Urinary <i>myo</i>-Inositol-to-<i>chiro</i>-Inositol Ratios and Insulin Resistance

Larner, Joseph; Craig, James W.

doi:10.2337/diacare.19.1.76

Cited by 57 publications

(46 citation statements)

References 5 publications

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“…In a review of the published literature, we reported increased ratios of urine myo-inositol to chiro-inositol in our data, data from a Japanese study and data from separate investigators in the US (52). This latter group had studied inositol urinary excretion in obese type II diabetic patients compared with obese control subjects and had found, in contrast to our findings, higher urine chiro-inositol in the obese type II diabetic patients compared with obese control subjects (54).…”

Section: R E V I E W a R T I C L E M O L M Econtrasting

confidence: 53%

“…The higher myo-inositol and the lower chiro-inositol in the type II diabetic tissue and urine compared with controls was termed an inositol imbalance. It was expressed as a ratio of myoinositol to chiro-inositol (52). In urine, for example, ratios of myo-inositol to chiroinositol of about two in control subjects were increased to about 20-fold in type II diabetic subjects.…”

Section: The Inositol Imbalance Of Myo-inositol and Chiro-inositol Inmentioning

confidence: 99%

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D-Chiro-Inositol Glycans in Insulin Signaling and Insulin Resistance

Larner

Brautigan

Thorner

2010

Mol Med

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158

156

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SYNTHESISInsulin stimulates both glucose transport and glycogen synthesis; however, these actions sometimes occur in a disconnected manner. Current models for the mechanism of action for insulin, for which the dominant paradigm involves the activity of the insulin receptor Tyr kinase and its primary Tyr phosphorylated substrates-the insulin receptor substrate (IRS) family of proteins (1), are inadequate to account for these historical observations. Under certain conditions, control of glucose transport by insulin is observed in the absence of an effect on glycogen synthesis, whereas under other conditions, control of glycogen synthesis by insulin is observed in the absence of an effect on glucose transport. For example, application of insulin during perfusion of the rat heart stimulated glucose transport, but did not activate glycogen synthase (GS) (2). On the other hand, when the rat diaphragm was treated with N-ethylmaleimide, to test the effect of this sulfhydryl reagent on metabolism, no effect of insulin was observed on glucose transport, but insulin-activated GS and glycogen synthesis (3). Thus, insulin signaling proceeded along one pathway while another pathway was unaffected, suggesting the possibility that no single pathway accounts for events downstream of the IR, but parallel signaling connects the IR to activation of glucose transport and glucose metabolism. These considerations led us to the concept that a cytoplasmic second messenger was generated in parallel with the phosphorylation events initiated by the receptor Tyr kinase (4). We have emphasized the hypothesis that the phosphorylation network and the second messenger pathway operate in parallel and together are required to fully account for insulin effects on metabolic disposal of intracellular glucose (4). EVIDENCE FOR INSULIN SECOND MESSENGERSThe initial evidence to support the existence of a second messenger for insulin followed classical methods used to discover cAMP. Rats were injected with insulin and killed, and then muscle and/or liver were used to prepare heatinactivated, deproteinized extracts. The extracts from insulin-stimulated rat tissues had one or more substances that inhibited protein kinase A (PKA) and activated GS phosphatase, compared with extracts from control rats. Insulin administration maintained PKA in muscle as an inactive holoenzyme, presumably desensitized to cAMP by the soluble second D 1 6 ( 1 1 -1 2 ) 5 4 3 -5 5 1 , N Classical actions of insulin involve increased glucose uptake from the bloodstream and its metabolism in peripheral tissues, the most important and relevant effects for human health. However, nonoxidative and oxidative glucose disposal by activation of glycogen synthase (GS) and mitochondrial pyruvate dehydrogenase (PDH) remain incompletely explained by current models for insulin action. Since the discovery of insulin receptor Tyr kinase activity about 25 years ago, the dominant paradigm for intracellular signaling by insulin invokes protein phosphorylation downstream of the receptor and its primar...

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Section: R E V I E W a R T I C L E M O L M Econtrasting

confidence: 53%

Section: The Inositol Imbalance Of Myo-inositol and Chiro-inositol Inmentioning

confidence: 99%

D-Chiro-Inositol Glycans in Insulin Signaling and Insulin Resistance

Larner

Brautigan

Thorner

2010

Mol Med

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158

156

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“…On the other hand, Ostlund et al [23] showed that patients with NIDDM, as well as insulin-dependent diabetes IDDM, excreted substantially more d -chiro-inositol in urine than obese nondiabetic patients (control group), while plasma d -chiro-inositol levels were similar among the three groups. The possibility exists, however, that the obese non-diabetic patients were insulin resistant [24], and therefore were not appropriate control subjects. The present results show no significant differences in bioactivity of the pH 2.0 PDH activator between groups in the basal state.…”

Section: Discussionmentioning

confidence: 99%

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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“…Larner et al described a decreased urinary excretion of DCI and an increased urinary excretion of MI in human subjects and rhesus monkey with DM2 [73]. In monkeys the inositol excretion pattern became more marked with the progression of the diabetic disease and additional studies demonstrated that this altered inositol profile in urine is more directly related to the underlying IR so much so that the altered ratios of increased MI to decreased DCI in urine have been proposed as index of IR in human [12,77]. A defect in MI to DCI epimerization activity was demonstrated in vivo in rats and in vitro in fibroblasts to explain this inositol imbalance [72,78].…”

Section: Inositol and Insulin Resistancementioning

confidence: 99%

The Prevention of Gestational Diabetes

Cagnazzo¹,

Caserta²

2013

J Diabetes Metab

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The negative impact of the gestational diabetes on the maternal and fetal health is well known and this impact is closely related to gestational age at which the diagnosis is done. Therefore, the use of therapeutic options able to prevent or delay the gestational diabetes occurrence has a positive impact on maternal and neonatal outcomes.Physical activity and dietary advice represent the first choice and they are the most studied as well. They represent a non-pharmacological option and have a positive impact on insulin resistance although they do not seem to prevent the gestational diabetes onset.The preconceptional use of metformin in women with polycystic ovary syndrome protects the pancreatic beta cell reserve preventing or delaying the occurrence of gestational diabetes. However, there are also doubts on the drug safety in pregnancy since it completely crosses the placenta.From this point of view, the inositol could represent an excellent alternative.Its role as insulin sensitizing agent is well documented on improving both the hormonal and reproductive parameters. However, the studies on its preconceptional use in preventing gestational diabetes are too limited though the first results are extremely encouraging.

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Urinary myo-Inositol-to-chiro-Inositol Ratios and Insulin Resistance

Cited by 57 publications

References 5 publications

D-Chiro-Inositol Glycans in Insulin Signaling and Insulin Resistance

D-Chiro-Inositol Glycans in Insulin Signaling and Insulin Resistance

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

The Prevention of Gestational Diabetes

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