Nutritional and Acquired Deficiencies in Inositol Bioavailability. Correlations with Metabolic Disorders

Abstract

Communities eating a western-like diet, rich in fat, sugar and significantly deprived of fibers, share a relevant increased risk of both metabolic and cancerous diseases. Even more remarkable is that a low-fiber diet lacks some key components-as phytates and inositols-for which a mechanistic link has been clearly established in the pathogenesis of both cancer and metabolic illness. Reduced bioavailability of inositol in living organisms could arise from reduced food supply or from metabolism deregulation. Inositol deregulation has been found in a number of conditions mechanistically and epidemiologically associated to high-glucose diets or altered glucose metabolism. Indeed, high glucose levels hinder inositol availability by increasing its degradation and by inhibiting both myo-Ins biosynthesis and absorption. These underappreciated mechanisms may likely account for acquired, metabolic deficiency in inositol bioavailability.

Keywords: Inositol-3-Phosphate Synthase 1 (ISYNA1); cancer; diabetes; diabetic nephropathy; inositol hexakisphosphate kinase (IP6K1); myo-Inositol; myo-inositol oxygenase (MIOX); phosphatidic acid; phytate (InsP6).

Figure 1

Glucose-inositol relationships. High glucose levels inhibit myo-Ins uptake by cells, by competing with SMT1/2 transporter systems. Moreover, through the activation of the polyol pathway, glucose extrudes myo-Ins from cells, thus “buffering” the increased osmolarity due to the augmented sorbitol levels. Biosynthesis of myo-Ins begins with G-6P enzymatic transformation into inositol-1-phosphate. However, high glucose levels indirectly inhibit myo-Ins biosynthesis, by increasing intracellular PA and consequently activating IP6K1, the principal negative regulator of myo-Ins de novo synthesis. Ultimately, glucose increases renal tubular catabolism and urinary loss of inositol through MIOX activation and overexpression. DAG, diacylglycerol; PKC, PKA, protein kinase C and A; G, glucose; G-6P, glucose-6-phosphate; Fru-6P, Fructose-6-phosphate; M, myo-inositol; IP6K1, inositol hexakisphosphate kinase; PA, phosphatidic acid; ISYNA1, d-3-myoinositol-phosphate synthase; IP3, inositol-3-phosphate; IMPA-1, inositol monophosphatase-1; MIOX, myo-inositol oxygenase; MIOXp, phosphorylated myo-inositol oxygenase; IP, inositol phosphate; PI, phosphatidyl-inositol; PIP2, phosphatidyl-inositol-4,5-biphosphate; PDK1, Pyruvate Dehydrogenase Kinase 1; AC, adenylate cyclase; G-PCR, G-protein coupled receptor.