Effect of high-fat diet on KKAy and ob/ob mouse liver and adipose tissue corticosterone and 11-dehydrocorticosterone concentrations.

The present study was performed to compare glucocorticoid levels in obese KKA (y) and ob/ob mice with those in normal C57BL/6J mice, and the effect of high-fat diet on glucocorticoids in KKA (y) and ob/ob mice. Liver, mesenteric and epididymal adipose tissue corticosterone and 11-dehydrocorticosterone concentrations as well as circulating corticosterone concentrations were measured. The KKA (y) and ob/ob mice displayed elevated serum corticosterone levels compared to normal mice, 2.0 to 2.8-fold in KKA (y), and 11 to 16-fold in ob/ob mice. Liver corticosterone levels were 3.0 to 5.1 and 6.2 to 8.1-fold, and 11-dehydrocorticosterone levels were 3.4 to 3.6 and 6.7 to 8.2-fold higher in KKA (y) and ob/ob mice compared to normal mice. Mesenteric adipose tissue corticosterone levels were 2.7 to 4.2-fold higher, and 11-dehydrocorticosterone levels were 2 to 4-fold higher in ob/ob than in KKA (y) mice. Epididymal adipose tissue corticosterone levels were 3.0 to 6.2-fold higher, and 11-dehydrocorticosterone levels were 1.8 to 2.0-fold higher in ob/ob than in KKA (y) mice. Circulating, hepatic, and mesenteric and epididymal adipose tissue glucocorticoid concentrations were low in the normal C57BL/6J mouse, high in the ob/ob mouse, and intermediate in the KKA (y) mouse. 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) mRNA levels were doubled in ob/ ob compared to KKA (y) mice in all three tissues. Glucocorticoid concentrations correlated with 11beta-HSD1 mRNA levels. High-fat diet had no effect on the tissue glucocorticoid concentrations.

Selective inhibition of 11beta-hydroxysteroid dehydrogenase type 1 decreases blood glucose concentrations in hyperglycaemic mice.

AIMS/HYPOTHESIS: Current pharmacological treatments for Type II (non-insulin-dependent) diabetes mellitus have various limitations. New treatments are needed to reduce long-term risks for diabetic complications and mortality. We tested a new principle for lowering blood glucose. It is well known that glucocorticoids in excess cause glucose intolerance and insulin resistance. The enzymes 11beta-hydroxysteroid dehydrogenase type 1 and type 2 inter-convert inactive and active glucocorticoids, thereby playing a major role in local modulation of agonist concentration and activation of corticosteroid receptors in target tissues. It has been hypothesized that selective inhibition of 11beta-hydroxysteroid dehydrogenase type 1 decreases excessive hepatic glucose production in hyperglycemia and diabetes. BVT.2733 is a new, small molecule, non-steroidal, isoform-selective inhibitor of mouse 11beta-hydroxysteroid dehydrogenase type 1. The aim of the present study is to test if selective inhibition of 11beta-hydroxysteroid dehydrogenase type 1 lowers blood glucose concentrations in a hyperglycaemic and hyperinsulinaemic mouse model. METHODS: BVT.2733 was given to spontaneously hyperglycaemic KKA(y) mice for 7 days using subcutaneous osmotic mini-pumps. RESULTS: BVT.2733 lowered hepatic PEPCK and glucose-6-phosphatase mRNA, blood glucose and serum insulin concentrations compared with vehicle treated mice. In contrast, hepatic 11beta-hydroxysteroid dehydrogenase type 1 mRNA, liver function marker enzyme expression (aspartate aminotransferase, alanine aminotransferase and alkaline phosphatases), daily food intake and body weight were not altered by the treatment. CONCLUSION/INTERPRETATION: These results suggest that a selective inhibitor of human 11beta-hydroxysteroid dehydrogenase type 1 can become a new approach for lowering blood glucose concentrations in Type II diabetes.

Cost analysis of the Novacor Left Ventricular Assist System as an outpatient bridge to heart transplantation.

Three patients were bridged to heart transplantation with the wearable Novacor Left Ventricular Assist System (Baxter Healthcare Corp., Oakland, CA) (LVAS). Two have been transplanted and discharged. The third patient remains at home. Hospitalization costs, which include the unit room charge, admission profile to the unit, and daily supply charge, were determined for all patients and compared. The patients were transferred from the surgical intensive care unit to a telemetry unit once they were hemodynamically stable. The projected hospitalization costs, if the patients had remained in the hospital, were calculated to determine probable savings for the third party payer. The average period from admission to placement of the Novacor LVAS was 15 days (range, 7-21 days). The average hospitalization cost from admission to time of Novacor left ventricular assist device implant was $2,240/day, and the average hospitalization cost after implant to discharge was $1,570/day. Hospitalization cost savings were $2,632 for the first patient, $5,922 for the second patient, and $132,124 for the third patient, who has not been transplanted. Although the number of patients is small, the daily hospitalization cost was higher before the Novacor LVAS was implanted. This is related to the severity of the disease and the length of stay in a surgical intensive care unit. There also is a significant cost savings for the third party payer, especially if the patient has to wait a significant amount of time before heart transplantation. These are important considerations in this time of managed care.