Inositol-containing Phospholipids Research Articles

Analysis of Phosphatidylinositol Transfer at ER-PM Junctions in Receptor-Stimulated Live Cells.

Phosphatidylinositol (PI) is an inositol-containing phospholipid synthesized in the endoplasmic reticulum (ER). PI is a precursor lipid for PI 4,5-bisphosphate (PI(4,5)P2) in the plasma membrane (PM) important for Ca2+ signaling in response to extracellular stimuli. Thus, ER-to-PM PI transfer becomes essential for cells to maintain PI(4,5)P2 homeostasis during receptor stimulation. In this chapter, we discuss two live-cell imaging protocols to analyze ER-to-PM PI transfer at ER-PM junctions, where the two membrane compartments make close appositions accommodating PI transfer. First, we describe how to monitor PI(4,5)P2 replenishment following receptor stimulation, as a readout of PI transfer, using a PI(4,5)P2 biosensor and total internal reflection fluorescencemicroscopy. The second protocol directly visualizes PI transfer proteins that accumulate at ER-PM junctions and mediate PI(4,5)P2 replenishment with PI in the ER in stimulated cells. These methods provide spatial and temporal analysis of ER-to-PM PI transfer during receptor stimulation and can be adapted to other research questions related to this topic.

Jeremy Baskin: A Life at the Interface between Chemical and Cell Biology

Operating at the interface of chemical biology, biochemistry, and cell biology, the Baskin Lab develops innovative methods for imaging and probing various classes of lipids and couples these methods to the discovery of novel functions for cellular lipids. Notably, the Baskin Lab has developed a method for imaging the production the signaling lipid phosphatidic acid by phospholipase D enzymes and is applying this method, termed IMPACT, to reveal new biological roles for this lipid second messenger. As well, the Baskin Lab focuses on identifying new roles for inositol-containing phospholipids, or phosphoinositides, in the regulation of developmental and oncogenic signaling by characterizing novel phosphoinositide-binding proteins that act as readers of the membrane bilayer 'phosphoinositide code'. Collectively, work in the Baskin Lab will elucidate mechanisms of fundamental biological processes and also contribute to the understanding of diseases caused by perturbations in lipid metabolism, including cancer, developmental disorders, and neurological diseases affecting the myelin sheath such as multiple sclerosis.

Inositol, neural tube closure and the prevention of neural tube defects.

Susceptibility to neural tube defects (NTDs), such as anencephaly and spina bifida is influenced by genetic and environmental factors including maternal nutrition. Maternal periconceptional supplementation with folic acid significantly reduces the risk of an NTD‐affected pregnancy, but does not prevent all NTDs, and “folic acid non‐responsive” NTDs continue to occur. Similarly, among mouse models of NTDs, some are responsive to folic acid but others are not.Among nutritional factors, inositol deficiency causes cranial NTDs in mice while supplemental inositol prevents spinal and cranial NTDs in the curly tail (Grhl3 hypomorph) mouse, rodent models of hyperglycemia or induced diabetes, and in a folate‐deficiency induced NTD model. NTDs also occur in mice lacking expression of certain inositol kinases. Inositol‐containing phospholipids (phosphoinositides) and soluble inositol phosphates mediate a range of functions, including intracellular signaling, interaction with cytoskeletal proteins, and regulation of membrane identity in trafficking and cell division. Myo‐inositol has been trialed in humans for a range of conditions and appears safe for use in human pregnancy. In pilot studies in Italy and the United Kingdom, women took inositol together with folic acid preconceptionally, after one or more previous NTD‐affected pregnancies. In nonrandomized cohorts and a randomized double‐blind study in the United Kingdom, no recurrent NTDs were observed among 52 pregnancies reported to date.Larger‐scale fully powered trials are needed to determine whether supplementation with inositol and folic acid would more effectively prevent NTDs than folic acid alone. Birth Defects Research 109:68–80, 2017. © 2016 The Authors Birth Defects Research Published by Wiley Periodicals, Inc.

