A Putative Mediator of Insulin Action Which Inhibits Adenylate Cyclase and Adenosine 3′,5′-Monophosphate- Dependent Protein Kinase: Partial Purificaton from Rat Liver: Site and Kinetic Mechanism of Action*

Malchoff, Carl D.; Huang, Laura C.; Gillespie, Nicole D.; Palasi, Carlos Villar; Schwartz, Charles; Cheng, Kang; Hewlett, Erik L.; Larner, Joseph

doi:10.1210/endo-120-4-1327

Cited by 38 publications

(14 citation statements)

References 29 publications

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“…High concentrations of insulin increase bioactivity of the pH 1.3 IPG as well as the myo-inositol content of the IPG isolated from skeletal muscle [1,8] and liver [26]. The lack of increase in the serum pH 1.3 IPG in the present study could thus be due to an insufficient increase in the extracellular insulin concentration, suggesting differential sensitivities of different IPG generating/releasing systems to insulin.…”

Section: Discussionmentioning

confidence: 44%

Insulin mediators in man: effects of glucose ingestion and insulin resistance

et al. 1997

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Insulin generates/releases chemical substances that alter the activities of purified enzymes [1,2] and the metabolism of intact cells [3,4] in an insulin mimetic fashion. These substances have therefore been termed mediators or second messengers of insulin [5]. Two different insulin mediators have been separated from rat liver [6]. These mediators have been identified as inositol phosphoglycans (IPGs), containing inositol, non-acetylated amino sugars, neutral sugars, ethanolamine, phosphate and, possibly, amino acids [5]. One contains d -chiro-inositol and activates pyruvate dehydrogenase (PDH) phosphatase, whereas another contains myo-inositol and inhibits cyclic AMP-dependent protein kinase (PKA). Injection of each of these IPGs into low-dose streptozotocin-diabetic rats lowers blood glucose [7].Body fluids of patients with non-insulin-dependent diabetes mellitus (NIDDM) have abnormally low levels of Summary Insulin mediators (inositol phosphoglycans) have been shown to mimic insulin action in vitro and in intact mammals, but it is not known which mediator is involved in insulin action under physiological conditions, nor is it known whether insulin resistance alters the mediator profile under such conditions. We therefore investigated the effects of glucose ingestion on changes in the bioactivity of serum inositol phosphoglycan-like substances (IPG) in healthy men and insulin resistant (obese, non-insulin-dependent diabetic) men. Two classes of mediators were partially purified from serum before and after glucose ingestion. The first was eluted from an anion exchange resin with HCl pH 2.0, and bioactivity was determined by activation of pyruvate dehydrogenase in vitro. The second was eluted with HCl pH 1.3, and bioactivity was determined by inhibition of cyclic AMP-dependent protein kinase. In healthy men, the bioactivity of the pH 1.3 IPG was not altered by glucose ingestion, whereas bioactivity of the pH 2.0 IPG increased to approximately 120 % of the pre-glucose ingestion value at 60-240 min post-glucose ingestion (p < 0.05 vs pre-glucose). There was no change in either IPG after glucose ingestion in the insulin-resistant group. These data suggest that the pH 2.0 IPG plays an important role in mediating insulin's effect on peripheral glucose utilization in man under physiological conditions. The data further show, for the first time, a defective change in the bioactivity of an insulin mediator isolated from insulin-resistant humans after hyperinsulinaemia, suggesting that inadequate generation/release of IPGs is associated with insulin resistance. [Diabetologia (1997) 40: 557-563] Keywords Inositol phosphoglycans, non-insulin dependent diabetes mellitus, pyruvate dehydrogenase, cyclic AMP dependent protein kinase.

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Section: Discussionmentioning

confidence: 44%

Insulin mediators in man: effects of glucose ingestion and insulin resistance

et al. 1997

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“…Bovine heart PDH phosphatase and PDH complex were purified as described by Newman et al (18). cAMP-dependent protein kinase was prepared from rabbit skeletal muscle as described by Malchoff et al (19). Crude insulin mediator preparations were obtained from rat liver by heat treatment in acid followed by ion-exchange chromatography with AG-1X8 as described (4 Mg2+.…”

Section: Methodsmentioning

confidence: 99%

“…Crude insulin mediator preparations were obtained from rat liver by heat treatment in acid followed by ion-exchange chromatography with AG-1X8 as described (4 Mg2+. The inhibition of cAMP-dependent protein kinase by mediator fractions was measured as described (19). RESULTS Characterization of the Antibodies.…”

Section: Methodsmentioning

confidence: 99%

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Anti-inositolglycan antibodies selectively block some of the actions of insulin in intact BC3H1 cells.

