Identification of a novel inositol glycan signaling pathway with significant therapeutic relevance to insulin resistance: an insulin signaling model using both tyrosine kinase and G-proteins

A novel insulin receptor G-protein-linked insulin signaling system has been demonstrated to involve inositol glycan (IG) generated from membrane-bound precursor lipids and/or proteins. Evidence has been brought forward to ser iously consider these IGs as putative insulin mediators acting allosterical ly intracellularly to control protein and enzyme phosphorylation state and at the cell membrane to initiate signaling via novel tyrosine kinase mechan isms. Two classes of IGs have been isolated from rat and beef liver and par tially characterized chemically, One, termed pH 2.0 (pH of elution from ani on exchange column), activates pyruvate dehydrogenase (PDH) phosphatase in a kinetic manner, mimicking insulin action on fat segments, and also activa tes phosphatase 2C, a related Mg2+-requiring family member known to activat e glycogen synthase. The second, termed pH 1.3, markedly inhibits cAMP prot ein kinase and adenylate cyclase. Both are increased with insulin action in tissues and both are active in vivo to decrease hyperglycemia in streptozo tocin (STZ)-induced diabetic rats at doses comparable to insulin (10(-9) mo l/l) and to promote glycogen synthesis in diaphragms of normal rats injecte d intraperitoneally in vivo. The pH 2.0 species contains the rare inositol D-chiro-inositol and galactosamine, whereas the pH 1.3 species is larger an d contains myo-inositol, glucosamine, mannose, and galactose. A deficiency in the chiro-inositol IG signaling system in G/K rats, Rhesus monkeys, and humans has been directly associated with insulin resistance. Decreased urin e, muscle, hemodialysate chiro-inositol, and pH 2.0 IG bioactivity have bee n observed in type 2 diabetic subjects and their first-degree relatives and in nondiabetic insulin-resistant obese Rhesus monkeys, Decreased muscle bi opsy chiro-inositol in pH 2.0 fractions in type 2 diabetic Pima Indians and in autopsy specimens from type 2 diabetic Caucasians has been observed, as well as decreased pH 2.0 fraction bioactivity in blood of Caucasian type 2 diabetic subjects after a glucose tolerance test, No deficiency has been o bserved in the pH 1.3 IG species associated with insulin resistance, indica ting an IG specificity. Administration of the pH 2.0 species precursor D-ch iro-inositol effectively decreased hyperglycemia in low-dose STZ-induced di abetic rats and improved glucose disposal in insulin-resistant and diabetic Rhesus monkeys and insulin-resistant and glucose-intolerant human subjects , fn women with polycystic ovarian disease, oral administration of D-chiro- inositol for 6-8 weeks effectively relieved significantly all common signs of the disease, including ovulation rate, serum testosterone, and set hormo ne-binding globulin, glucose intolerance and hyperinsulinemia, and elevated systolic and diastolic blood pressures. Food and Drug Administration-appro ved phase 2 multicenter clinical trials in type 2 diabetic patients and wom en with polycystic ovarian disease are under way in the U.S.