Trypanosoma brucei Bloodstream Forms Depend upon Uptake of myo-Inositol for Golgi Complex Phosphatidylinositol Synthesis and Normal Cell Growth.

myo-Inositol is a building block for all inositol-containing phospholipids in eukaryotes. It can be synthesized de novo from glucose-6-phosphate in the cytosol and endoplasmic reticulum. Alternatively, it can be taken up from the environment via Na(+)- or H(+)-linked myo-inositol transporters. While Na(+)-coupled myo-inositol transporters are found exclusively in the plasma membrane, H(+)-linked myo-inositol transporters are detected in intracellular organelles. In Trypanosoma brucei, the causative agent of human African sleeping sickness, myo-inositol metabolism is compartmentalized. De novo-synthesized myo-inositol is used for glycosylphosphatidylinositol production in the endoplasmic reticulum, whereas the myo-inositol taken up from the environment is used for bulk phosphatidylinositol synthesis in the Golgi complex. We now provide evidence that the Golgi complex-localized T. brucei H(+)-linked myo-inositol transporter (TbHMIT) is essential in bloodstream-form T. brucei. Downregulation of TbHMIT expression by RNA interference blocked phosphatidylinositol production and inhibited growth of parasites in culture. Characterization of the transporter in a heterologous expression system demonstrated a remarkable selectivity of TbHMIT for myo-inositol. It tolerates only a single modification on the inositol ring, such as the removal of a hydroxyl group or the inversion of stereochemistry at a single hydroxyl group relative to myo-inositol.

Arranged marriage in lipid signalling? The limited choices ofPtdIns(4,5)P2in finding the right partner

Inositol-containing phospholipids (phosphoinositides, PIs) control numerous cellular processes in eukaryotic cells. For plants, a key involvement of PIs has been demonstrated in the regulation of membrane trafficking, cytoskeletal dynamics and in processes mediating the adaptation to changing environmental conditions. Phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P(2)) mediates its cellular functions via binding to various alternative target proteins. Such downstream targets of PtdIns(4,5)P(2) are characterised by the possession of specific lipid-binding domains, and binding of the PtdIns(4,5)P(2) ligand exerts effects on their activity or localisation. The large number of potential alternative binding partners - and associated cellular processes - raises the question how alternative or even contrapuntal effects of PtdIns(4,5)P(2) are orchestrated to enable cellular function. This article aims to provide an overview of recent insights and new views on how distinct functional pools of PtdIns(4,5)P(2) are generated and maintained. The emerging picture suggests that PtdIns(4,5)P(2) species containing different fatty acids influence the lateral mobility of the lipids in the membrane, possibly enabling specific interactions of PtdIns(4,5)P(2) pools with certain downstream targets. PtdIns(4,5)P(2) pools with certain functions might also be defined by protein-protein interactions of PI4P 5-kinases, which pass PtdIns(4,5)P(2) only to certain downstream partners. Individually or in combination, PtdIns(4,5)P(2) species and specific protein-protein interactions of PI4P 5-kinases might contribute to the channelling of PtdIns(4,5)P(2) signals towards specific functional effects. The dynamic nature of PI-dependent signalling complexes with specific functions is an added challenge for future studies of plant PI signalling.

Synthesis of new derivatives of inositolcontaining phospholipid dimer analogs as potential inhibitors of virus adsorption

The majority of known agents against human immunodeficiency virus (HIV) are targeted at the virus enzymes protease and integrase but do not prevent HIV entry into host cells. Therefore, it is critical to seek small polyanionic molecules as potential inhibitors of virus adsorption. Inositol-containing phospholipids, which are naturally occurring biologically active compounds that are involved in cell regulation, may be promising lead compounds for antiviral drug design. In the present study, dimer analogs of inositol-containing phospholipids were synthesized using the H-phosphonate method. Carboxymethyl and sulfate derivatives based on them were obtained and proposed as potential virus adsorption inhibitors.

Direct Activation of Human Phospholipase C by Its Well Known Inhibitor U73122

Phospholipase C (PLC) enzymes are an important family of regulatory proteins involved in numerous cellular functions, primarily through hydrolysis of the polar head group from inositol-containing membrane phospholipids. U73122 (1-(6-((17β-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione), one of only a few small molecules reported to inhibit the activity of these enzymes, has been broadly applied as a pharmacological tool to implicate PLCs in diverse experimental phenotypes. The purpose of this study was to develop a better understanding of molecular interactions between U73122 and PLCs. Hence, the effects of U73122 on human PLCβ3 (hPLCβ3) were evaluated in a cell-free micellar system. Surprisingly, U73122 increased the activity of hPLCβ3 in a concentration- and time-dependent manner; up to an 8-fold increase in enzyme activity was observed with an EC50=13.6±5 μm. Activation of hPLCβ3 by U73122 required covalent modification of cysteines as evidenced by the observation that enzyme activation was attenuated by thiol-containing nucleophiles, l-cysteine and glutathione. Mass spectrometric analysis confirmed covalent reaction with U73122 at eight cysteines, although maximum activation was achieved without complete alkylation; the modified residues were identified by LC/MS/MS peptide sequencing. Interestingly, U73122 (10 μm) also activated hPLCγ1 (>10-fold) and hPLCβ2 (∼2-fold); PLCδ1 was neither activated nor inhibited. Therefore, in contrast to its reported inhibitory potential, U73122 failed to inhibit several purified PLCs. Most of these PLCs were directly activated by U73122, and a simple mechanism for the activation is proposed. These results strongly suggest a need to re-evaluate the use of U73122 as a general inhibitor of PLC isozymes.

