Insulin resistance in genetically obese (fa/fa) rats: changes in the glycosyl-phosphatidylinositol signaling system in isolated hepatocytes.

Sánchez-Gutiérrez, J C; Sánchez‐Arias, Juan A.; Valle, Juan Carlos del; Guadaño, Ana; Samper, B; Mato, José M.; Feliu, Jaume Cruz i

doi:10.1210/endo.134.3.8119190

Cited by 7 publications

(5 citation statements)

References 29 publications

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“…Another possible explanation is that the pattern of impaired GPI/IPG signaling in hepatocytes of fa/fa rats reported by Sancbez-Gutierrez et at. (12) was less dramatic than the STZ rats (11) and is concomitant with normoglycemia of fa/fa rats. Furthermore, results from the present study indicate that urinary chiro-inositol and myo-inositol excretion increases with the severity of diabetes, as observed in the db/db mice.…”

Section: Resultsmentioning

confidence: 80%

“…Although the exact mechanism and the role of inositols in GPI/IPG signaling is not fully understood, increased renal excretion of chiroand myo-inositol is in keeping with this observed defect. To date, no data on the GPI/IPG signaling system has been reported for db/db mice, however, a similar pattern of impaired GPI-dependent insulin signaling was demonstrated in 14-to 21-week-old fa/fa rats (12). Hepatocyte content of GPI and IPG uptake were reduced by approximately 30% in fa/fa rats compared with lean control animals.…”

Section: Resultsmentioning

confidence: 82%

“…IPG was reduced in hepatocytes and adipocytes of diabetic Goto-Kakizaki rats compared with normal rats (10). Impaired GPI-IPG-dependent insulin-signaling systems have been reported in hepatocytes of streptozotocin (STZ)induced diabetic rats (11) and obese fa/fa Zucker rats (12).…”

Section: Insulin-induced Generation Of the Chiro-inositol-containingmentioning

confidence: 99%

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Urinary chiro-Inositol and myo-inositol Excretion is Elevated in the Diabetic db/db Mouse and Streptozotocin Diabetic Rat

Przybylski

Taylor

2003

Exp Biol Med (Maywood)

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Inositol phosphoglycan molecules containing either D-chiro-inositol or myo-inositol have been isolated from various mammalian tissues and are putative mediators of insulin action. Urinary excretion of inositols appears to be altered in diabetes mellitus; however, the relationships with different types of diabetes are unclear. The objective of this study was to determine the urinary excretion of chiro- and myo-inositol in diabetic animal models, including streptozotocin (STZ) rats, db/db mice, and fa/fa Zucker rats. In STZ rats (type 1 diabetes), 12-hr urinary excretion of chiro-inositol was elevated 336-fold and myo-inositol excretion was elevated 47-fold compared with their nondiabetic counterparts. When corrected for creatinine, chiro-inositol excretion was 259-fold higher and myo-inositol excretion was 36-fold higher in STZ rats than in normal rats. The same pattern was observed in db/db mice (type 2 diabetes), where 12-hr urinary chiro-inositol excretion was elevated 247-fold compared with normal mice. When corrected for creatinine, chiro-inositol excretion was 2455-fold higher and urinary myo-inositol excretion was elevated 8.5-fold in db/db mice compared with normal mice. The fa/fa Zucker rats (impaired glucose tolerance) had a pattern of urinary inositol excretion that was similar to the nondiabetic animals (lean Zucker rats, C57BL/6 mice, and Sprague-Dawley rats). In summary, urinary chiro-inositol and myo-inositol excretion was elevated in animal models of type 1 and type 2 diabetes mellitus, concomitant with hyperglycemia and glucosuria.

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Section: Resultsmentioning

confidence: 80%

Section: Resultsmentioning

confidence: 82%

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Urinary chiro-Inositol and myo-inositol Excretion is Elevated in the Diabetic db/db Mouse and Streptozotocin Diabetic Rat

Przybylski

Taylor

2003

Exp Biol Med (Maywood)

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“…In this regard it is noteworthy that adipocytes isolated from the genetically inbred insulin resistant Goto-Kakizaki rat, a model of non-obese NIDDM, which has a low rate of urinary chiro-inositol excretion, did not release IPGs in response to insulin, whereas adipocytes from control rats did release IPGs in response to insulin [21]. Moreover, four different states of insulin resistance, i. e. glucocorticoid treatment, streptozotocininduced diabetes, aging and genetic obesity, are associated with similar defects in the ability of insulin to elicit the release of IPGs from isolated hepatocytes [22]. This suggests that insulin resistance, rather than diabetes or obesity, is the factor primarily responsible for the lack of increase in the serum PDH activator after glucose ingestion in the IRM group.…”

