Stimulation of a glycosyl-phosphatidylinositol-specific phospholipase by insulin and the sulfonylurea, glimepiride, in rat adipocytes depends on increased glucose transport

Abstract. Lipoprotein lipase (LPL) and glycolipidanchored cAMP-binding ectoprotein (Gcel) are modified by glycosyl-phosphatidylinositol (GPI) in rat adipocytes, however, the linkage is potentially unstable. Incubation of the cells with either insulin (0.1-30 nM) or the sulfonylurea, glimepiride (0.5-20/zM), in the presence of glucose led to conversion of up to 35 and 20%, respectively, of the total amphiphilic LPL and Gcel to their hydrophilic versions. Inositol-phosphate was retained in the residual protein-linked anchor structure. This suggests cleavage of the GPI anchors by an endogenous GPI-specific insulin- and glimepiride-inducible phospholipase (GPI-PL). Despite cleavage, hydrophilic LPL and Creel remained membrane associated and were released only if a competitor, e.g., inositol-(cyclic)monophosphate, had been added. Other constituents of the GPI anchor (glucosamine and mannose) were less efficient. This suggests reat body of information exists regarding the structural diversity as well as the biosynthesis and posttranslational attachment of glycosyl-phosphatidylinositol (GPI) ~ structures (for recent reviews see Low, 1989; McConville et al., 1993). However, the functional significance of membrane anchorage via GPI structures versus transmembrane polypeptide domains is still a matter of debate. The accessibility of GPI molecules to cleavage by phospholipase [(G)PI-PL] opens the possibility of a regu-Address all correspondence to Dr. (;tinter Miiller, Hoechst AG Frankfurt

Wiring optimization explanation in neuroscience: What is Special about it?

This paper examines the explanatory distinctness of wiring optimization models in neuroscience. Wiring optimization models aim to represent the organizational features of neural and brain systems as optimal (or near-optimal) solutions to wiring optimization problems. My claim is that that wiring optimization models provide design explanations. In particular, they support ideal interventions on the decision variables of the relevant design problem and assess the impact of such interventions on the viability of the target system

ANGPTL4 gene E40K variation protects against obesity-associated dyslipidemia in participants with obesity

Objective ANGPTL4 inhibits lipoprotein lipase in adipose tissue, regulating plasma triglycerides levels. In persons with obesity plasma ANGPTL4 levels have been positively correlated with body fat mass, TG levels and low HDL. A loss-of-function E40K mutation in ANGPTL4 prevents LPL inhibition, resulting in lower TGs and higher HDLc in the general population. Since obesity determines metabolic alterations and consequently is a major risk factor for cardiovascular disease, the aim was to explore if obesity-related metabolic abnormalities are modified by the ANGPTL4-E40K mutation. Methods ANGPTL4-E40K was screened in 1206 Italian participants, of which 863 (71.5%) with obesity. All subjects without diabetes underwent OGTT with calculation of indices of insulin-sensitivity. Results Participants with obesity carrying the E40K variant had significantly lower TG (p = 0.001) and higher HDLc levels (p = 0.024). Also in the whole population low TGs and high HDLc were confirmed in E40K carriers. In the obese subpopulation it was observed that almost all E40K carriers were within the lowest quartile of TGs (p = 1.1 x 10(-9)). E40K had no substantial effect of on glucose metabolism. Finally, none of the obese E40K carriers had T2D, and together with the favourable lipid profile, they resemble a metabolically healthy obese (MHO) phenotype, compared to 38% of E40E wild-type obese that had diabetes and/or dyslipidaemia (p = 0.0106). Conclusions In participants with obesity the ANGPTL4-E40K variant protects against dyslipidemia. The phenotype of obese E40K carriers is that of a patient with obesity without metabolic alterations, similar to the phenotype described as metabolic healthy obesity

Perfluorocarbon Enhanced Glasgow Oxygen Level Dependent (GOLD) magnetic resonance metabolic imaging identifies the penumbra following acute ischemic stroke

The ability to identify metabolically active and potentially salvageable ischaemic penumbra is crucial for improving treatment decisions in acute stroke patients. Our solution involves two complementary novel MRI techniques (Glasgow Oxygen Level Dependant (GOLD) Metabolic Imaging), which when combined with a perfluorocarbon (PFC) based oxygen carrier and hyperoxia can identify penumbra due to dynamic changes related to continued metabolism within this tissue compartment. Our aims were (i) to investigate whether PFC offers similar enhancement of the second technique (Lactate Change) as previously demonstrated for the T2*OC technique (ii) to demonstrate both GOLD metabolic imaging techniques working concurrently to identify penumbra, following administration of Oxycyte® (O-PFC) with hyperoxia. Methods: An established rat stroke model was utilised. Part-1: Following either saline or PFC, magnetic resonance spectroscopy was applied to investigate the effect of hyperoxia on lactate change in presumed penumbra. Part-2; rats received O-PFC prior to T2*OC (technique 1) and MR spectroscopic imaging, which was used to identify regions of tissue lactate change (technique 2) in response to hyperoxia. In order to validate the techniques, imaging was followed by [14C]2-deoxyglucose autoradiography to correlate tissue metabolic status to areas identified as penumbra. Results: Part-1: PFC+hyperoxia resulted in an enhanced reduction of lactate in the penumbra when compared to saline+hyperoxia. Part-2: Regions of brain tissue identified as potential penumbra by both GOLD metabolic imaging techniques utilising O-PFC, demonstrated maintained glucose metabolism as compared to adjacent core tissue. Conclusion: For the first time in vivo, enhancement of both GOLD metabolic imaging techniques has been demonstrated following intravenous O-PFC+hyperoxia to identify ischaemic penumbra. We have also presented preliminary evidence of the potential therapeutic benefit offered by O-PFC. These unique theranostic applications would enable treatment based on metabolic status of the brain tissue, independent of time from stroke onset, leading to increased uptake and safer use of currently available treatment options