Ciglitazone prevents and reverses dexamethasone-induced hyperglycemia in female viable yellow mice.

Hypercorticism has been observed in numerous obese and diabetic animal models. Adrenalectomy reduces adiposity, hyperglycemia, hyperinsulinemia, and insulin resistance in these animals. The effects of adrenalectomy can be reversed by glucocorticoid replacement. Male and female viable yellow mice share all phenotypic expressions caused by the viable yellow mutation except that males are hyperglycemic and most females are either normoglycemic or only mildly hyperglycemic. The mechanisms that protect female viable yellow mice from hyperglycemia are not known. Implantation of dexamethasone pellets induced hyperglycemia in female viable yellow mice but had no effect on blood glucose of male viable yellow mice and male and female normal mice. The duration of dexamethasone-induced hyperglycemia correlated to the time endogenous plasma corticosterone levels were suppressed. Plasma insulin levels rose in normal mice but only transiently in viable yellow mice. Ciglitazone prevented and reversed dexamethasone-induced hyperglycemia in female viable yellow mice. Since female viable yellow mice, similar to male viable yellow mice, are obese, hyperinsulinemic and insulin resistant, and since dexamethasone is known to cause insulin resistance, these data suggest that dexamethasone increased insulin resistance to a degree that the protective mechanism was overwhelmed and hyperglycemia was induced. Ciglitazone, a compound known to improve insulin sensitivity, may prevent and reverse dexamethasone-induced hyperglycemia by ameliorating the additional insulin resistance caused by dexamethasone. On a molecular level, since dexamethasone suppresses glucose transport, an insulin-sensitive process in many tissues, whereas ciglitazone and other thiazolidinediones facilitate glucose transport, it is possible that ciglitazone prevents and reverses dexamethasone-induced hyperglycemia by regulating the glucose transport systems in insulin-sensitive tissues.

Acquired von Willebrand's disease: demonstration of a circulating inhibitor to the factor VIII complex in four cases.

We have studied four patients suffering from acquired von Willebrand's disease. All patients had a severe bleeding diathesis with recurrent life-threatening haemorrhages. Three of the patients had a monoclonal gammopathy and one of these developed multiple myeloma. In three patients tested, a plasma inhibitor to ristocetin cofactor activity was detected. In each case this was localized to the IgG fraction of plasma. In addition, VIII:C activity was found to be associated with the IgG fraction of patients' plasma and altered mobility of VIII:C was detected on Laurell immunoelectrophoresis. Furthermore, plasma from all four patients and the IgG fraction therefrom resulted in a dissociation of normal VIII:C into two components separable by gel-filtration on Sepharose 6B. Finally the circulating half-life of the three factor VIII activities was found to be markedly reduced in the patients with acquired von Willebrand's disease. We conclude that in the patients studied the coagulation defect was related to the presence of a circulating inhibitor to the factor VIII complex and that this inhibitor was associated with the IgG fraction of plasma.