Inositol Phosphoglycans in Diabetes and Obesity: Urinary Levels of IPG A-Type and IPG P-Type, and Relationship to Pathophysiological Changes

Kunjara, Sirilaksana; Wang, Dennis Y.; Greenbaum, A. L.; McLean, Patricia; Kurtz, A. B.; Rademacher, Thomas W.

doi:10.1006/mgme.1999.2936

Cited by 42 publications

(54 citation statements)

References 42 publications

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“…Because the assay was not linear above 150%, dilutions were required to get true comparative values into the linear region (Figure 3). Bioactivity of P-IPG was then normalized on urinary creatinine as we reported previously a direct correlation of urinary P-IPG levels (expressed as units of P-IPG per micromole of urinary creatinine) and units of P-IPG in 24-hour collections of urine 14 (93.5Ϯ64.6% versus 37.6Ϯ20.2%; PϽ0.001; Table 1). …”

Section: ͻ0001mentioning

confidence: 99%

Inositol Phosphoglycan P-Type in Preeclampsia

et al. 2007

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Abstract-A state of insulin resistance has been demonstrated in active preeclampsia, and women with clinical evidence of insulin resistance are at higher risk to develop this syndrome during pregnancy. Recently, inositol phosphoglycan P-type, a putative second messenger of insulin action, has been implicated in the pathophysiology of preeclampsia and is increased in the placenta, amniotic fluid, and maternal urine of preeclamptic women compared with normal pregnant women. We report here a case-control study to assess the potential of urinary levels of inositol phosphoglycan P-type as a screening test for preeclampsia. Twenty-seven preeclamptic women and 47 healthy pregnant women were recruited. A polyclonal antibody-based ELISA was developed to detect levels of inositol phosphoglycan P-type in urine. Its content in urinary specimens was found to be 30-fold higher in preeclamptic subjects than control subjects (329.1Ϯ21.8 versus 9.2Ϯ1.5; PϽ0.001), with a higher level in all of the preeclamptic cases. For 6 women who developed preeclampsia, Ͼ1 gestational date sample of urine was available, and retrospective analysis showed a significant time-related increase of the urinary level of inositol phosphoglycan P-type Յ7 weeks before clinical diagnosis of preeclampsia. Urinary level of inositol phosphoglycan P-type increased after diagnosis indicating a possible pathophysiological threshold level and steeply decreased after delivery. Key Words: preeclampsia Ⅲ screening test Ⅲ inositol phosphoglycan Ⅲ biological marker Ⅲ insulin resistance P reeclampsia (PE) represents the most severe form of hypertensive disorder of human pregnancy being associated with a substantial maternal and perinatal morbidity and mortality. 1 It affects Ϸ5% of all pregnancies, although its causes remain unclear. A state of insulin resistance has been demonstrated in active PE, 2,3 and women with clinical evidence of insulin resistance are at higher risk of developing this syndrome during pregnancy. 4 Recently, a family of putative insulin mediators, inositol phosphoglycans (IPGs), have been implicated in the pathophysiology of PE. A high concentration of bioactive IPG P-type (P-IPG) was found in human preeclamptic placenta, 5 urine, and amniotic fluid. 6 Further studies have provided evidence of insulin resistance in human placentas from preeclamptic pregnancies and demonstrated an association between P-IPG and the insulin signaling cascade. 7 IPGs have been demonstrated to exert insulin-mimetic activity in both glucose and lipid metabolism mainly through the activation of pyruvate dehydrogenase phosphatase, glycogen synthase phosphatase, and glycerol-3-phosphate acyltransferase. 8,9 The elevated concentration of glycogen in terminal villi from preeclamptic placentas, because of an increased activity of glycogen synthase, 10 may be a consequence of the abnormal content of P-IPG in the placentas of preeclamptic patients.In this report, we focus our attention on the urinary excretion of IPGs using a novel assay specifically developed to analyze uri...

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confidence: 99%

Inositol Phosphoglycan P-Type in Preeclampsia

et al. 2007

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“…Multiple isoenzymic forms of PDK in different tissues raises the possibility that targeted responses could be elicited by specific IPGs (15,19,40,41). The linear and sigmoidal effects of IPG-P on PDP and PDK add a significant degree of fine control, respectively, and this is further enhanced by the interaction of IPGs, IPG-A counteracting the effect of IPG-P activation of PDP (23).…”

Section: Discussionmentioning

confidence: 99%

“…Representative structures are shown in Figs. 1, 2, and 8: series 1, GlcNH 2 ␣1-6-Dmyo-inositol (1) and GlcNH 2 ␤1-6-D-myo-inositol (2); series 2, (5), and 3ЈO-methyl-GlcNH 2 ␣1-6-D-myo-inositol-3,4 di-O-PO 3 (6); series 3, 6-O-PO 3 GlcNH 2 ␣1-6-D-myoinositol (7), 4-O-PO 3 -GlcNH 2 ␣1-6-D-myo-inositol (8), and 3-O-PO 3 -GlcNH 2 ␣1-6-D-myo-inositol (9); series 4, GlcNH 2 ␣1-6-D-myo-inositol-5-O-acetate (10), GlcNH 2 ␣1-5-D-myo-inositol-6-O-acetate (11), and 2-azido-2-deoxy-3-Obenzyl-GlcNH 2 ␣1-6-D-myo-inositol-6-O-acetate (12); series 5, GlcNH 2 ␤1-6-D-chiro-inositol (13), GlcNH 2 ␣1-6-D-chiroinositol (14), and GalNH 2 ␤1-6-GalNH 2 ␤1-1-D-chiro-inositol (15); series 6, GlcNH 2 ␣1-6-D-chiro-inositol-1-O-PO 3 (16) and (22), and GalNH 2 ␣1-6-D-pinitol (23).…”

