Safety, efficacy and weight effect of two 11ß-HSD1 inhibitors in metformin-treated patients with type 2 diabetes.

AIMS: We assessed safety and efficacy of two selective 11ß-HSD1 inhibitors (RO5093151/RO-151 and RO5027383/RO-838) in this randomized, controlled study in metformin-treated patients with type 2 diabetes. METHODS: Patients either received placebo (N = 21), RO-151 BID 5 mg (N = 24) or 200 mg (N = 20) or RO-838 QD 50 mg (N = 21) or 200 mg (N = 24) for 28 days. Metabolic assessments comprising of nine-point plasma glucose profiles, oral glucose tolerance tests and determination of metabolic biomarkers including insulin, C-peptide, glucagon, HbA1c and lipids were done at baseline and end of treatment. RESULTS: Despite the short treatment duration, both RO-151 and RO-838 showed trends for improved HbA1c and consistent reductions in body weight (-0.86 to -1.67 kg) exceeding those observed with placebo (-0.28 kg, p = 0.019 for 200 mg RO-151 vs. placebo). Insulin sensitivity parameters (e.g. HOMA-IR and Matsuda-Index) improved non-significantly with 200 mg RO-151. Lipid parameters did not consistently improve with either compound, but RO-838 led to non-significant increases in triglycerides and VLDL-cholesterol versus placebo. Both compounds were well tolerated and showed inhibitory effects on 11ß-HSD1 activity based on urinary corticosteroid excretion. As reported for other 11ß-HSD1-inhibitors increased concentrations of ACTH and adrenal androgen precursors were found with RO-151, but not with RO-838. CONCLUSIONS: Slight metabolic improvements were seen, in particular with RO-151 high dose, however, the observed changes often did not reach statistical significance and were not clearly dose dependent. Studies of longer duration are needed to further investigate potential benefits and risks of these compounds.

Neurochemical parameters of the main neurotransmission systems in aging mice.

The present work was designed to study the effect of aging on some parameters of the glutamatergic, aminergic and cholinergic neurotransmission, in the main brain areas of mice of the long-surviving BALB/c-nu strain. We have assayed: (1) the density of three ionotropic receptors for excitatory aminoacids (EAA) which selectively bind kainic acid (KA), N-methyl-D-aspartate (NMDA) and 2-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA); (2) the content of dopamine (DA), norepinephrine (NE) and serotonin (5-HT) and the levels of the DA metabolite dihydrophenylacetic acid (DOPAC) and the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA); (3) the level of the choline acetyltransferase (ChAT), the enzyme catalyzing the synthesis of acetylcholine. The parameters were measured in animals at the age of 6, 12, 18 and 24 months; the brain zones under test were the frontal cortex (FC), the corpus striatum (STR), the hippocampus (HIP), the medio-dorsal cortex (DC) and the cerebellum (CER). Significant age-related variations for the density of KA-type and NMDA-type receptors were found in STR and a decrease of the NMDA parameter was found in DC. Neither the monoamine and metabolite contents nor the ChAT levels showed any significant variation in all the tested areas. These findings suggest that an unbalance among different neurotransmission activities could take place with normal aging in rodents: it could be involved in the onset of the motor deficit which occurs in the elderly of these and other mammals.