Derepression ofINO1Transcription Requires Cooperation between the Ino2p-Ino4p Heterodimer and Cbf1p and Recruitment of the ISW2 Chromatin-Remodeling Complex

The Saccharomyces cerevisiae INO1 gene encodes the structural enzyme inositol-3-phosphate synthase for the synthesis de novo of inositol and inositol-containing phospholipids. The transcription of INO1 is completely derepressed in the absence of inositol and choline (I(-) C(-)). Derepression requires the binding of the Ino2p-Ino4p basic helix-loop-helix (bHLH) heterodimer to the UAS(INO) promoter element. We report here the requirement of a third bHLH protein, centromere-binding factor 1 (Cbf1p), for the complete derepression of INO1 transcription. We found that Cbf1p regulates INO1 transcription by binding to sites distal to the INO1 promoter and encompassing the upstream SNA3 open reading frame (ORF) and promoter. The binding of Cbf1p requires Ino2p-Ino4p binding to the UAS(INO) sites in the INO1 promoter and vice versa, suggesting a cooperative mechanism. Furthermore, Cbf1p binding to the upstream sites was required for the binding of the ISW2 chromatin-remodeling complex to the Ino2p-Ino4p-binding sites on the INO1 promoter. Consistent with this, ISW2 was also required for the complete derepression of INO1 transcription.

Mycobacterial Glycophosphoinositides: the Work of Clinton E. Ballou

Biosynthesis of Mannophosphoinositides by Mycobacterium phlei. The Family of Dimannophosphoinositides (Brennan, P., and Ballou, C. E. (1967) J. Biol. Chem. 242, 3046–3056) Biosynthesis of Mannophosphoinositides by Mycobacterium phlei. Enzymatic Acylation of the Dimannophosphoinositides (Brennan, P., and Ballou, C. E. (1968) J. Biol. Chem. 243, 2975–2984)

Abstract A42: The dietary agents indole-3-carbinol and myo-inositol prevent lung cancer induced by vinyl carbamate in A/J mice