Section: Methodsmentioning

confidence: 99%

“…The bioassays were as described previously (16,23,29). In brief, IPG-P was determined using the activation of PDP by the spectrophotometric variant of the two-stage system described by Lilley et al (29).…”

Section: Measurement Of Ipg-p and Ipg-a-mentioning

confidence: 99%

“…There is a fall in the tissue content, serum levels, and excretion of IPG-P and shifts in the IPG-P/IPG-A quotient in human diabetes type 2 and in experimental diabetes (20 -23). Of particular importance in the present context is the interaction of the two classes of IPGs in the regulation of PDP, IPG-A counteracting the stimulatory effect of IPG-P (23).…”

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Reciprocal Control of Pyruvate Dehydrogenase Kinase and Phosphatase by Inositol Phosphoglycans: Dynamic State Set by “Push-Pull” System

McLean

Kunjara

Greenbaum

et al. 2008

Journal of Biological Chemistry

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Reversible phosphorylation of proteins regulates numerous aspects of cell function, and abnormal phosphorylation is causal in many diseases. Pyruvate dehydrogenase complex (PDC) is central to the regulation of glucose homeostasis. PDC exists in a dynamic equilibrium between de-phospho-(active) and phosphorylated (inactive) forms controlled by pyruvate dehydrogenase phosphatases (PDP1,2) and pyruvate dehydrogenase kinases (PDK1-4). In contrast to the reciprocal regulation of the phospho-/de-phospho cycle of PDC and at the level of expression of the isoforms of PDK and PDP regulated by hormones and diet, there is scant evidence for regulatory factors acting in vivo as reciprocal "on-off" switches. Here we show that the putative insulin mediator inositol phosphoglycan P-type (IPG-P) has a sigmoidal inhibitory action on PDK in addition to its known linear stimulation of PDP. Thus, at critical levels of IPG-P, this sigmoidal/linear model markedly enhances the switchover from the inactive to the active form of PDC, a "push-pull" system that, combined with the developmental and hormonal control of IPG-P, indicates their powerful regulatory function. The release of IPGs from cell membranes by insulin is significant in relation to diabetes. The chelation of IPGs with Mn 2؉ and Zn 2؉ suggests a role as "catalytic chelators" coordinating the traffic of metal ions in cells. Synthetic inositol hexosamine analogues are shown here to have a similar linear/sigmoidal reciprocal action on PDC exerting push-pull effects, suggesting their potential for treatment of metabolic disorders, including diabetes. Pyruvate dehydrogenase complex (PDC),2 an enzyme at the interface between glycolysis and the citric acid cycle, is influenced by dietary and hormonal control and by phosphorylation/dephosphorylation reactions, the former regulated by pyruvate dehydrogenase kinases (PDK1-4) and the latter by dedicated mitochondrial pyruvate dehydrogenase phosphatases (PDP1,2) (1-4). Phosphorylation forms the basis of the dynamic state of cell cycling networks, thus the balance between the active (de-phospho-) and the inactive (phospho-) forms of PDC is dependent upon the regulation of PDK and PDP (2,5,6). Cycling between two phosphorylated states is, classically, one mode of control, permitting rapid alterations in catalytic activity, e.g. in response to insulin, adrenaline, shifts in Ca 2ϩ distribution, and effector molecules. In addition, adaptive changes due to altered hormonal or dietary states, such as diabetes, starvation, or high fat/high carbohydrate diets, and related changes in the expression of isoforms of PDK and PDP in a tissue-specific manner regulate the phosphorylation state of the PDC (2, 7-12). The profile of the regulation of PDK1-4 to activation by NADH and to NADH plus acetyl CoA and ATP, together with differences in the apparent K i values for ADP, confers upon tissues individual patterns of response to alterations in metabolite profile linked to hormonal and dietary changes (2, 3, 9 -12).Inositol phosphoglycans (IPGs) are bro...

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Inositolphosphoglycan Mediators Structurally Related to Glycosyl Phosphatidylinositol Anchors: Synthesis, Structure and Biological Activity

Martín‐Lomas¹,

Khiar²,

Garcı́a³

et al. 2000

Chem. Eur. J.

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The preparation of the pseudopentasaccharide 1a, an inositol-phosphoglycan (IPG) that contains the conserved linear structure of glycosyl phosphatidylinositol anchors (GPI anchors), was carried out by using a highly convergent 2+3-block synthesis approach which involves imidate and sulfoxide glycosylation reactions. The preferred solution conformation of this structure was determined by using NMR spectroscopy and molecular dynamics simulations prior to carrying out quantitative structure--activity relationship studies in connection with the insulin signalling process. The ability of 1a to stimulate lipogenesis in rat adipocytes as well as to inhibit cAMP dependent protein kinase and to activate pyruvate dehydrogenase phosphatase was investigated. Compound 1a did not show any significant activity, which may be taken as a strong indication that the GPI anchors are not the precursors of the IPG mediators.

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Inositol Phosphoglycans in Diabetes and Obesity: Urinary Levels of IPG A-Type and IPG P-Type, and Relationship to Pathophysiological Changes

Cited by 42 publications

References 42 publications

Inositol Phosphoglycan P-Type in Preeclampsia

Inositol Phosphoglycan P-Type in Preeclampsia

Reciprocal Control of Pyruvate Dehydrogenase Kinase and Phosphatase by Inositol Phosphoglycans: Dynamic State Set by “Push-Pull” System

Inositolphosphoglycan Mediators Structurally Related to Glycosyl Phosphatidylinositol Anchors: Synthesis, Structure and Biological Activity

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