High Sorbitol Levels Research Articles

Sorbitol reduction via AT-007 (govorestat) ameliorates synaptic dysfunction and neurodegeneration in models of sorbitol dehydrogenase deficiency.

Sorbitol dehydrogenase (SORD) deficiency has been identified as the most frequent autosomal recessive form of hereditary neuropathy. Loss of SORD causes high sorbitol levels in tissues due to the inability to convert sorbitol to fructose in the two-step polyol pathway, leading to degenerative neuropathy. The underlying mechanisms of sorbitol-induced degeneration have not been fully elucidated, and no current FDA-approved therapeutic options are available to reduce sorbitol levels in the nervous system. Here, in a Drosophila model of SORD deficiency, we showed synaptic degeneration in the brain, neurotransmission defect, locomotor impairment, and structural abnormalities in the neuromuscular junctions. In addition, we found reduced ATP production in the brain and reactive oxygen species accumulation in the central nervous system (CNS) and muscle, indicating mitochondrial dysfunction. Applied Therapeutics, Inc has developed a CNS-penetrant next-generation aldose reductase inhibitor (ARI), AT-007 (govorestat), which inhibits the conversion of glucose to sorbitol. AT-007 significantly reduced sorbitol levels in patient-derived fibroblasts, iPSC-derived motor neurons, and Drosophila brains. AT-007 feeding in Sord-deficient Drosophila mitigated synaptic degeneration and significantly improved synaptic transduction, locomotor activity, and mitochondrial function. Moreover, AT-007 treatment significantly reduced ROS accumulation in Drosophila CNS, muscle, and patient-derived fibroblasts. These findings uncover the molecular and cellular pathophysiology of SORD neuropathy and provide a potential treatment strategy for patients with SORD deficiency.

Nutrient, fibre, sorbitol and chlorogenic acid content of prunes (Prunus domestica): an updated analysis and comparison of different countries of origin and database values

Current prune composition data are outdated and require a comprehensive and comparative re-analysis. This novel study aimed to: (i) analyse and compare prune composition from major countries of origin; and (ii) provide a comprehensive compositional analysis of prunes of USA origin and compare this with UK and USA database data. Prune samples were analysed for major nutrients and bioactive compounds and compared between countries of origin. Total fibre was higher in prunes from the USA (12.0 g/100 g) and Chile (11.5 g/100 g) compared with France (8.4 g/100 g) and Argentina (8.9 g/100 g), while prunes from all countries contained high levels of sorbitol (11.2–15.5 g/100 g). Differences in energy and starch values compared with national databases reflected different approaches to sampling and analysis. In conclusion, prunes contain high levels of fibre and other bioactive compounds. Variations between country of origin and database values highlight the importance of transparency in documenting sampling and analysis methods.

Identification and characterisation of a sequence related to human sorbitol dehydrogenase.

The polyol pathway comprises the enzymes aldose reductase and sorbitol dehydrogenase which convert glucose to fructose via sorbitol. Accumulation of sorbitol within the cell has been suggested to contribute to the progression of secondary complications of diabetes. High levels of sorbitol accumulate within the cell due to inadequate regulation of blood glucose levels. It has also been suggested that polymorphism in either the aldose reductase or sorbitol dehydrogenase genes might contribute to sorbitol accumulation. The human sorbitol dehydrogenase gene (SORD) has been described previously and a range of putative polymorphic variants were identified. Further analysis of human SORD yeast artificial chromosome clones has now shown that there is a second SORD-like sequence in man, which is extremely similar in sequence to SORD itself and which also maps to chromosome 15. Detailed sequence analysis suggests that this SORD-related gene cannot be expressed as a full-length sorbitol dehydrogenase isoenzyme. However, knowledge of the presence of this highly similar sequence in the human genome is essential to ensure that sequence variations identified during genetic analysis of SORD are not attributed to polymorphisms within that gene itself.

Sugar and anthocyanidin content of two processing‐grade sweet cherry cultivars and cherry products

Abstract The individual sugars and anthocyanidins in processing‐grade ‘Dawson’ and ‘Bing’ cherries and cherry products were investigated in order to assess the quality of the processed fruit. Glucose, fructose, and relatively high levels of sorbitol were found in fresh and frozen cherries of both cultivars. During glaceing, sucrose was predictably absorbed by the fruit but glucose was preferentially leached into the glaceing syrups. In contrast, sorbitol is preferentially lost during the manufacture of cherry leathers. Cyanidin was the only anthocyanidin detected in both cherry cultivars. ‘Dawson’ and ‘Bing’ frozen cherries contained cyanidin levels of 76 mg/100 g and 74 mg/100 g wet weight of fruit flesh respectively. Processing the cherries to give glace cherries and cherry leathers reduced the cyanidin contents by 9 to 30%. The reduction in cyanidin due to processing was organoleptically acceptable.

Sorbitol Generation and Its Inhibition by Sorbinil® in the Aging Normal Human and Rabbit Lens and Human Diabetic Cataracts

Fresh intact human cataracts (derived from patients with mature-onset diabetes mellitus and from nondiabetic patients), normal human lenses between 2 and 71 years old and lenses derived from 1.5- to 5-kg rabbits were incubated in Earle's media containing enriched 13C-glucose (5 and 15 mM). 31P NMR organophosphate profiles were obtained at the start and end of each incubation. Sorbinil was added to one of each pair of selected lenses, both incubated with 13C-glucose. All the lenses were frozen after 4h of incubation and were subsequently assayed by 13C NMR spectroscopy. The results demonstrate significant sorbitol generation only in young lenses which can be inhibited by Sorbinil. None of the older normal and cataractous human lenses or the mature-onset diabetic cataracts were capable of generating measurable sorbitol levels although they all showed active glucose metabolism and their organophosphate profiles demonstrated normal high-energy phosphate levels. Increased sugar phosphate levels were usually found in the mature-onset diabetic cataracts. Although our NMR spectroscopy is only sensitive to 10(-3) M levels, such concentrations of sorbitol are required to exert their osmotic effects. These data indicate that high sorbitol levels can only be generated in young human and rabbit lenses and correlate well with the age-related changes in aldose reductase activity in these lenses.

Detection of Adulteration in Blackberry Juice Concentrates and Wines

Adulteration of blackberry juice concentrates and wines with juice of sorbitol-containing fruits was detected by determining carbohydrates by high performance liquid chromatography, gas-liquid chromatography, and thin layer chromatography. Sorbitol is not fermented by yeast and can be detected in wines made from blackberry juice concentrates that contain sorbitol. High levels of sorbitol and quinic and malic acids suggest that an imported blackberry concentrate may have been adulterated with plum. Degradation of anthocyanin pigments during processing and storage limits the utility of pigment analyses in detecting adulteration.