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

Abstract

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...

Chronic consumption of an inositol-enriched carob extract improves postprandial glycaemia and insulin sensitivity in healthy subjects: A randomized controlled trial

“…Recent evidence published by our group has shown that tolerance to glucose and sensitivity to insulin are altered by acute consumption of a carob pod extract containing bioactive carbohydrates and pinitol in healthy subjects [7]. Pinitol (3-O-methyl-D-chiro-inositol) is thought to be a mediator of the insulin signalling pathway and to be involved in glycosylphosphatidil-inositol protein anchors [8]. Some studies have explored how continued pinitol supplementation can alter glycaemic control, but the results obtained do not provide a clear picture.…”

d-chiro-Inositol Attenuates Epinephrine-stimulated Hepatic Glucose Output in the Isolated Perfused Liver Independently of Insulin

“…DCI administration also improves insulin sensitivity, hyperinsulinemia, and ovulatory function in patients with polycystic ovary syndrome (PCOS), a condition where insulin resistance is a primary feature [ 3 ] . By contrast, the stereoisomer, myo -inositol, which is ubiquitously found in all mammalian tissues and involved in a wide range of physiological functions, does not display these properties [ 1 ] . Body stores of DCI reportedly decrease in diabetes and obesity [ 4 , 5 ] , which may be in part due to the phenomenon of increased DCI renal excretion through currently undefi ned mechanisms [ 6 ] .…”

“…One agent that evokes antidiabetic eff ects is the naturally-occurring cyclic sugar alcohol, D -chiro -inositol (DCI) [ 1 ] , which attenuates hyperglycaemia in animal models of diabetes mellitus [ 2 ] . DCI administration also improves insulin sensitivity, hyperinsulinemia, and ovulatory function in patients with polycystic ovary syndrome (PCOS), a condition where insulin resistance is a primary feature [ 3 ] .…”

Studies on bovine heart glycogen synthase phosphatase

“…Synthase I is converted into D through a synthase kinasecatalyzed reaction by incorporation of the terminal phosphate of ATP into serine residues in the enzyme (10,13). Synthase phospha tase catalyzed the hydrolytic removal of the phosphate from the phosphoserine in synthase D to convert it into I (10).…”

“…Thus, the foregoing data indicate some lack of substrate specificity for several protein phosphatases and suggest a close relationship between these enzymes. Of particular interest in this regard is the finding that the amino acid sequence of the peptide around the phosphorylated site of muscle synthase D is very similar to or identical with that of phosphorylase a (13,52), suggesting that synthase D and phosphorylase a might be substrates of one phosphatase.…”