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The Open Biochemistry Journal, 2014, 8, 74-82

Open Access

Certain Diet and Lifestyle May Contribute to Islet β-cells Protection in
Type-2 Diabetes via the Modulation of Cellular PI3K/AKT Pathway
Yasuko Kitagishi*,#, Atsuko Nakanishi*,#, Akari Minami*,#, Yurina Asai, Mai Yasui, Akiko Iwaizako,
Miho Suzuki, Yuna Ono, Yasunori Ogura and Satoru Matsuda*,#

Department of Food Science and Nutrition, Nara Women's University, Kita-Uoya Nishimachi, Nara 630-8506, Japan
Abstract: PI3K/AKT pathway has been shown to play a pivotal role on islet β-cell protection, enhancing β-cell survival
by stimulating cell proliferation and inhibiting cell apoptosis. Accordingly, this pathway appears to be crucial in type-2
diabetes. Understanding the regulations of this pathway may provide a better efficacy of new therapeutic approaches. In
this review, we summarize advances on the involvement of the PI3K/AKT pathway in hypothetical intra-cellular signaling
of islet β-cells. As recent findings may show the nutritional regulation of the survival pathway in the islet β-cells through
activation of the PI3K/AKT pathway, we also review studies on the features of several diets, correlated lifestyle, and its
signaling pathway involved in type-2 diabetes. The molecular mechanisms contributing to the disease are the subject of
considerable investigation, as a better understanding of the pathogenesis will lead to novel therapies against a condition of
the disease.

Keywords: AKT, GSK3β cell signaling, islet β-cells, type-2 diabetes, PI3K.
Diabetes mellitus is the most common endocrine disease,
which is mainly characterized by pancreatic islet β-cells
failure. It is well-known that several stressors like chemical
toxins, cigarette smoke, hypertension, and hypercholesterolemia are all risk factors to the disease [1, 2]. In addition,
inflammation is major targets of the diabetes research, which
is believed to be the principal reason behind the disease [3].
Diabetes was historically considered as a metabolic disease
of just ageing. However, the role of chronic systemic
inflammation is important in the development of insulin
resistance and following progression to the disease. Now,
pathophysiology of type-2 diabetes has identified to be the
presence of islet-specific T-cells in the patients [4].
Furthermore, the T-cell-mediated islet autoimmune status has
also been correlated with the progressive loss of β-cell
function [4]. In general, the quantity of islet β-cells is
determined by the combined rates of proliferation of existing
cells by neogenesis and by cell death [5]. Reactive oxygen
species (ROS), endotoxins, and inflammatory cytokines,
result in the decrease of islet β-cells henceforward to the
diabetic disease development [6]. Chronic hyperlipidemia
also causes β-cells apoptosis and dysfunction, thereby
contributing to the pathogenesis of diabetes [7].
Because phosphatidylinositol-3 kinase (PI3K) and
serine–threonine protein kinase AKT (also known as protein
kinase B) seem to make the islet β-cells activation by
*Address correspondence to this author at the Department of Food
Science and Nutrition, Nara Women's University, Kita-Uoya Nishimachi,
Nara 630-8506, Japan; Tel: +81 742 20 3451; Fax: +81 742 20 3451;

*These four authors contributed equally to this work.


regulation of the key inflammatory cytokines [8], alterations
in the PI3K/AKT signaling pathway may contribute to
specific therapeutic effects for diabetes. In addition, the
physiological function of PTEN is to dephosphorylate the
second messengers generated by the PI3K, thereby downregulating insulin signaling downstream of the PI3K [9].
Therefore, potential role of these PI3K/AKT/PTEN signaling
seems to be involved in the development of diabetes. For
example, expression of constitutively active AKT linked to
an insulin gene promoter in transgenic mice results in
increased islet β-cells mass by altering β-cells size and
number [10]. These mice are also resistant to diabetes [10].
Thus, the signaling activation may be of importance in both
islet β-cells proliferation and survival. Searching for agents
to promote pancreatic β-cells survival and improve its
function could be a promising strategy to prevent and to treat
for diabetes. Here, we provide an overview of research on
the characterization of the PI3K/AKT/PTEN pathway at the
viewpoint of pathogenesis for diabetes. Overall, certain diets
and lifestyle as well as the synthesis of serotonin may be the
most helpful in preventing type-2 diabetes, which are all
involved in the PI3K/AKT/PTEN signaling pathway.
Intervention and therapy that alter the pathogenesis may
serve to reduce the risk of the development of the disease,
leading to better efficacy of therapeutic approaches.
PI3Ks are crucial signaling components in a diverse
range of cellular functions including cell proliferation,
migration, and survival. It is reasonable that dysregulation of
the pathway has been implicated in the induction and/or
progression of a variety of diseases. The PI3K forms a
family that can be divided into three classes based on the
2014 Bentham Open