Abstract A42 Because of their expected safety, food-derived products could be highly interesting for development as chemopreventive agents. Among promising cancer preventive dietary agents are indole-3-carbinol (I3C) and myo-inositol (MI). I3C is derived from the enzymatic hydrolysis of indolyl glucosinolates contained in cruciferous vegetables. MI is found in a variety of animal and plant foods in its free form, as an inositol-containing phospholipid, and inositol hexaphosphate (IP6, phytic acid,). In earlier studies, we found that both I3C and MI prevent lung adenoma induced by tobacco smoke carcinogens in A/J mice. In the present study, we examined the efficacy of I3C and MI to prevent lung adenocarcinoma. Female A/J mice were injected i.p. with two doses of vinyl carbamate (VC, 0.32 mg per mouse) dissolved in physiological saline, 1 week apart, and then randomized into the different treatment groups. After waiting 1 week following the second injection of the carcinogen, mice were maintained either on untreated control diet, or diets supplemented with I3C (70 µmol/g diet) or MI (56 µmol/g diet) for 15 weeks. At necropsy, lungs were removed and grossly visible lesions on the surface of all lobes of the lung were counted and the size of the tumors determined using a dissecting microscope. Then, the left lobe of the lung from each mouse was preserved in buffered formalin for histopathological analysis. Mice treated with VC and fed conventional diet had 42.6 ± 11.9 lung tumors/mouse. Compared to mice treated with VC alone, carcinogen-treated mice given I3C or MI-supplemented diet had a significantly lower tumor multiplicity, 31.6 ±4.8 and 33.9 ± 6.1 lung tumors, corresponding to a reduction by 26% and 20% respectively (p = 0.0003 for VC + I3C group and p = 0.0005 for VC + MI group compared using Wilcoxon non-paramteric test). Classification of the tumors into three different size groups (<1 mm, 1-2 mm, and > 2 mm) showed that the multiplicity of only the larger tumors was reduced by the chemopreventive agents (25.4 ± 6.8, 16.4 ± 8.3 and 0.69 ±1.3 tumors/mouse for < 1mm, 1-2 mm, and > 2 mm size groups, respectively, in mice treated with VC alone versus 28.8 ± 4.9, 2.8 ± 2.0, and 0.05 ± 0.22 tumors/mouse in the group treated with VC + I3Cand26.8 ± 5.1, 6.7 ± 2.3, and 0.40 ± 0.6 tumors/mouse in VC + MI-treated mice). Furthermore, we determined the effect of the chemopreventive agents on the incidence and multiplicity of the different microscopic lesions (hyperplasia, adenoma, adenoma with cellular pleomorphism and adenocarcinoma). Preliminary results showed that I3C reduced the incidence (71% in the VC group versus 36% in the VC + I3C group) and multiplicity (1.1 /mouse in the VC group versus 0.4 /mouse in the VC + I3C group) of adenocarcinoma. I3C also reduced the multiplicity (3.6/mouse in the VC group versus 2.4 /mouse in the VC + I3C group) of adenoma with cellular pleomorphism lesions. In mice maintained on MI-supplemented diet, there was no change either in the incidence or multiplicity of adenocarcinoma but the multiplicity of adenoma with cellular pleomorphism lesions was markedly reduced (3.6/mouse in the VC group versus 1.5/mouse in the VC + MI group). The chemopreventive agents did not affect the incidence or multiplicity of hyperplastic or adenoma lesions. In conclusion, our results indicate the potential lung cancer chemopreventive effects of I3C and MI in former smokers. Citation Information: Cancer Prev Res 2008;1(7 Suppl):A42.

Synthesis of anionic derivatives of myo-inositol and other polyols and investigation of their antiviral activity

The search for new, effective antiviral agents currently includes assessment of polyanionic compounds of various structures; these are highly active inhibitors of viral penetration into cells. The present report describes the preparation of phosphate and sulfate derivatives based on 2,3,4,5-tetra-O-benzyl-D,L-iditol, 1,12-dodecanediol, and a dimeric analog of inositol-containing phospholipids. The dimeric derivative, which contains two myo-inositol cyclitol rings linked by a single hydrophobic fragment, was synthesized at high yield using the H-phosphonate method. The antiviral activity of the series of compounds synthesized here was assessed against a panel of viruses. All were inactive against rhinoviruses; the disulfate of tetra-O-benzyl-D,L-iditol inhibited Coxsackie virus and had the greatest cytotoxicity; the disulfate of 1,2-dodecanediol was inactive against all viruses, while the diphosphate of 2,3,4,5-tetra-O-benzyl-D,L-iditol and the monosulfate of 1,2-dodecanediol were active against herpes simplex viruses types 1 and 2.

Secretion of the mammalian Sec14p‐like phosphoinositide‐binding p45 protein

Protein-lipid interactions are important for protein targeting, signal transduction, lipid transport, and the maintenance of cellular compartments and membranes. Specific lipid-binding protein domains, such as PH, FYVE, PX, PHD, C2 and SEC14 homology domains, mediate interactions between proteins and specific phospholipids. We recently cloned a 45-kDa protein from rat olfactory epithelium, which is homologous to the yeast Sec14p phosphatidylinositol (PtdIns) transfer protein and we report here that this protein binds to PtdIns(3,4,5)P3 and far weaker to less phosphorylated derivatives of PtdIns. Expression of the p45 protein in COS-1 cells resulted in accumulation of the protein in secretory vesicles and in the extracellular space. The secreted material contained PtdIns(3,4,5)P3. Our findings are the first report of a Sec14p-like protein involved in transport out of a cell and, to the best of our knowledge, inositol-containing phospholipids have not previously been detected in the extracellular space. Our findings suggest that p45 and phosphoinositides may participate in the formation of the protective mucus on nasal epithelium.

