Acute peripheral but not central administration of olanzapine induces hyperglycemia associated with hepatic and extra-hepatic insulin resistance

Atypical antipsychotic drugs such as Olanzapine induce weight gain and metabolic changes associated with the development of type 2 diabetes. The mechanisms underlying the metabolic side-effects of these centrally acting drugs are still unknown to a large extent. We compared the effects of peripheral (intragastric; 3 mg/kg/h) versus central (intracerebroventricular; 30 μg/kg/h) administration of Olanzapine on glucose metabolism using the stable isotope dilution technique (Experiment 1) in combination with low and high hyperinsulinemic-euglycemic clamps (Experiments 2 and 3), in order to evaluate hepatic and extra-hepatic insulin sensitivity, in adult male Wistar rats. Blood glucose, plasma corticosterone and insulin levels were measured alongside endogenous glucose production and glucose disappearance. Livers were harvested to determine glycogen content. Under basal conditions peripheral administration of Olanzapine induced pronounced hyperglycemia without a significant increase in hepatic glucose production (Experiment 1). The clamp experiments revealed a clear insulin resistance both at hepatic (Experiment 2) and extra-hepatic levels (Experiment 3). The induction of insulin resistance in Experiments 2 and 3 was supported by decreased hepatic glycogen stores in Olanzapine-treated rats. Central administration of Olanzapine, however, did not result in any significant changes in blood glucose, plasma insulin or corticosterone concentrations nor in glucose production. In conclusion, acute intragastric administration of Olanzapine leads to hyperglycemia and insulin resistance in male rats. The metabolic side-effects of Olanzapine appear to be mediated primarily via a peripheral mechanism, and not to have a central origin.     

Serum lipids and urinary albumin excretion in non insulin-dependent diabetics

The increase of urinary albumin excretion has a predictive value for cardiovascular disease in insulin-dependent and non insulin-dependent diabetics. To study the relationship between urinary albumin excretion and serum lipids, 380 non insulin-dependent diabetics, 40 to 75 yr old, with urinary albumin excretion from 0 to 200 mg/l, and normal serum creatinine (less than 150 µmol/1), were surveyed. Urinary albumin excretion, was related positively to age (r² = 0.014; p = 0.02), to systolic blood pressure (r² = 0.073, p = 0.0001) and diastolic blood pressure (r² = 0.052, p = 0.0001); a negative correlation existed with HDL-cholesterol (r² = 0.043, p = 0.0001) and Apoprotein A1 (r² = 0.044, p = 0.0001). A stepwise regression analysis was performed and resulted in three independently contributing variables related to urinary albumin excretion: First systolic blood pressure (F = 36), second Apoprotein A1 (F 24), third hemoglobin AlC (F = 6). The presence of hypertension or insulin therapy did not modify these findings. In conclusion, serum lipid seems an important determinant of urinary albumin excretion in non insulin-dependent diabetics.Abbreviations UAE Urinary Albumin Excretion - IDDs Insulin-Dependent Diabetics - NIDDs Non Insulin-Dependent Diabetics - ACE Angiotensin-converting-enzyme - HDL High Density Lipoproteins - VLDL Very Low Density Lipoproteins - LDL Low Density Lipoproteins     

Characterization in Mammalian Brain of a DARPP-32 Serine Kinase Identical to Casein Kinase II

DARPP-32, a dopamine- and cyclic AMP-regulated phosphoprotein of Mr 32,000, is phosphorylated in vitro by casein kinase II at a site which is also phosphorylated in intact cells. In the present study, we show that a protein kinase activity, present in caudate-putamen cytosol, phosphorylates DARPP-32 on a seryl residue located on the same thermolytic peptide that is phosphorylated by purified casein kinase II. This DARPP-32 serine kinase was indistinguishable from casein kinase II on the basis of a number of biochemical criteria. Excitotoxic lesions of the caudate-putamen and immunocytochemistry revealed the presence of casein kinase II in the medium-sized striatonigral neurons which are known to contain DARPP-32. Casein kinase II activity was high in all rat brain regions studied, and casein kinase II-like immunoreactivity was detected in most brain neurons, although some neuronal populations (e.g., cortical pyramidal cells and large striatal neurons) were stained more intensely than others. In rat caudate-putamen, 45% of the total casein kinase II activity was in the cytosol and 20% in the synaptosomal fraction. In mouse cerebral cortex and caudate-putamen, casein kinase II activity was high at embryonic day 16, and remained elevated during development. In addition to DARPP-32, several major substrates for casein kinase II were observed specifically in brain, but not in liver extracts. The high activity of casein kinase II in brain from the embryonic period to adult age and the existence of a number of specific substrates suggest that this enzyme may play an important role in both developing and mature brain, possibly in modulating the responsiveness of target proteins to various extracellular signals.     

Metastatic rat carcinoma cells express a new retrotransposon.

Genes differentially expressed by a rat bladder carcinoma NBT-II cells and their in-vivo-selected metastatic M-NBT-II variant were analysed. Amplification and cloning of a 277-bp B sequence, exclusively expressed by the M-NBT-II cells, were performed, and this sequence was detected as a 6.7-kb RNA. This fragment shares 46-50% identities with the gag-related protein of mouse and hamster Intracisternal A Particles (IAPs). Screening of a M-NBT-II cDNA library with the B probe selected a 1671-bp sequence corresponding to the 5' end of a novel retrotransposon member of the rat IAP family. This sequence has a strong identity with the Ecker Rat IAP (ERA-IAP) except for the B portion and has an open reading frame potentially encoding a 114-amino-acid gag retrovirus-related protein. Rearrangement of this new retrotransposon could be relevant with the tumor progression in our model system since it is only expressed in the M-NBT-II in-vivo-selected carcinoma metastasis.     

Infants' exploration of scented toys: effects of prior experiences

To evaluate breastfed infants' responses to scented objects, we videotaped the facial and bodily reactions of sixty-three infants as they explored, in succession, three toys that were identical in appearance but different in their characteristic odor. Two of the toys were scented with odorants previously shown to be transmitted to human milk, one with ethanol and the other with vanilla, whereas the third toy was unscented. Each videotape was subjected to frame-by-frame analysis to measure a variety of behaviors that are considered either to be exploratory in nature in that they lead to perceptual information about the object or to reflect the infants' hedonic reaction. Analyses of these behaviors revealed that the infants looked more and vocalized less in the presence of the vanilla-scented toy and spent less time manipulating the ethanol-scented toy when compared with the unscented toy. Moreover, differential exposure to the odors of ethanol and vanilla, as indicated by differential consumption of alcohol by a parent or use of vanilla-scented product by the mother, was related to differential responses to these odors. These findings suggest that human infants are able to detect and retain information about the chemical features of their environment.