IL-12. leads to the membrane recruitment of AKTs. hypoxia. whereas the mTOR seem to upregulate the anti-inflammatory cytokines [21]. and so forth [14]. 2014. and also binds to phosphoinositide-dependent kinase 1 (PDK1) via the plekstrin homology (PH) domains. Human AKT has three isoforms. AKT1. These PI3Ks are heterodimers consisting of a regulatory subunit (p85) and a catalytic subunit (p110). PDK1 phosphorylates AKT in the kinase domain (Thr-308 in AKT1). . For the further activation of AKT. Note that some critical pathways have been omitted for clarity. 1). AKT substrates include GSK3β. The other AKT substrate. TSC2. and TNFα. and is phosphorylated by p70S6 kinase [17]. AKT mediated phosphorylation of these target proteins leads to their activation or inhibition. The structure endows PTEN with its preference for phospholipid substrates such as PIP3. A product of PI3K. The NOXs sense persistent hyperglycemia. NOS. The IRS1 associated PI3K/AKT activity is severely impaired in high fat-fed animals [19]. suggesting a mechanism for the development of insulin resistance [18]. Arrowhead means stimulation whereas hammerhead represents inhibition. After activated. PTEN is a dual- Fig. In addition. p27. The S6 ribosomal protein belongs to the PI3K/AKT/PTEN/mTOR signaling pathway. Then.Certain Diet and Lifestyle May Contribute to Islet β-cells Protection structure and mechanism of activation [11]. Consequently. Examples of molecules known to act on the regulatory pathway are shown. Caspase-9. Volume 8 75 serine/threonine kinase that was initially identified as playing a role in the regulation of glycogen synthesis in response to insulin receptor stimulation [16]. AKT is a major downstream target of those PI3Ks. the phosphorylation within the carboxyl site (Ser-473 in human AKT1) by PDK2 is required [13]. Altered activity of these mediators then causes various effects on several cytokine expressions. leading to the accumulation and activation of mTOR [15]. activation of PI3K/AKT pathway results in the inhibition of pro-inflammatory events such as expression of type-I interferon. then. Uncontrolled generation of ROS might then contribute to the various pathway signaling. (1). and so on. AKT2. DNA stress. is also a The Open Biochemistry Journal. AKT inhibits the GTPase-activating protein (GAP) activity of the tuberous sclerosis complex 1 (TSC1) and TSC2 by phosphorylating TSC2. It has been shown that a negative feedback loop runs from p70S6 kinase to the upstream insulin receptor substrate-1 (IRS1) through the PI3K/PDK1/AKT pathway. For example. the PI3K/AKT activation by insulin is associated with translocation of glucose transporter type 4 (GLUT4) [20]. IKKα. AKT moves to the cytoplasm and nucleus. MDM2. and AKT3 [12]. GSK3β. AKT phosphorylates many downstream targets to regulate various cellular functions (Fig. Bad. PIP3. which modulate NOXs-derived reactive oxygen species (ROS) generation. Hypothetical representation of PI3K/AKT/PTEN signaling in pancreatic β-cells is shown.