My Brief Encounter with the Phosphoinositides and IP3

. Before describing thisresearch, however, I should say how that choice came about. While in graduate school at theUniversity of Wisconsin, I had had the good fortune to study under Karl Paul Link, who waswidely renowned for his discovery of dicumarol and the synthesis of related blood anticoagu-lants such as warfarin, work that was recognized with two Lasker Awards (1). On the side,however, Link remained a carbohydrate chemist at heart, a hobby that had grown out of hisstudies on plant polysaccharides and uronic acids while a student and then a young facultymember. In fact, Stanford Moore had completed his doctoral dissertation with Link on amethod for characterizing aldo-monosaccharides as benzimidazole derivatives (2).I arrived at Madison in the fall of 1946, fresh from a stint in the United States Navy, andI found Link’s laboratory bursting at the seams with about 15 ex-GIs, all hard at work tryingto make up for lost time. During earlier investigations on the structure-function relationshipof coumarin anticoagulants, an attempt to synthesize the glucoside of dicumarol had beenfrustrated because the acetylated intermediate was degraded in alkali under conditions usedfor deacetylation (3). Because glycosides are acetals, which are typically acid-labile andalkali-stable, I found the anomaly intriguing and decided to study a variety of syntheticcompounds in an effort to understand the structural basis for alkali sensitivity (4). Thisresearch formed the core of my doctoral dissertation, and although I failed to recognize it at thetime, the chance exposure to carbohydrate chemistry was to have a lasting influence on thedirection my career would take.I continued my indoctrination in sugar chemistry during a postdoctoral year in Edinburgh,Scotland, with E. G. V. Percival in the new Department of Chemistry at Kings Buildingsheaded by Edwin Hirst. This was a time of economic depression in Britain, which was stillsuffering the aftermath of the war, and I discovered that I had left a well equipped laboratoryin Madison to engage an unexpectedly primitive research environment. Wisely I did not letthis change in fortunes discourage me. Instead I undertook a project dealing with the structureof maple sapwood starch and did the best that I could with the available facilities (5). Myefforts were well rewarded because, in the process, I became adept at the uses of analytical andpreparative filter paper and cellulose column chromatography, skills that were to be extremelyvaluable in my later research. The greatest challenge to my ingenuity, however, was toconstruct an electric stirring device from a small board-mounted motor, a couple of woodenpulleys, a piece of string, and a glass rod. The speed of the motor was regulated by adjustinglight bulbs that were wired in series with the power cord to draw off electricity, a crude buteffective method of control. I have always enjoyed working with my hands, so this mundaneproject even took on a certain appeal.Living in a new environment always has its fringe benefits. While in Edinburgh, I developeda special affection for the Scots and a better understanding for the lingering resentment that

Characterization of acyl-phosphatidylinositol from the opportunistic pathogen Corynebacterium amycolatum

The aim of the present study was to characterize a new lipid detected in the opportunistic pathogen Corynebacterium amycolatum. It was identified as acyl-phosphatidylinositol (acyl-PI), and revealed as a mixture of homologues compounds by electrospray ionization mass spectrometry, with pseudomolecular ions, ( M − H) −, observed at 1099 (the major one) 1113, and 1127. Acyl-PI exclusively contained octadecenoyl on the inositol moiety (as 3- O-acyl), an unsaturated fatty acyl (mostly octadecenoyl) at sn-1 position of the glycerol and a saturated fatty acyl (mainly hexadecanoyl) at the sn-2 position. Acyl-PI constitutes a new natural substance and seems to be unique among the phospholipids of C. amycolatum. Other more complex molecules, previously undetected, and assigned in this work to several acyl forms of phosphatidylinositol trimannosides, lacked octadecenoyl in their polar heads. The present study reveals the existence of acyl-PI in C. amycolatum as rather unexpected finding and, additionally, gives evidence for the ability of this species to synthesize a great variety of inositol-containing phospholipids.

Endocrine and messenger systems during adaptation to high-altitude conditions

Of endocrine cascades and messenger systems, the authors con­ducted this study involving two series of experiments. The pattern of interaction of hormones and secondary messengers while adapting to high-altitude was clarified in the first series. The re­sponse of phosphoinositide to exogenous epinephrine was exam­ined in the second series. The experimental data are represented as primary mean values ± standard deviations. Two phases of activity of the hormonal system are shown. These are the exci­tation of the hypothalamopituitary cascade and the enhanced production of glucocorticoids and catecholamines during early adaptation and the return of activity of the hormonal system to the baseline values by day 14 of adaptation. By that time the re­arrangements in the phosphoinositide messenger system consists in increasing the proportion of polyphosphoinositides in the total membranous fraction of inositol-containing phospholipids, in adrenalectomized animals to a greater extent. The above events give rise to new coordination relations between hormones and secondary messengers. It is concluded that that the phosphoi­nositide messenger system is involved in the formation of defense mechanisms the reduce the destructive effects of large amounts of epinephrine.

