Urinary <i>chiro</i>-Inositol Excretion is an Index Marker of Insulin Sensitivity in Japanese Type II Diabetes

Suzuki, Susumu; Kawasaki, Hiroya; Satoh, Yoshinori; Ohtomo, Masataka; Hirai, Masashi; Hirai, Atsuko; Hirai, Satoshi; Onoda, Masatoshi; Matsumoto, Masahiro; Hinokio, Yoshinori; Akai, Hiroaki; Craig, James W.; Larner, Joseph; Toyota, Takayoshi

doi:10.2337/diacare.17.12.1465

Cited by 89 publications

(77 citation statements)

References 8 publications

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“…In a collaborative study with our Japanese colleagues we demonstrated that, as subjects progressed from normal glucose tolerance to impaired glucose tolerance to type II diabetes, urine chiro-inositol decreased progressively (57). These data and data from Rhesus monkeys (Table 3) suggest that the chiro-inositol deficiency and imbalance with myo-inositol are related more directly to the insulin resistance per se rather than to the type II diabetes.…”

Section: Inositol Imbalance and Insulin Resistancementioning

confidence: 57%

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: Inositol Imbalance and Insulin Resistancementioning

confidence: 57%

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

Larner

Brautigan

Thorner

2010

Mol Med

Self Cite

158

156

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“…In human urine (17), monkey urine (18), genetic G͞K type 2 diabetic rat urine (19), G͞K rat muscle, liver, and kidney (20), and human type 2 diabetic muscle (21), the level of chiro-inositol is decreased and myo-INS content increased compared to controls. The decrease in urinary chiro-inositol in humans (22) and monkeys (18) was inversely correlated to the degree of insulin resistance. Administration of DCI to streptozotocin type 2 diabetic rats (23), monkeys (24), and humans (25,26) effectively decreased hyperglycemia and hypertriglyceridemia (HTG).…”

mentioning

confidence: 92%

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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“…Insulin resistance has been linked to decreased urinary excretion of chiro-inositol (a component of the putative D-chiro-inositol phosphoglycan mediator) in primates 47 and in humans with impaired glucose tolerance. 48 The amount of chiro-inositol in muscle is lower in subjects with type 2 diabetes mellitus than in normal subjects Administration of D-Chiro-insitol has been demonstrated to improve glucose tolerance, decrease serum androgens and improve ovulation in PCOS patients. 49 Nestler J E reported improvement in the insulin sensitivity by D-chiro-inositol hence improves ovulatory function and decreases serum androgen concentrations along with blood pressure and metabolic parameters such as plasma triglyceride concentrations.…”

Section: D-chiro-inositolmentioning

confidence: 99%