45]. followed by reduced insulin expression and secretion [57]. Consequently. indicating that PI3K/AKT and PKC are in the same pathway and are required for the ROS production. acetylation. 33]. In this way. acting as regulator of keeping basal levels of PIP3 below a threshold for the signaling activation. In addition. whose signal activates a chains of stress pathways involving a family of serine/threonine kinases including AKT and/or p38 MAPK (Fig. ROS could play a critical role in β-cells dysfunction through PTEN-dependent JNK activation and AKT inhibition [50]. serum withdrawal kills human U937 cells by elevating cellular ROS levels. also inhibits the translocation of NOXs subunits and reduces ROS production. It has been shown that PTEN activity can be regulated by the post-translational regulation including phosphorylation. and protects from diabetes [23. ROS directly interact with critical molecules including PI3K. The combination of obesity and type-2 diabetes is associated with elevated plasma FFAs which lead to apoptosis of β-cells through PTEN-dependent AKT inhibition. In particular. 54]. Persistent hyperglycemia during diabetes also Kitagishi et al. exerts toxic effects on islet cells by creating redox imbalance arising from overproduction of the ROS [38]. 1). Accordingly. interventions that attenuate ROS-influences on β-cells might prevent or slow down the development of diabetes. Under the basal conditions. Data suggest a correlation between insulin sensitivity/insulin resistance and ROS levels [44. OXIDATIVE STRESS DAMAGES ISLET-CELLS VIA THE PI3K/AKT PATHWAY Type-2 diabetes is characterized by diminished pancreatic β-cells function that is to secrete insulin in response to changes at extracellular glucose concentration [32]. controlling PTEN expression could be a therapeutic target to prevent the degeneration of β-cells. and oxidation [31]. the excessive oxidative environment may contribute to mitochondrial dysfunction. increased oxidative damage. AKT is also activated by inactivating protein Ser/Thr phosphatases via the ROS [49]. 3. which impair membrane integrity and leads to cytochrome-c release into cytosol and consequent cell apoptosis. and apoptotic cells in islet β-cells. Moreover. The ROS are also produced in cellular response to inflammatory cytokines and to bacterial invasion [40. enhanced insulin-PI3K signaling via deletion of PTEN leads to increased pancreatic β-cell mass because of both increased proliferation and reduced apoptosis [23]. Animals with diabetes shows histological changes including inflammation foci. Volume 8 specificity phosphatase which has protein phosphatase activity and lipid phosphatase activity that antagonizes the PI3K activity [22]. 28]. PTEN may be an important negative regulator of insulin-stimulated glucose uptake [27]. tissue targeted deletion of PTEN lead to improved insulin sensitivity in the insulin-responsive tissues. there is increased synthesis and storage of triglyceride due to the up-regulation of PI3K/AKT activity [26]. Oxidative stress is also implicated in the pathogenesis of free fatty acids (FFAs)induced β-cells dysfunction [56]. It has been reported that cell membrane depolarization. In addition. Hence. AKT. which is a critical parameter in regulating glucose-stimulated insulin secretion [36]. 2014. the relationship between PTEN function and adipocyte-specific fatty-acid-binding protein FABP4 is of interest in β-cell signaling [24]. Increased intra-cellular generation of ROS via the mitochondria seems to be implicated in the pathology of diabetes [34]. . Insulin signaling within the β-cells has also been shown to play an important role in maintaining the function of the β-cells. in which the role of PI3K signaling might be involved [53. NADPH oxidases (NOXs) are the principal source for cellular ROS as a result of metabolic stresses [34. even the partial reduction of PTEN is enough to elicit enhanced insulin sensitivity and glucose tolerance. LY294002. which is followed by PI3K/AKT and PKC activation causes NOXs assembly and ROS production. up-regulated levels of inflammatory cytokines. which exhibited beta-cell hyperplasia. PTEN expression in pancreatic islets is up-regulated in models of type-2 diabetes [30]. a PI3K inhibitor. which occurs through PI3K activation [51]. another PI3K inhibitor. 1). Defects in insulin secretion and decreased sensitivity of target tissues to insulin action are the key features of type-2 diabetes [32. In addition. which can cause various metabolic complications including pancreatic β-cells damage. AKT and NF-kB inducing kinase (NIK) are involved in these processes [47]. PTEN.76 The Open Biochemistry Journal. 35]. Several stress-response pathways including ROS leads to reduced ATP content and synthesis in β-cells. The ROS production is abolished by the wortmannin as well as the PKC inhibitor H7 [55]. PI3K/AKT pathway plays an apparent role in various oxidative stress pathways (Fig. Oxidative stress occurs as a result of an imbalance due to excess ROS production over the capability of the cells to support effective antioxidant responses. ROS activate PI3K and inactivate PTEN by oxidizing cysteine residues within the active center [48]. Hence. In particular. Serotonin reuptake transporter deficient mice exhibits glucose intolerance and insulin resistance and progressively developed obesity. 4. Furthermore. The interaction of PTEN to FABP4 suggests a role for this phosphatase in the regulation of lipid metabolism [25]. In PTEN-deficient mice. and impaired glucose tolerance. Evidences indicate that mitochondrial dysfunction is a contributor to β-cells failure in the development of diabetes. Activation of NF-kB by IKK occurs in association with ROS produced by NOXs in response to activation of IL-1β and/or TNFα receptors [46]. which can lead to the diabetic disease. 41]. However. and several phosphatases to initiate signaling in a variety of cellular processes such as proliferation and survival [43]. SEROTONIN PROTECTS ISLET-CELLS VIA THE PI3K/AKT PATHWAY Pancreatic islet cells share common developmental features with serotonin-producing neurons [58]. Accumulation of ROS disturbs the integrity and physiological function of cellular biomolecules impairing functionality and viability of the islet cells [39]. On the other hand. has been shown to reduce chemokineinduced ROS generation [52]. β-cells dysfunction. PTEN exerts a critical negative effect upon islet β-cell function. ROS oxidize polyunsaturated fatty acids in mitochondrial cardiolipin and other phospholipids [37]. which in turn have a negative effect on insulin signaling [42]. PTEN has been shown to be up-regulated in insulin resistance model of insulin or insulin-like growth factor-1 signaling ablation in β-cells [29]. Since wortmannin.

