner is a Senior Investigator of the New York Heart Association, and Dr. Killian holds U. S. Public Health Service Grant TIAM-5397.Received May 1, 1969. Accepted for publication June 12, 1969. shown that ouabain in vitro inhibits the metabolic effects of epinephrine (10, 11). All these in-vitro studies were performed with 10~r' M to K H M concentrations of ouabain.To study the metabolic effects of ouabain in vivo, experiments were performed in dogs which were given ouabain, 1.0 /i,g/kg/min iv for 60 minutes (12), a substantially lower dose than that used in vitro. This dose, which corresponds approximately to four times the therapeutic dosage, did not produce any marked electrocardiographic or plasma potassium changes, but caused a significant decrease in glucose and glycerol plasma concentrations. The same dose of ouabain significantly inhibited the lipolytic and glycogenolytic effects of epinephrine (12). The purpose of the present series of experiments was to investigate the mechanism of the hypoglycemic effect of ouabain, i.e., to establish whether it is a direct effect of the drug on glucose metabolism or whether it is mediated through insulin.

Modeling Congenital Hyperinsulinism with ABCC8-Deficient Human Embryonic Stem Cells Generated by CRISPR/Cas9

“…The Na-K pump is located in the plasma membrane of all animal cells and functions to pump sodium outward and potassium inward. Ouabain increases insulin secretion as an Na-K pump inhibitor 36, 37 . However, it remains unknown whether the insulin secretion increased by ouabain is dependent on K ATP channels.…”

Effect of Ouabain on Insulin Secretion in Man

“…Triner, Kypson & Nahas (1968) reported that the intravenous infusion of ouabain in a dose of 1 pglmin-' kg-' for 1 h resulted in a significant decrease (30%; P<0*05) of blood glucose concentration in anaesthetized dogs. Loubatieres et al (1968) and Triner et al (1969) subsequently demonstrated that the fall in blood glucose concentration observed during similar ouabain infusions was associated with a significant increase in plasma insulin concentration in the portal vein. However, both groups used doses four times greater than that used in the present studies, the maximum safe dose in man, whereas Milner & Hales (1967) used concentrations of ouabain 400 times greater.…”

“…Ouabain is capable of stimulating the release of insulin from tissue slices of rabbit pancreas (Milner & Hales, 1967) and from the pancreas of the anaesthetized dog (Loubatieres, Mariani, Sonel & Sonel, 1968;Triner, Papayoanou, Killian, Vulliemoz, Castany & Nahas, 1969). This is of considerable clinical interest in the light of the recent finding that insulin secretion is suppressed in patients with severe heart failure (Sharma, Majid, Pakrashi, Dykes & Taylor, 1970;Majid, Saxton, Dykes, Galvin & Taylor, 1970), particularly as digitalis glycosides are frequently employed in the treatment of these patients.…”

“…However, as the relief of heart failure itself results in significant improvement in insulin secretion (Sharma et al, 1970; the direct importance of these glycosides in the relief of insulin suppression in such patients is difficult to define. Triner et al (1969) also suggested that the mechanism whereby ouabain exerted its hypoglycaemic activity was either by suppression of release of catecholamines or by interference with their metabolic effects. In view of the possible therapeutic implications of these observations studies were undertaken to determine the effect of ouabain on plasma insulin, blood glucose and urinary excretion of catecholamines in normal man and to examine the effect of treatment with digitalis on the response of insulin secretion by the pancreas after intravenous tolbutamide.…”

Rethinking Heart Failure

“…This effect is synergistically enhanced by addition of insulin. Furthermore, ouabain induces increased secretion of insulin and in vitro inhibits the metabolic effects of epinephrine [80]. A clear-cut stimulatory effect of ouabain on the production of insulin in the anesthetized dog has been demonstrated in both infusion and “one shot” experiments [81].…”