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      Insulin but Not Phlorizin Treatment Induces a Transient Increase in GLUT2 Gene Expression in the Kidney of Diabetic Rats

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          Background/Aims: Increases in the renal glucose transporter gene expression are involved in renal tubule-glomerular diseases.Here we investigate the GLUT2 gene expression changes in the kidney of diabetic rats, by using insulin or phlorizin treatment. Methods:Rats were rendered diabetic and studied 20 days later: 4–12 h after one single injection of insulin or phlorizin, and 1–6 days after insulin or phlorizin injection twice a day, comparing with diabetic rats injected with placebo. GLUT2 was investigated by Northern and Western analysis. Results: In 20-day diabetic rats, acute treatment with insulin lowered the plasma glucose and increased the GLUT2 mRNA (∼100%, p < 0.001) without changes in the protein content, while phlorizin lowered the plasma glucose, but changed neither the GLUT2 mRNA nor the protein expression. Twenty-four hours of insulin treatment increased both GLUT2 mRNA (∼100%, p < 0.001) and protein (∼50%, p < 0.01), but no effects of phlorizin were observed. After 6 days, insulin and phlorizin similarly reduced glycemia, with opposite effects upon plasma insulin and urinary glucose, and both treatments decreased GLUT2 mRNA and protein (p < 0.05). Conclusion: In kidney of diabetic rats, an initial and transient upregulation of GLUT2 was induced specifically by insulin only. The 6-day normalization of GLUT2, however, was induced by both insulin and phlorizin treatment, which seems to be related to the plasma glucose lowering.

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          Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats.

          Insulin resistance is characteristic of the diabetic state. To define the role of hyperglycemia in generation of the insulin resistance, we examined the effect of phlorizin treatment on tissue sensitivity to insulin in partially pancreatectomized rats. Five groups were studied: group I, sham-operated controls; group II, partially pancreatectomized diabetic rats with moderate glucose intolerance; group III, diabetic rats treated with phlorizin to normalize glucose tolerance; group IV, phlorizin-treated controls; and group V, phlorizin-treated diabetic rats restudied after discontinuation of phlorizin. Insulin sensitivity was assessed with the euglyemic hyperinsulinemic clamp technique in awake, unstressed rats. Insulin-mediated glucose metabolism was reduced by approximately 30% (P less than 0.001) in diabetic rats. Phlorizin treatment of diabetic rats completely normalized insulin sensitivity but had no effect on insulin action in controls. Discontinuation of phlorizin in phlorizin-treated diabetic rats resulted in the reemergence of insulin resistance. These data demonstrate that a reduction of beta-cell mass leads to the development of insulin resistance, and correction of hyperglycemia with phlorizin, without change in insulin levels, normalizes insulin sensitivity. These results provide the first in vivo evidence that hyperglycemia per se can lead to the development of insulin resistance.
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            Mutations in GLUT2, the gene for the liver-type glucose transporter, in patients with Fanconi-Bickel syndrome.

            Fanconi-Bickel syndrome (FBS) is a rare autosomal-recessive inborn error of metabolism characterized by hepatorenal glycogen accumulation, Fanconi nephropathy and impaired utilization of glucose and galactose. To date, no underlying enzymatic defect in carbohydrate metabolism has been identified. Therefore, and because of the impairment of both glucose and galactose metabolism, a primary defect of monosaccharide transport across membranes has been suggested. Here we report mutations in the gene encoding the facilitative glucose transporter 2 (GLUT2) in three FBS families, including the original patient described in 1949 by Fanconi and Bickel. Homozygous mutations were found in affected individuals, whereas all parents tested were heterozygous for the respective mutation. Because all detected mutations (delta T446-449, C1251T and C1405T) predict truncated translation products that cannot be expected to have functional monosaccharide transport activity, GLUT2 mutations are probably the cause of FBS.
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              Regulation of protein synthesis associated with skeletal muscle hypertrophy by insulin-, amino acid- and exercise-induced signalling.

              Although insulin, amino acids and exercise individually activate multiple signal transduction pathways in skeletal muscle, one pathway, the phosphatidylinositol 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) signalling pathway, is a target of all three. Activation of the PI3K-mTOR signal transduction pathway results in both acute (i.e. occurring in minutes to hours) and long-term (i.e. occurring in hours to days) up-regulation of protein synthesis through modulation of multiple steps involved in mediating the initiation of mRNA translation and ribosome biogenesis respectively. In addition, changes in gene expression through altered patterns of mRNA translation promote cell growth, which in turn promotes muscle hypertrophy. The focus of the present discussion is to review current knowledge concerning the mechanism(s) through which insulin, amino acids and resistance exercise act to activate the PI3K-mTOR signal transduction pathway and thereby enhance the rate of protein synthesis in muscle.

                Author and article information

                Nephron Physiol
                Nephron Physiology
                S. Karger AG
                February 2007
                09 January 2007
                : 105
                : 3
                : p42-p51
                aDepartment of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, and bExperimental Medicine Department, Institute of Cardiology of the State of Rio Grande do Sul/University Foundation of Cardiology, Porto Alegre, Rio Grande do Sul, Brazil
                98442 Nephron Physiol 2007;105:p42–p51
                © 2007 S. Karger AG, Basel

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                Figures: 5, Tables: 2, References: 36, Pages: 1
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