Phlorizin or Vanadate Treatment Reverses Impaired Expression of Albumin and Hepatocyte Nuclear Factor 1 in Diabetic Rats

Barrera-Hernandez, Gonzalo; Wanke, Irene; Wong, Norman C.W.

doi:10.2337/diab.45.9.1217

Cited by 11 publications

(8 citation statements)

References 36 publications

(76 reference statements)

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“…An identical protein-binding pattern was obtained with these extracts in a gel retardation assay when the G6P WT oligonucleotide was used as the labeled probe (data not shown). This result is consistent with those of Wong and coworkers (42) who showed that although the abundance of HNF-1 protein, though not mRNA, is decreased in streptozotocin-treated diabetic rats and this represents an effect of hyperglycemia rather than hypoinsulinemia because it is reversible upon phlorizin treatment (43). Although these results suggest that insulin treatment does not modify HNF-1 expression or DNA-binding activity, they do not preclude an action of insulin on the transactivation potential of HNF-1.…”

Section: Resultssupporting

confidence: 93%

Hepatocyte nuclear factor-1 acts as an accessory factor to enhance the inhibitory action of insulin on mouse glucose-6-phosphatase gene transcription

Streeper

Eaton

Ebert

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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Glucose-6-phosphatase catalyzes the terminal step in the gluconeogenic and glycogenolytic pathways. Transcription of the gene encoding the glucose-6-phosphatase catalytic subunit (G6Pase) is stimulated by cAMP and glucocorticoids whereas insulin strongly inhibits both this induction and basal G6Pase gene transcription. Previously, we have demonstrated that the maximum repression of basal G6Pase gene transcription by insulin requires two distinct promoter regions, designated A (from ؊271 to ؊199) and B (from ؊198 to ؊159). Region B contains an insulin response sequence because it can confer an inhibitory effect of insulin on the expression of a heterologous fusion gene. By contrast, region A fails to mediate an insulin response in a heterologous context, and the mutation of region B within an otherwise intact promoter almost completely abolishes the effect of insulin on basal G6Pase gene transcription. Therefore, region A is acting as an accessory element to enhance the effect of insulin, mediated through region B, on G6Pase gene transcription. Such an arrangement is a common feature of cAMP and glucocorticoid-regulated genes but has not been previously described for insulin. A combination of fusion gene and protein-binding analyses revealed that the accessory factor binding region A is hepatocyte nuclear factor-1. Thus, despite the usually antagonistic effects of cAMP͞glucocorticoids and insulin, all three agents are able to use the same factor to enhance their action on gene transcription. The potential role of G6Pase overexpression in the pathophysiology of MODY3 and 5, rare forms of diabetes caused by hepatocyte nuclear factor-1 mutations, is discussed.

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Section: Resultssupporting

confidence: 93%

Hepatocyte nuclear factor-1 acts as an accessory factor to enhance the inhibitory action of insulin on mouse glucose-6-phosphatase gene transcription

Streeper

Eaton

Ebert

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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“…Furthermore, vanadate treatment fully normalized the insulin receptor mRNA level, indicating that its in vivo effect on the expression of the insulin receptor gene, as with other genes (4-11), occurs at a pretranslational step. In previous studies, phlorizin treatment of steptozotocininduced diabetic rats has been shown to normalize the altered expression of the liver phosphoenolpyruvate carboxykinase (12), Glut 2 (12) and albumin (10) genes, but, unlike vanadate (8), it did not correct the lowered expression of the pyruvate kinase gene (12). In the present study, vanadate and phlorizin treatments were almost equally effective in their ability to prevent the increase in liver insulin receptor number and insulin receptor mRNA level observed in diabetic rats.…”

Section: Discussionmentioning

confidence: 99%

“…Treatments with vanadate (4-11) and, to some extent, phlorizin (10,12), have been shown to reverse the altered expression of a number of hepatic genes in streptozotocin-induced diabetic rats. Here, we have extended these findings to the insulin receptor gene, which is over-expressed in diabetic rats.…”

