Leptin resistance following over-expression of protein tyrosine phosphatase 1B in liver.

Obesity is typically associated with resistance to leptin, yet the mechanism by which leptin signaling becomes impaired is poorly understood. Here we sought to determine if the development of obesity and leptin resistance correlates with increased expression of protein tyrosine phosphatase 1B (PTP1B) in peripheral tissues and whether over-expression of this phosphatase, specifically in liver, could alter the leptin-mediated effects on feeding and glucose metabolism. Obesity was induced in mice through a high-fat diet that resulted in hyperglycemia, hyperinsulinemia and hyperleptinemia. Resistance to leptin was confirmed as exogenous leptin administration reduced food intake in animals on low-fat, but not high-fat diets. Diet-induced resistance to leptin and insulin was associated with increased hepatic levels of PTP1B. Intriguingly, hepatic adenoviral over-expression of PTP1B in ob/ob mice attenuated the ability of exogenous leptin to reduce both plasma glucose levels and food intake. These findings suggest that leptin reduces both plasma glucose and food intake in part through actions on the liver, and hepatic leptin resistance resulting from over-expression of PTP1B may contribute to the development of both diabetes and obesity.

Evaluation of argatroban and DUP 714 as anticoagulants for blood gas, electrolyte and ionized calcium analyses.

The objective of this study was to determine if the thrombin inhibitors Argatroban and DUP 714 could anticoagulate whole blood without influencing the analyses of blood gases, electrolytes, ionized calcium or CO-oximetry. The anticoagulant potency of DUP 714 (0.5-68 micromol/l) and Argatroban (1.5-390 micromol/l) was evaluated using the activated partial thromboplastin time (APTT), prothrombin time (PT) and whole blood clot time (WBCT). APTT and the PT were measured using a Behring Fibrintimer. APTT was found to be more sensitive to prolongation by both of the thrombin inhibitors than were the PT or WBCT assays. DUP 714 was found to a more potent anticoagulant than Argatroban. DUP 714 anticoagulated specimens (>2.2 micromol/l) did not clot for at least 2 days, whereas Argatroban preserved specimens (390 micromol/l) clotted within 5.5 h of collection. No statistically significant changes in the measurement of pH, PCO2, PO2, Na, K, ionized calcium, oxyhaemoglobin, deoxyhaemoglobin, methaemoglobin or carboxyhaemoglobin (measured using a Corning 288 Blood Gas/Electrolyte Analyzer and a Coming 270 CO-oximeter) were detected in DUP 714 (34 micromol/l) or Argatroban (390 micromol/l) anticoagulated whole blood specimens. In conclusion, DUP 714 and Argatroban are suitable anticoagulants for preserving blood prior to blood gas and electrolyte analyses.