Strategies to prevent diabetic microvascular angiopathy focus on the vascular endothelium. Because red blood cells (RBCs) are less deformable in diabetes, we explored an original concept linking decreased RBC deformability to RBC ascorbate and hyperglycemia. We characterized ascorbate concentrations from human and mouse RBCs and plasma, and showed an inverse relationship between RBC ascorbate concentrations and deformability, measured by osmotic fragility. RBCs from ascorbate deficient mice were osmotically sensitive, appeared as spherocytes, and had decreased β-spectrin. These aberrancies reversed with ascorbate repletion in vivo. Under physiologic conditions, only ascorbate's oxidation product dehydroascorbic acid (DHA), a substrate for facilitated glucose transporters, was transported into mouse and human RBCs, with immediate intracellular reduction to ascorbate. In vitro, glucose inhibited entry of physiologic concentrations of dehydroascorbic acid into mouse and human RBCs. In vivo, plasma glucose concentrations in normal and diabetic mice and humans were inversely related to respective RBC ascorbate concentrations, as was osmotic fragility. Human RBC β-spectrin declined as diabetes worsened. Taken together, hyperglycemia in diabetes produced lower RBC ascorbate with increased RBC rigidity, a candidate to drive microvascular angiopathy. Because glucose transporter expression, DHA transport, and its inhibition by glucose differed for mouse versus human RBCs, human experimentation is indicated.
The elaboration of neuronal axons and dendrites is dependent on a functional cytoskeleton. Cytoskeletal components have been shown to play a major role in the maintenance of the nervous system through adulthood, and changes in neurofilaments and microtubule-associated proteins (MAPs) have been linked to a variety of neurodegenerative diseases. Here we show that Futsch, the fly homolog of MAP1B, is involved in progressive neurodegeneration. Although Futsch is widely expressed throughout the CNS, degeneration in futsch(olk) primarily occurs in the olfactory system and mushroom bodies. Consistent with the predicted function of Futsch, we find abnormalities in the microtubule network and defects in axonal transport. Degeneration in the adult brain is preceded by learning deficits, revealing a neuronal dysfunction before detectable levels of cell death. Futsch is negatively regulated by the Drosophila Fragile X mental retardation gene, and a mutation in this gene delays the onset of neurodegeneration in futsch(olk). A similar effect is obtained by expression of either fly or bovine tau, suggesting a certain degree of functional redundancy of MAPs. The futsch(olk) mutants exhibit several characteristics of human neurodegenerative diseases, providing an opportunity to study the role of MAPs in progressive neurodegeneration within an experimentally accessible, in vivo model system.
Patients with CAH after an adrenalectomy may experience recurrent hyperandrogenism due to adrenal rest tissue. 18F-FDG PET/CT with cosyntropin stimulation accurately identified adrenal rest tissue not visualized with conventional imaging, allowing for successful surgical resection.
BACKGROUND. We hypothesized that obesity-associated hepatosteatosis is a pathophysiological chemical depot for fat-soluble vitamins and altered normal physiology. Using α-tocopherol (vitamin E) as a model vitamin, pharmacokinetics and kinetics principles were used to determine whether excess liver fat sequestered α-tocopherol in women with obesity-associated hepatosteatosis versus healthy controls. METHODS. Custom-synthesized deuterated α-tocopherols (d 3-and d 6-α-tocopherols) were administered to hospitalized healthy women and women with hepatosteatosis under investigational new drug guidelines. Fluorescently labeled α-tocopherol was custom-synthesized for cell studies. RESULTS. In healthy subjects, 85% of intravenous d 6-α-tocopherol disappeared from the circulation within 20 minutes but reappeared within minutes and peaked at 3-4 hours; d 3-and d 6-α-tocopherols localized to lipoproteins. Lipoprotein redistribution occurred only in vivo within 1 hour, indicating a key role of the liver in uptake and re-release. Compared with healthy subjects who received 2 mg, subjects with hepatosteatosis had similar d 6-α-tocopherol entry rates into liver but reduced initial release rates (P < 0.001). Similarly, pharmacokinetics parameters were reduced in hepatosteatosis subjects, indicating reduced hepatic d 6-α-tocopherol output. Reductions in kinetics and pharmacokinetics parameters in hepatosteatosis subjects who received 2 mg were echoed by similar reductions in healthy subjects when comparing 5-and 2-mg doses. In vitro, fluorescentlabeled α-tocopherol localized to lipid in fat-loaded hepatocytes, indicating sequestration. CONCLUSIONS. The unique role of the liver in vitamin E physiology is dysregulated by excess liver fat. Obesity-associated hepatosteatosis may produce unrecognized hepatic vitamin E sequestration, which might subsequently drive liver disease. Our findings raise the possibility that hepatosteatosis may similarly alter hepatic physiology of other fat-soluble vitamins. TRIAL REGISTRATION. ClinicalTrials.gov, NCT00862433.
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