Male obese Zucker Diabetic Fatty (ZDF) rats develop type 2 diabetes around eight weeks of age, and are widely used as a model for human diabetes and its complications. The objective of the study was to test whether the complications manifested in the kidney and nerves of ZDF rats really correspond to human diabetic complications in their being related to the hyperglycaemic state. Four groups of ZDF rats were used. One lean (Fa/?) and one obese (fa/fa) untreated group served as non-diabetic and diabetic controls. In two further groups of obese (fa/fa) rats, diabetes was prevented by pioglitazone or delayed by food restriction. All rats were monitored up to 35 weeks of age with respect to their blood glucose, HbA1c and insulin levels, their kidney function (urinary glucose excretion, renal glucose filtration, glomerular filtration rate, albumin/creatinine ratio), and their nerve function (tactile and thermal sensory threshold and nerve conduction velocity). Pioglitazone prevented the development of diabetes, while food restriction delayed its onset for 8-10 weeks. Accordingly, kidney function parameters were similar to lean non-diabetic rats in pioglitazone-treated rats and significantly improved in food-restricted rats compared with obese controls. Kidney histology paralleled the functional results. By contrast, nerve functional evaluations did not mirror the differing blood glucose levels. We conclude that the ZDF rat is a good model for diabetic nephropathy, while alterations in nerve functions were not diabetes-related.

Objective: The severity of obesity is often more determined by the distribution of fat depots rather than by body weight itself. Therefore, the effect of rimonabant on fat distribution pattern was investigated in female candy-fed Wistar rats. Design: Female Wistar rats were fed a high fat, high carbohydrate (candy-) diet for 12 weeks. During the last 6 weeks rats were treated with rimonabant. Food intake and body weight development were investigated, as well as effects on total body fat, especially visceral fat and ectopic lipid accumulation in skeletal muscle and liver, determined by in vivo magnetic resonance imaging/magnetic resonance spectroscopy. Results: Candy-diet increased body weight, which was predominantly due to the increased total fat mass with predominance of visceral fat accumulation. Treatment with rimonabant fully reversed the weight gain and fat deposition in the visceral cavity and skeletal muscle, in contrast to pair feeding. In spite of an only transient reduction of food intake, body weight reduction, as well as normalized body fat, reduced visceral fat and intramyocellular lipids were maintained over the treatment period. Conclusions: We conclude that additional factors other than reduced caloric intake must be responsible for the improvements in these lipid parameters. The complete cluster of results is consistent with increased lipid oxidation caused by rimonabant.

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Acid secretion in isolated rabbit gastric glands was measured by means of the 14C-aminopyrine accumulation technique. Hoe 760 (TZU-0460) and Hoe 062, the desacetylated compound of Hoe 760, caused a concentration-dependent reduction of histamine (100 microM) induced aminopyrine-accumulation. The IC50-values were 3.16 +/- 0.84 microM (n = 5) and 1.58 +/- 0.6 microM (n = 6) for Hoe 760 and Hoe 062, respectively. In comparison an IC50 of 9.0 +/- 0.72 microM (n = 6) was obtained for cimetidine and 3.3 +/- 1.4 microM (n = 5) for ranitidine. The IC50-values of ranitidine, Hoe 760 and Hoe 062 were significantly different (p less than 0.05) from cimetidine. The addition of increasing concentrations of Hoe 760 to the histamine concentration-response curve caused a parallel rightward shift. The transformation of these concentration-response curves according to Arunlakshana and Schild indicated that this inhibition was caused by a competitive antagonism of the histamine receptor on the parietal cell. In agreement with these findings the dbc-AMP stimulated aminopyrine accumulation remained unaffected by the H2-receptor antagonists.

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Glycosylphosphatidylinositol-anchored proteins (GPI-AP), which represent about 1% of all proteins in eukaryotes, are constituted by a highly conserved hydrophobic glycolipidic membrane anchor (GPI) and variable large hydrophilic protein moieties 1-3 . On basis of their amphiphilic nature, GPI-AP equipped with the complete GPI anchor together with exogenous lipids (phospholipids, cholesterol), presumably required to shield their fatty acyl moieties from the aqueous environment, into extracellular complexes (GLEC) may be regarded as candidates for release from the extracellular face of plasma membranes upon exposure towards endogenous or exogenous cues, such as metabolites and mechanical forces. The putative release of GLEC was first studied with adipocytes since their plasma membranes undergo extensive stretching upon lipid filling and are in intimate contact with serum albumin and fatty acids. To avoid isolation of the presumably labile GLEC, a chipbased sensor was developed. It relies on specific capturing of the GLEC streaming through the microfluidic channels of the chip by their gold surface coated with α-toxin.Coating with α-toxin, which binds to the glycan core of the GPI anchor 4 , was performed with conventional coupling chemistry ( Supplementary Fig. 1). Any (covalent or secondary) interaction of materials with the chip surface will lead to right-ward shifts in phase and/or reductions in amplitude of the horizontal surface acoustic waves (SAW) propagating along the chip surface. This reflects mass loading and/or increased viscosity, respectively, exerted by the interacting materials 5-7 . Consequently, the coating with α-toxin per se (Supplementary Fig. 1) and the capturing of GLEC can be monitored by chipbased sensing (see below).Initially, the sensor was developed and validated using so-called extracellular vesicles (EV) as analytes. EV are membrane vesicles which are released from most cell types 8 , in particular upon challenge with exogenous stressors 9 . A subset of EV released from adipocytes into the incubation medium are known to harbor complete GPI-AP at the outer surface of their phospholipid bilayer 10,11 and consequently can be regarded as subtype of GLEC. Injection of EV isolated from rat adipocyte incubation medium into α-toxin-coated, but not albumin-coated chips caused volume-dependent phases shifts of the SAW (Fig. 1a). Depletion of the GPI-AP-harboring EV upon adsorption to α-toxin-coupled magnetic beads or cleavage of the GPI anchor by bacterial PI-PLC prior to injection (partially) prevented phase shift. The presence of GPI-AP, such as CD73, and phospholipids in the EV was shown by sequential binding "in sandwich" of anti-CD73 antibodies and the Ca 2+dependent phospholipid-sequestering protein annexin-V (in the presence of Ca 2+ , but not EGTA) to the chip (Fig. 1b). The specificity of detection of GPI-AP in association with lipids was confirmed by the lack of SAW phase shift using (i) chips (non-covalently) coated with rat serum albumin, (ii) EV depleted from GPI-AP or (iii) antib...