2014. and hyperinsulinemia [59]. Through the G-protein coupled receptors. demonstrating a novel role for PI3K/AKT pathway in maintaining serotonin receptor function [74]. Arrowhead means stimulation whereas hammerhead represents inhibition. sleep. The receptors mediating the action of serotonin are mainly classified into 7 major groups known as serotonin receptors [65]. Accordingly. plays a crucial role in regulating mood. Serotonin (5hydroxytryptamine). which is accompanied by an increase of plasma serotonin level. it is probable that serotonin is one of the restorative factors for islet β-cells. In fact. and metabolism [60]. body temperature. several serotonin receptor antagonists improve intestinal inflammation [68]. Antidepressants acting on serotonin neurotransmission activate AKT and inhibit GSK3β. (2). Lithium also activates PI3K/AKT signaling.Certain Diet and Lifestyle May Contribute to Islet β-cells Protection islet-mass expansion. particularly in the enterochromaffin cells [62]. serotonin activates the PI3K/AKT/mTOR/p70S6K signaling (Fig. Actually. One of the major functions of the PI3K/AKT pathway is to promote growth factor-mediated cell survival and to block cell apoptosis. Studies have indicated that serotonin exerts part of their actions by modulating the activity of PI3K/AKT pathway [69]. serotonin . Serotonin also regulates glucosestimulated insulin secretion from pancreatic β-cells [63]. The mood stabilizers such as valproate also inhibit GSK3β [73]. The Open Biochemistry Journal. Some of the serotonin receptors. 2). which are generally considered to be localized in the nervous systems. whereas the other subtypes serve as G-protein-coupled receptors [66]. SSRI: Selective Serotonin Reuptake Inhibitors MAOi: Monoamine oxidase inhibitors 5-HT: 5-hydroxytryptamine. Volume 8 77 Findings have provided evidence of the role of serotonin receptors in the regulation of inflammatory responses [67]. suggesting implication of PI3K/AKT/ PTEN modulators for the therapy of diabetes via the pancreatic β-cells protection. It is plausible that PI3K/AKT/GSK3β pathway also functions downstream the serotonin receptor in Fig. and this activation is similar to that seen in VEGF signaling [70]. Defective central AKT function alters serotonin signaling as well as serotonin associated behaviors. most of the serotonin is synthesized and localized in the gastro-intestinal tract. In addition. are also involved in processes associated with gastrointestinal functions including the secretion and motility [61]. GSK3β has a role for the regulation of serotonin receptor in cell surface trafficking [71]. appetite. Several modulators linked to the PI3K/AKT/PTEN pathway are demonstrated. In addition. drugs like SSRIs and MAO inhibitors that elevate serotonin synaptic transmission have been shown to inhibit GSK3β [72]. The islet β-cells proliferate during pregnancy in adaptation to the insulin resistance. Note that some critical events have been omitted for clarity. The 5-HT-3 receptor is distinguished from among the other serotonin receptor subtypes because it is an associated ion channel. whose potential molecular targets may be based on the predominant sites. an well-characterized neurotransmitter in the central nervous system. selective serotonin reuptake inhibitors (SSRIs) inhibit insulin secretion in pancreatic β-cells [64].