Plant SEC14-like proteins controlling a phosphoinositide traffic jam

Phosphatidylinositol transfer proteins (PITPs) are defined by their ability to transfer phosphatidylinositol or a phosphatidylcholine monomer between membrane bilayers in vitro. Studies in mammalian systems have suggested that PITPs play a key role in controlling the activities of various inositol lipid-signalling pathways by regulating the production of some phosphoinositides. These inositol-containing phospholipids belong to a large and heterogeneous group of lipids with structural and key regulatory roles in a wide range of cellular signalling events. Recently, several plant proteins similar to yeast PITP (SEC14) have also been identified and characterized.

Inositol metabolism in Trypanosoma cruzi: potential target for chemotherapy against Chagas' disease.

Chagas' disease is a debilitating and often fatal disease caused by the protozoan parasite Trypanosoma cruzi. The great majority of surface molecules in trypanosomes are either inositol-containing phospholipids or glycoproteins that are anchored into the plasma membrane by glycosylphosphatidylinositol anchors. The polyalcohol myo-inositol is the precursor for the biosynthesis of these molecules. In this brief review, recent findings on some aspects of the molecular and cellular fate of inositol in T. cruzi life cycle are discussed and identified some points that could be targets for the development of parasite-specific therapeutic agents.

Differential Effects of Ethanol on Signal Transduction

PC12 pheochromocytoma cells were used as a model to study the effect of long-term ethanol exposure on signal transduction systems. In PC12 cells, the agonist bradykinin stimulates a phospholipase C specific for inositol-containing phospholipids and a phospholipase D specific for phosphatidylcholine. PC12 cells were grown in monolayer and cultured in the presence and absence of 1% ethanol for 5 days. After this period, bradykinin-stimulated phospholipase C and D were measured. The effect of long-term ethanol on the bradykinin-mediated activation of mitogen-activated protein (MAP) kinase was also measured. In cells exposed to 1% ethanol for 5 days, bradykinin-stimulated phospholipase D was greatly attenuated, whereas bradykinin-stimulated phospholipase C was not altered. The tyrosine kinase inhibitor, genistein, blocked the bradykinin-mediated activation of phospholipase D but did not affect the stimulation of phospholipase C. However, long-term ethanol treatment did not attenuate the ability of bradykinin to activate MAP kinase, which suggests that ethanol did not have a general effect on all tyrosine kinase pathways. Ethanol has a differential effect on signal transduction in PC12 cells. Activation of phospholipase D may be mediated by a kinase, whereas the activation of phospholipase C is probably mediated by the guanine nucleotide binding protein, Gq. Because of these differences in activation mechanism, the pathways may adapt differently to long-term exposure to ethanol.

Diabetes and the Role of Inositol-Containing Lipids in Insulin Signaling

Among metabolic diseases, diabetes is considered one of the most prevalent throughout the world. Currently, statistics show that over 10% of the world's aged population (60 years and older) suffers from diabetes. As a consequence, it consumes a considerable proportion of world health expenditure. This review considers both past and current research into the molecular basis of insulin resistance found in type II diabetes and focuses on the role of inositol-containing phospholipid metabolism. It has been firmly established that the activation of phosphatidylinositol 3-kinase (PI3-K) is important for the propagation of the metabolic actions of insulin. In addition to the 3-phosphorylated phosphatidylinositols formed via the action of PI3-K, the glycosyl-phosphatidylinositol/inositol phosphoglycan (GPI/IPG) signaling component is also strongly implicated in mediating numerous metabolic actions of insulin. Although all the elements within the type II diabetes phenotype have not been fully defined, it has been proposed that defects in insulin transmembrane signaling through malfunction of inositol-containing phospholipid metabolism and absenteeism of the generation of phospholipid-derived second messengers may be associated with the appearance of the type II diabetic phenotype. Pharmaceutical approaches using synthetically produced IPG analogues, which themselves mimic insulin's actions, alone or in combination with other drugs, may lead the way toward introducing alternative therapies for type II diabetes in the coming years.

Lipid signalling

Lipid signalling