GSK256073, a selective agonist of G-protein coupled receptor 109A (GPR109A) reduces serum glucose in subjects with type 2 diabetes mellitus.

AIMS: This clinical trial assessed whether a potent, selective GPR109A agonist, GSK256073, could, through inhibition of lipolysis, acutely improve glucose homeostasis in subjects with type 2 diabetes mellitus. METHODS: Thirty-nine diabetic subjects were enrolled in the randomized, single-blind, placebo-controlled, three-period crossover trial. Each subject received placebo and two of four regimens of GSK256073 for 2 days. GSK256073 was dosed 5 mg every 12 h before breakfast and supper (BID), 10 mg every 24 h before breakfast (QD), 25 mg BID and 50 mg QD. RESULTS: The change from baseline weighted mean glucose concentration for an interval from 24 to 48 h after the initial drug dose was significantly reduced for all GSK256073 regimens, reaching a maximum of -0.87 mmol/l (-1.20, -0.52) with the 25 mg BID dose. Sustained suppression of non-esterified fatty acid (NEFA) and glycerol concentrations was observed with all GSK256073 doses throughout the 48-h dosing period. Serum insulin and C-peptide concentrations fell in concert with glucose concentrations and calculated HOMA-IR scores decreased 27-47%, consistent with insulin sensitization. No marked differences were evident between either 10 and 50 mg total daily doses or QD versus BID dosing. CONCLUSIONS: Administration of a GPR109A agonist for 2 days significantly decreased serum NEFA and glucose concentrations in diabetic subjects. Glucose improvements were associated with decreased insulin concentrations and measures of enhanced insulin sensitivity. Improved glucose control occurred with GSK256073 doses that were generally safe and not associated with events of flushing or gastrointestinal disturbances.

Managed care and the evolution of patient rights.

Managed care has grown into the driving force for coordinating and managing healthcare delivery and its financing. At the same time, major initiatives have gained momentum in societal and legislative efforts regarding patient rights. This article provides a historical, legal, and philosophical review of the major events that have shaped the evolution of healthcare services and development of the patient rights issue. As the healthcare industry finds itself in a state of needed reform, the future evolution of managed care in light of the patient rights issue will have important implications for legislators, clinicians, and healthcare organizations as they struggle to provide quality care and improve cost controls.

Protective effect of glutamine from glucocorticoid-induced muscle atrophy occurs without alterations in circulating insulin-like growth factor (IGF)-I and IGF-binding protein levels.

We investigated whether the prevention of glucocorticoid-induced muscle atrophy by glutamine infusion is associated with alterations in serum levels of insulin-like growth factor (IGF)-I and its binding proteins (IGFBPs). Hormone (cortisol acetate [CA], 100 mg/kg body wt/day) and vehicle (carboxymethyl cellulose [CMC])-treated female rats were infused with either saline or glutamine (240 mM, 0.75 ml/hr) for a 7-day period. Glutamine infusion prevented over 70% of the skeletal muscle mass loss due to the glucocorticoid injections. Serum IGF-I concentrations, which were measured by radioimmunoassay (RIA) after acid solid-phase extraction of IGFBPs, were not significantly different among groups (range of means: 373-395 ng/ml). Saline/CA treatment resulted in a 2-fold increase in circulating levels of IGFBP-3 (38- to 50-kDa bands from ligand blotting measurements) versus the saline/CMC group. Levels of 30- to 32-kDa bands were increased by approximately 3-fold in the CA-treated rats. Immunoprecipitation studies suggested that the increase in the 30- to 32-kDa binding proteins were not due to elevated levels of IGFBP-1, -2, or -5. None of the treatments significantly modified circulating levels of IGFBP-4 (24 kDa). Glutamine infusion did not reverse the effects of glucocorticoids on circulating levels of 38- to 50- and 30- to 32-kDa IGFBPs. We conclude that the attenuation of glucocorticoid-induced muscle atrophy by glutamine infusion is not associated with changes in circulating levels of IGF-I or IGFBPs.

Research in EPA: A congressional point of view.

From lessons learned in several years of overseeing the research programs of the Environmental Protection Agency, the authors conclude that the agency should give more support to the accumulation of the scientific "intellectual capital" needed for managing the environment in the long term.