and walnuts. oxidative damage can be reduced by controlling hyperglycemia. GABA receptor also acts as a chemo-attractant receptor via an AKT-dependent pathway in neutrophils [82]. 3). sulfonylureas and the dipeptidyl peptidase-4(DPP-4) inhibitors. CERTAIN DIET AND LIFESTYLE MAY CONTRIBUTE TO ISLET Β-CELLS PROTECTION Some of anti-inflammation drugs and antioxidants function as a blocker of radical processes by eliminating harmful ROS produced during normal cellular metabolism [84. for example. can attenuate the PI3K/AKT signaling by up-regulation of PTEN expression [103]. Gamma-aminobutyric acid (GABA) has been shown to inhibit apoptosis of animal β-cells [75] (Fig. Melatonin is found in many common fruits and vegetables including grape skins. In addition. Melatonin also prevents cell-injury expansion through the PI3K/AKT dependent HO-1 expression [89]. In addition. It has been shown that β-cells express the GABA receptors and produce GABA through GAD65 [76]. Combination of honokiol with the mTOR inhibitor rapamycin presents the synergistic effects [104]. 2). Diets and some serotonin therapy presented here may be involved in the insulin secretion group through the effect of the islet β-cells protection (Fig. Activation of PI3K/AKT/GSK3β signaling may not only up-regulate the HO-1 expression. Kaempferol is a flavonol that is present in various plants including grapefruit and some edible berries. in which the phosphorylation of AKT is activated. PTEN indirectly promotes serotonin synthesis and secretion [101]. treatment of ghrelin. exerts protective effects on islet β-cells. These findings might be translated into new dietary treatments for diabetes in the future. protects islet cells from apoptosis. which largely comprise three groups by the pharmacological targets: glucose balance. Volume 8 pancreatic islet β-cells. In addition. Besides. So. and specifically repressed by inhibitors of PI3K such as LY294002 [79]. Realizing the susceptibility of islet β-cells to oxidative damage. 5. The representative drugs are αglucosidase inhibitors. Furthermore. Interestingly. As serotonin secretion may occur in a good situation of sleep. insulin secretion. Some of rosemary extract represses PTEN expression in K562 leukemic culture cells [95]. promising regulators for PI3K/AKT pathway for the islet β-cells survival may be as follows. GABA increases β-cells proliferation. several efforts to enhance their defense mechanism in the form of oral administration of antioxidants have proven successful [86]. and prevents hyperglycemia [83]. Therefore. 99]. pineapples.78 The Open Biochemistry Journal. molecular targets including phosphorylated AKT and mTOR are down-regulated by the combination of curcumin and resveratrol due to the activation of PTEN [105]. In addition. 2014. Augmentation of the GAD65 expression is induced by serotonin treatment. a chemical compounds in traditional eastern herbal medicines by the way. There is crosstalk between PTEN and serotonin receptor [102]. and vitamins [87]. PERSPECTIVE Several non-insulin anti-hyperglycemic drugs have been approved for the treatment of type-2 diabetes mellitus. On the other hand. 6. restores PI3K/AKT pathways [97]. Guanosine can protect cells from mitochondrial oxidative stress by activating the PI3K/AKT/GSK3β signaling and by induction of the antioxidant enzyme HO1[88]. and metabolism and so forth. the clinical relevance needs to be studied further. increasing evidence shows that sleep has an influence on dietary choices [96]. In contrast. Guanosine is a purine nucleoside that is found in RNA. Now. mood. there are numerous foods such as bananas. Kaempferol treatments promote viability. which is a hormone produced by the pineal gland. rosemary (Rosmarinus officinalis) exerts remarkable anti-diabetogenic effect [94]. a furanocembranoid from gorgonian leptogorgia setacea. Activation of the GABA receptors in islet βcells increases insulin release. 78]. overexpression of PTEN has been shown to have inhibitory effects on insulin signaling. showing the contribution to insulin resistance [98. which is an essential part of life [96]. and reduces cell apoptosis in islet cells [80. Epoxypukalide. anti-diabetic drugs often present proven or potential cardiac hazards [106]. It is important to exploit the potential benefits of these agents for diabetes. because their survival may be crucial for achieving successful therapy [85]. which may be produced from dried fish or seaweed and could be used as food additives for flavor enhancers. inhibited apoptosis. tomatoes. Diet promotes sleep duration and quality. Kaempferol treatment improve the expression of anti-apoptotic AKT that is significantly reduced in islet β-cells chronically exposed to hyper-glycemia [92]. GABA has been shown to increase DNA synthesis in pancreatic cell line [81]. 81]. Epidemiologic studies have demonstrated that those who sleep less are more probable to eat energy-rich foods including fats and carbohydrates [96]. Although there are clear physiological connections behind the effects. induces the activation of PI3K and AKT [91]. 3). but also the protective effects of this pathway may be linked to the actual effects of HO-1. these conditions should be well-maintained to prevent diabetes and to avoid the disease progression by proper serotonin secretion. including decreased AKT activity and GLUT4 translocation to the cell membrane. biguanides and dual peroxisome proliferator-activated receptors (PPAR) agonists (thiazolidinediones or glitazones). minerals. down-regulation of PTEN has the opposite effect with increased glucose uptake in response to insulin [100]. calorie intake. However. The GAD65 is a crucial target of auto-anti-GAD65 antibodies associated with the development of type-1 diabetes [77. Several herbs may also be promising. appetite. Interestingly. optimal use of treatments for diabetes is of importance to the sustainability of health care. In addition. and reduced caspase-3 activity in human islet β-cells. Honokiol. Inhibiting the signaling via PI3K/AKT. At present. several antioxidants could be used as a supplement to scavenge local ROS thereby improving the survival of islet β-cells. and oranges to naturally boost melatonin production [90]. and metabolic improvement (Fig. 81]. induces β-cells proliferation and protects against cytokine-mediated β-cells death in cultured islet cells [93]. GABA activates three types of membrane receptors. there is a progression from monotherapy to multiple-therapy with or without additional agents in the treatment of diabetes. Kaempferol also Kitagishi et al. body temperature. The precise involvement of the PI3K/AKT/PTEN /GSK3β/mTOR in islet . a hormone that stimulates hunger.