Section: Discussionmentioning

confidence: 92%

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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“…The glycan also promotes serine/threonine dephosphorylation in adipocyte extracts via a mechanism requiring PP1, the phosphatase that regulates the activity of both glycogen synthetase and phosphorylase (46). Moreover, reduced cellular GPI content and insulin-stimulated turnover was accompanied by a marked decrease in stimulation of glycogen synthase activity and net glycogen accumulation in hepatocytes isolated from insulinresistant, genetically obese rats (47). While these observations indicated a correlation between GPI metabolism and glycogen synthesis, an absolute dependence has not been demonstrated.…”

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confidence: 99%

Stimulation of glycogen synthesis by insulin in human erythroleukemia cells requires the synthesis of glycosyl-phosphatidylinositol.

Lazar¹,

Knez²,

Medof³

et al. 1994

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

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Although the insulin-dependent hydrolysis of glycosyl-phosphatidyllnositol (GPI) may play an important role in insulin action, an absolute requirement for this glycolipid has not been demonstrated. Human K562 cells were mutated to produce a cell line (IA) incapable of the earliest step in PI glycosylation, the formation of PI-GlcNAc. Another cell line (IVD) was deficient in the deacetylation of PI-GlcNAc to form PI-GlcN and subsequent m lated species. Each line was transfected with wild-type human insulin receptors. Similar insulin-stimulated receptor autophosphorylation was observed in all three lines, along with a nearly identical increase in the association of phosphorylated insulin receptor substrate 1 with endogenous PI 3-kinase. Both normal and GPI-defective lines also displayed a similar 2-to 3-fold increase in phosphorylation of the Shc protein and its association with growth factor receptor-bound protein 2 in response to insulin. In contrast to these results, striking differences were noted in insulinstimulated glycogen synthesis. In normal cells, glycogen synthesis was significantly increased by insulin, whereas no insulin stimulation was observed in GPI-deflcient IA cells, and only a trace of stimulation was detected in IVD cells. These results indicate that tyrosine phosphorylation produced by insulin is not dependent on GPI synthesis, and this effect is not sufficient to elicit at least some of the metabolic effects of the hormone. In contrast, GPI synthesis is required for the stimulation of glycogen synthesis by insulin in these cells. These findings support the existence of divergent pathways in the action of insulin.glycan has exhibited insulin-mimetic properties in a manner consistent with the promotion of dephosphorylation via serine/threonine phosphatase activities (reviewed in ref. 6). Although the precise structure of the molecule remains unknown, metabolic and chemical labeling studies (1-5) indicate a core structure of cyclic 1,2-inositol monophosphate-glucosamine-(mannose)3, similar to the core structure of the glycan portion of the GPI protein anchor (7). This conclusion has been supported by the observed insulinmimetic activities of an inositol glycan derived from the Trypanosoma brucei GPI anchor (8) and the blockade of some of the actions of insulin by antibodies raised against a T. brucei inositol phosphate glycan (9).Although the insulin-mimetic activities of inositol glycans have-been demonstrated in several systems, their absolute requirement in the various actions of insulin remains unknown. Human K562 erythroleukemia cells produce the common GPI core structure of phosphatidylinositolglucosamine-(mannose)3-phosphate-ethanolamine for anchoring of cell surface proteins, such as decay-accelerating factor (DAF) and CD59. Mutagenesis of these cells yielded one cell line (IA) incapable of the earliest step in PI glycosylation, the formation of PI-GlcNAc, and another (IVD) defective in the deacetylation of PI-GlcNAc to form PI-GlcN and subsequent mannosylated species (10, 11). ...

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Insulin resistance in genetically obese (fa/fa) rats: changes in the glycosyl-phosphatidylinositol signaling system in isolated hepatocytes.

Cited by 7 publications

References 29 publications

Urinary chiro-Inositol and myo-inositol Excretion is Elevated in the Diabetic db/db Mouse and Streptozotocin Diabetic Rat

Urinary chiro-Inositol and myo-inositol Excretion is Elevated in the Diabetic db/db Mouse and Streptozotocin Diabetic Rat

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

Stimulation of glycogen synthesis by insulin in human erythroleukemia cells requires the synthesis of glycosyl-phosphatidylinositol.

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