Liraglutide treatment in overweight and obese patients with type 1 diabetes: A 26-week randomized controlled trial; mechanisms of weight loss.

AIM: To investigate the effects of liraglutide treatment on glycaemic control and adipose tissue metabolism in overweight and obese people with type 1 diabetes (T1DM). RESEARCH DESIGN AND METHODS: A total of 84 adult overweight and obese patients with T1DM, with no detectable C-peptide, were randomized (1:1) to either placebo or 1.8 mg/d liraglutide for 6 months. Blood samples were collected at 0, 12 and 26 weeks. Subcutaneous adipose tissue biopsies, a high-calorie high-fat meal challenge test, continuous glucose monitoring, dual-energy X-ray absorptiometry and MRI were performed before and at the end of treatment. RESULTS: In all, 37 and 27 patients who received liraglutide and placebo, respectively, completed the study. Glycated haemoglobin fell by 0.41 ± 0.18% (4.5±1.4 mmol/mol) from baseline after liraglutide treatment (P = 0.001), and by 0.29 ± 0.19% (3.1±2.0 mmol/mol) compared to placebo (P = 0.1). There was no increase in hypoglycaemia, while the time spent in normal glycaemia increased (P = 0.015) and time spent in hyperglycaemia decreased (P = 0.019). Body weight fell significantly in the liraglutide group, mostly in the form of fat mass loss (including visceral fat), with no change in lean mass. Systolic blood pressure (SBP) also fell after liraglutide treatment. Liraglutide also caused a significant increase in the expression of adipose tissue triglyceride lipase, carnitine palmitoyl transferase-1, peroxisome proliferator-activated receptor (PPAR)α, PPARδ, uncoupling protein-2 and type 2 iodothyronine deiodinase in the adipose tissue. CONCLUSIONS: Liraglutide improves glycaemia, reduces adiposity and SBP. Liraglutide also stimulates mechanisms involved with an increase in lipid oxidation and thermogenesis, while conserving lean body mass.

Novel entry to the synthesis of (S)- and (R)-5-methoxycarbonylhydroxymethyluridines - a diastereomeric pair of wobble tRNA nucleosides.

Two novel methods for the preparation of the virtually equimolar mixtures of (S)- and (R)-diastereomers of 5-methoxycarbonylhydroxymethyluridine (mchm5U) have been developed. The first method involved α-hydroxylation of a 5-malonate ester derivative of uridine (5) with SeO2, followed by transformation to (S)- and (R)-5-carboxymethyluridines (cm5U, 8) and, finally, into the corresponding methyl esters. In the second approach, (S)- and (R)-mchm5-uridines were obtained starting from 5-formyluridine derivative (9) by hydrolysis of the imidate salt (11) prepared in the acid catalyzed reaction of 5-cyanohydrin-containing uridine (10b) with methyl alcohol. In both methods, the (S)- and (R) diastereomers of mchm5U were effectively separated by preparative C18 RP HPLC.