Antidiabetic Efficacy of BRL 49653, a Potent Orally Active Insulin Sensitizing Agent, Assessed in the C57BL/KsJ db/db Diabetic Mouse by Non-invasive 1H NMR Studies of Urine

Abstract

High resolution 1H nuclear magnetic resonance (NMR) spectroscopic analysis of biofluids is a recently established tool for evaluating inherited and acquired errors in metabolic control. In the present study 1H NMR analysis of urine was used to monitor efficacy of BRL 49653, a potent and selective antihyperglycaemic agent, following oral administration for up to 36 weeks to the genetically diabetic C57BL/KsJ db/db mouse. The effects of BRL 49653 on carbohydrate and fatty acid metabolism were monitored by determination of changes in concentrations of low molecular weight urinary metabolites. A qualitative comparison of the NMR spectra of urine from untreated diabetic mice with those of lean littermates and literature examples revealed several abnormalities, the majority of which could be explained in terms of the non-insulin dependent diabetes syndrome exhibited by these animals. Quantitatively the most prominent was the extreme glycosuria of both young (8-12 weeks; 0.9 g glucose kg-1 h-1) and older (42 weeks; 2 g glucose kg-1 h-1) diabetic mice. This was accompanied by the excretion of a number of unassigned sugar derivatives and by ketone bodies. Administration of BRL 49653 (3 mumol kg-1) to db/db mice for 24 days reduced blood glucose concentrations to values comparable with non-diabetic lean littermates and reduced glycosuria by > 90%. BRL 49653 significantly reduced excretion of unassigned sugars, acetate, lactate, and the ketone bodies, acetoacetate, 3-D-hydroxybutyrate and acetone. The anti-diabetic efficacy of BRL 49653, assessed from the pattern of urinary metabolites, was maintained over a 36-week treatment period. These results demonstrate the value of 1H NMR to evaluate non-invasively the efficacy of novel therapeutic agents.

Ectopic UCP1 Overexpression in White Adipose Tissue Improves Insulin Sensitivity in Lou/C Rats, a Model of Obesity Resistance

“…in 12) and normalizes hyperglycemia and hypertriglyceridemia in mouse models of diabetes and dyslipidemia (39)(40)(41). They also extend previous data (42), supporting the notion of interdependency between glucose uptake, lipid metabolism, and thermogenesis.…”

The Lyn Kinase Activator MLR-1023 Is a Novel Insulin Receptor Potentiator that Elicits a Rapid-Onset and Durable Improvement in Glucose Homeostasis in Animal Models of Type 2 Diabetes

“…However, rosiglitazone treatment did not significantly lower blood glucose levels until 10 days after the initial administration. This delayed rosiglitazone-mediated effect is consistent with reports of delayed onset of rosiglitazone-mediated blood glucose lowering in db/db mice (Zhang et al, 1996;Connor et al, 1997). Rosiglitazone administration produced a ), and glucose was intravenously infused at a variable rate.…”

“…These mice are responsive to a broad range of clinically approved pharmacological agents, and the blood glucose-lowering effects that these agents evoke in these mice are translatable to T2D patients. For example, metformin (an inhibitor of gluconeogenesis), rosiglitazone (an activator of PPAR␥), and exendin-4 (a glucagonlike peptide 1 receptor agonist) elicit dramatic improvements in metabolic function, including sustained reductions in blood glucose (Connor et al, 1997;Young et al, 1999;Fujita et al, 2005). In the current studies, chronic administration of MLR-1023 to db/db mice elicited a dose-dependent, durable blood glucose-lowering response when administration was initiated at an early stage of diabetic development and at a stage when pancreatic ␤-cells were functional.…”

Changes in the Pharmacokinetics of Rosiglitazone, a CYP2C8 Substrate, When Co-Administered with Amlodipine in Rats

“…Rosiglitazone, a second generation oral hypoglycemic thiazolidinedione, is used to treat non-insulin dependent diabetes mellitus (type 2 diabetes mellitus) (Connor et al, 1997). Rosiglitazone is rapidly absorbed after oral administration and exhibits high bioavailability of 99%.…”