An anomaly of insulin removal in perfused livers of obese-hyperglycemic (ob/ob) mice.

Obese-hyperglycemic (ob/ob) mice have the interesting feature of being hyperinsulinemic, thus having some characteristics in common with human maturity-onset diabetics. As the cause of hyperinsulinemia in these mice is not established, and as the liver is known to play a role in determining the amount of hormone that reaches the periphery, it was hypothesized that an anomaly in the hepatic handling of insulin might prevail in obese-hyperglycemic mice. Immunoreactive insulin was therefore measured in the perfusate before and after a single passage through perfused livers of lean and ob/ob mice, permitting. It was found that the removal of insulin by livers of lean mice increased with increasing concentrations of the hormone in the portal vein. The removal process had a limited capacity, however, and as a consequence the percentage of hormone removed by the liver actually decreased when portal insulin concentrations increased. Insulin removal by livers of ob/ob mice had qualitatively the same characteristics but was considerably less efficient than in normal livers. Due to this, more insulin was found in the perfusate leaving the liver of ob/9b mice than in that of controls, at any insulin concentration tested. These observations suggest that in obese-hyperglycemic mice more of the hormone may reach the periphery and thus contribute to hyperinsulinemia. The present study further suggests that the anomaly of insulin removal observed in perfused livers of ob/ob mice might be secondary to hyperinsulinemia, since it was partly corrected upon artificially decreasing the circulating levels of insulin (e.g. via a fast, anti-insulin serum, or streptozotocin treatment) before perfusion. The characteristics of hepatic insulin removal reported in this study, as well as the differences observed between livers of lean and ob/ob mice, may reflect changes in membrane insulin receptors and/or in processes responsible for the degradation of the horomone.