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.

Regulation of a blood-brain barrier-specific enzyme expressed by cerebral pericytes (pericytic aminopeptidase N/pAPN) under cell culture conditions.

In this study we show that the aminopeptidase N of cerebral pericytes (pAPN) associated with the blood-brain barrier (BBB) is downregulated in pericytic cell cultures. This observation is in accordance with previous data describing comparable in vitro effects for BBB-specific enzymes of endothelial or pericytic origin, such as gamma-glutamyl transpeptidase or alkaline phosphatase. By polymerase chain reaction and in situ hybridization we were able to determine that the down-regulation of pAPN occurs at the posttranscriptional level. The mRNA of pAPN was found to be constitutively expressed even when the protein is no longer detectable. Culturing the pericytes in an endothelial cell-conditioned medium allowed pAPN to be reexpressed. However, the reexpression effect depended largely on the culturing conditions of the pericytes. Although purified pericytes deprived of endothelial cells did not reveal a reexpression effect, pericytes that were kept in contact with endothelial cells were able to acquire a pAPN-positive phenotype, indicating that endothelial cells constitute an essential requirement for the in vitro reexpression of pAPN. Astrocytes, however, were insufficient in exerting any reexpression effect.

[Medullary sponge kidney. Diagnosis and course in 12 cases]. / Die Markschwammniere. Diagnostik und Verlauf an Hand von 12 Fällen.

12 adult patients with medullary sponge kidney (MSK), followed up for 1 to 14 years (mean 7 years) are presented. MSK was initially diagnosed in 4 cases. In 8 cases the initial diagnosis included pyelonephritis, nephrocalcinosis, and nephrolithiasis. Renal calculi (4 patients), urinary tract infection (8) and hematuria (5) were the most frequent symptoms. Renal tubular acidosis was documented in 2 patients and hypercalciuria without hyperparathyroidism in 2. Over the years renal calculi increased in size in 4 patients. Renal function was stable in 11. In one patient with associated, well controlled hypertension, serum creatinin rose from 141 to 298 mumol/l over 14 years.