serotonin HIF-1α = hypoxia-inducible factor-1α HO-1 = heme oxygenase-1 .5. Volume 8 79 Fig. IRS = insulin receptor substrate mTOR = mammalian target of rapamycin NF-κB = nuclear factor κB NIK = NF-kB inducing kinase NOXs = NADPH oxidases PDK1 = phosphoinositide-dependent kinase 1 ABBREVIATIONS PDK2 = phosphoinositide-dependent kinase 2 PH = plekstrin homology PIP2 = phosphatidylinositol 4. Representative drugs in a group are also presented.Certain Diet and Lifestyle May Contribute to Islet β-cells Protection The Open Biochemistry Journal. AGI: -Glucosidase inhibitors DPP4i: Dipeptidyl-peptidase-4 inhibitors GLP: Glucagon-like peptide-1 agonists MEG: Meglitinides MET: Metformin SU: Sulfonylurea TZD: Thiazolidinedione SIRT1: a member of the sirtuins. (3).5-triphosphate PI3K = phosphatidylinositol-3 kinase PPAR = peroxisome proliferator-activated receptors ROS = reactive oxygen species PTEN = phosphatase and tensin homologue deleted on chromosome 10 DPP-4 = dipeptidyl peptidase-4 FFAs = free fatty acids GABA = gamma-aminobutyric acid GAP = GTPase-activating protein GLUT4 = glucose transporter 4 5-HT = 5-hydroxytryptamine. Note that some critical drugs have been omitted for clarity. Further research is therefore required to determine whether agents differ in terms of long-term complications of diabetes and mortality. the cost-effectiveness of these drugs requires further study. More understanding of the precise intracellular mechanisms and variations in pathogenesis of diabetes could provide novel insights into the development of therapeutic approaches against diabetes. Annotated abbreviations used here. a distinct class of trichostatin A-insensitive lysyl-deacetylases β-cells signaling has remained unexplored. Simplified diagrams indicating the medicinal properties of non-insulin diabetes-treatments are shown.bisphosphate PIP3 = phosphatidylinositol 3.4. In addition. 2014.

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