Romero

Gamez

Huang

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

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We have studied the mechanism ofgeneration of insulin mediators by using specific antibodies raised against the oligosaccharide anchor of membrane proteins. These antibodies (i) block the in vitro effects ofpurified insulin mediators and (it) block the insulin-induced stimulation of pyruvate dehydrogenase in intact BC3H1 myocytes but not insulinstimulated glucose uptake, generation of diacylglycerol, or generation of insulin mediators. When added to intact cells in the presence of insulin, these antibodies induce the accumulation of insulin mediator activity in the extracellular medium. We therefore conclude that these anti-inositolglycan antibodies block some of the effects of insulin by inhibiting the uptake of specific insulin mediators generated outside the cell.

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“…Separate classes have been identified (3), one containing D-chiro-inositol (DCI) and galactosamine (4) and a second containing myo-inositol (myo-INS) and glucosamine (1)(2)(3)(4)(5). Generated rapidly from lipid and͞or protein precursors in response to insulin, they have insulin-like effects in vitro and in vivo (1,2,4,6,7).…”

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confidence: 99%

Inositols prevent and reverse endothelial dysfunction in diabetic rat and rabbit vasculature metabolically and by scavenging superoxide

Nascimento

Lessa

Kerntopf

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Endothelial dysfunction (ED) is an early feature of cardiovascular risk and diabetes. Hyperglycemia and hyperlipidemia are causative factors. Excessive endothelial mitochondrial superoxide (ROS) production with hyperglycemia and hyperlipidemia is a key mechanism. Inositol components of an insulin inositol glycan mediator, D-chiro-inositol (DCI) and 3-O-methyl DCI (pinitol), decrease hyperglycemia and hyperlipidemia. We tested whether these, myoinositol and dibutyryl DCI (db-DCI), would prevent or reverse ED in diabetic rats and rabbits. Oral inositols reduced hyperglycemia and hypertriglyceridemia with different potencies and prevented ED in rat aortic rings and mesenteric beds. Inositols added in vitro to five diabetic tissues reversed ED. Relaxation by Ach, NO, and electrical field stimulation was potentiated by inositols in vitro in rabbit penile corpus cavernosa. Inositols in vitro restored impaired contraction by the eNOS inhibitor L-NAME and increased NO effectiveness. DCI and db-DCI decreased elevated ROS in endothelial cells in high glucose and db-DCI reduced PKC activation, hexosamine pathway activity, and advanced glycation end products to basal levels. Xanthine͞xanthine oxidase generated superoxide was reduced by superoxide dismutase or inositols, with db-DCI efficacious in a mechanism requiring chelated Fe 3؉ . Histochemical examination of rat aortic rings for protein SNO demonstrated a decrease in diabetic rings with restoration by inositols. In summary, inositols prevented and reversed ED in rat and rabbit vessels, reduced elevated ROS in endothelial cells, potentiated nitrergic or vasculo-myogenic relaxations, and preserved NO signaling. These effects are related to their metabolic actions, direct superoxide scavenging, and enhancing and protecting NO signaling. Of the inositols tested, db-DCI was most effective.I nositol phosphoglycans (IPGs) are potentially important putative intracellular mediators of insulin action (1, 2). Separate classes have been identified (3), one containing D-chiro-inositol (DCI) and galactosamine (4) and a second containing myo-inositol (myo-INS) and glucosamine (1-5). Generated rapidly from lipid and͞or protein precursors in response to insulin, they have insulin-like effects in vitro and in vivo (1, 2, 4, 6, 7). Myo-INS phospho-glycans have been prepared by enzymatic cleavage of protein precursors and chemically synthesized (7-9). They have dose-dependent insulinlike effects on isolated adipocytes, cardiomyocytes, and diaphragms including increased glucose transport (7-9). One DCI containing IPG has been isolated from liver, and its structure has been determined and chemically synthesized (10). It is active in vivo; lowering elevated blood glucose when administered intravenously to diabetic rats (10-12). In vitro, it enhances insulin to stimulate [ 14 C]glucose incorporation into glycogen in H4IIE hepatoma cells (10). It activates pyruvate dehydrogenase (PDH) phosphatase (10), phosphoprotein phosphatase PP2C directly (13), and PP1 indirectly (4,14). Both PDH and glyco...

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A Putative Mediator of Insulin Action Which Inhibits Adenylate Cyclase and Adenosine 3′,5′-Monophosphate- Dependent Protein Kinase: Partial Purificaton from Rat Liver: Site and Kinetic Mechanism of Action*

Cited by 38 publications

References 29 publications

Insulin mediators in man: effects of glucose ingestion and insulin resistance

Insulin mediators in man: effects of glucose ingestion and insulin resistance

Anti-inositolglycan antibodies selectively block some of the actions of insulin in intact BC3H1 cells.

Inositols prevent and reverse endothelial dysfunction in diabetic rat and rabbit vasculature metabolically and by scavenging superoxide

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