Section: Discussionmentioning

confidence: 99%

“…These include enzymes involved in gluconeogenesis (4)(5)(6)(7)(8), glycolysis (4)(5)(6)(7)(8) and lipogenesis (9), the glucose transporter Glut 2 (8), serum albumin (10), and the transcription factors hepatocyte nuclear factor 1 (HNF1) (10), CAAT/enhancer binding protein a (7) and CAAT/ enhancer binding protein b (11). However, partial correction of the altered expression of glycolytic and neoglucogenic enzymes (12), albumin (10) and HNF1 (10) also occurred after administration of phlorizin, which corrects the hyperglycemia of diabetic rats by inhibiting the renal tubular reabsorption of glucose (13). These findings suggest that, although vanadate can alter the expression of enzymes of carbohydrate metabolism in cultured cells (14,15), its in vivo effects on diabetic rats may be mediated in part by correction of hyperglycemia.…”

Section: Introductionmentioning

confidence: 99%

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Treatment of streptozotocin-induced diabetic rats with vanadate and phlorizin prevents the over-expression of the liver insulin receptor gene

Amessou

Bortoli²,

Liemans³

et al. 1999

European Journal of Endocrinology

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Administration of vanadate, an insulinomimetic agent, has been shown to normalize the increased number of insulin receptors in the liver of streptozotocin-induced diabetic rats. In the present study, the effects of vanadate on various steps of expression of the liver insulin receptor gene in diabetic rats have been analyzed and compared with those of phlorizin, a glucopenic drug devoid of insulinomimetic properties.Livers of rats killed 23 days after streptozotocin injection showed a 30-40% increase in the number of cell surface and intracellular insulin receptors, a 50-90% increase in the levels of 9.5 and 7.5 kb insulin receptor mRNA species, and a 20% decrease in the relative abundance of the A (exon 11 ¹ ) insulin receptor mRNA isotype. Daily administration of vanadate or phlorizin from day 5 to day 23 prevented the increase in insulin receptor number and mRNA level, and vanadate treatment also normalized receptor mRNA isotype expression.Unlike observations in vivo, vanadate and phlorizin differentially affected the expression of the insulin receptor gene in Fao hepatoma cells. Vanadate treatment (0.5 mmol/l for 4 h) decreased the levels of the 9.5 and 7.5 kb insulin receptor transcripts by at least twofold, without affecting the relative abundance of the A insulin receptor mRNA isotype. In contrast, phlorizin treatment (5 mmol/l for 4 h) slightly increased or did not affect the levels of the 9.5 and 7.5 kb insulin receptor transcripts respectively, and increased by twofold the relative expression of the A insulin receptor mRNA isotype.It is suggested that, although mediated in part by a reversal of hyperglycemia, normalization of liver insulin receptor gene expression by vanadate treatment in diabetic rats may also involve a direct inhibitory effect of this drug on gene expression.

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“…Phlorizin Treatment-Phlorizin was dissolved in 1,2-propanediol (0.2 g/ml) and injected intraperitoneally twice a day at a dose of 0.8 g per kg body weight per day for 2 weeks (19). Sham animals received similar amounts of 1,2-propanediol as phlorizin-treated rats.…”

Section: Methodsmentioning

confidence: 99%

Chronic Hyperglycemia Triggers Loss of Pancreatic β Cell Differentiation in an Animal Model of Diabetes

Jonas¹,

Sharma²,

Hasenkamp

et al. 1999

Journal of Biological Chemistry

531

474

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Differentiated pancreatic ␤ cells are unique in their ability to secrete insulin in response to a rise in plasma glucose. We have proposed that the unique constellation of genes they express may be lost in diabetes due to the deleterious effect of chronic hyperglycemia. To test this hypothesis, Sprague-Dawley rats were submitted to a 85-95% pancreatectomy or sham pancreatectomy. One week later, the animals developed mild to severe chronic hyperglycemia that was stable for the next 3 weeks, without significant alteration of plasma nonesterified fatty acid levels. Expression of many genes important for glucose-induced insulin release decreased progressively with increasing hyperglycemia, in parallel with a reduction of several islet transcription factors involved in ␤ cell development and differentiation. In contrast, genes barely expressed in sham islets (lactate dehydrogenase A and hexokinase I) were markedly increased, in parallel with an increase in the transcription factor c-Myc, a potent stimulator of cell growth. These abnormalities were accompanied by ␤ cell hypertrophy. Changes in gene expression were fully developed 2 weeks after pancreatectomy. Correction of blood glucose by phlorizin for the next 2 weeks normalized islet gene expression and ␤ cell volume without affecting plasma nonesterified fatty acid levels, strongly suggesting that hyperglycemia triggers these abnormalities. In conclusion, chronic hyperglycemia leads to ␤ cell hypertrophy and loss of ␤ cell differentiation that is correlated with changes in c-Myc and other key transcription factors. A similar change in ␤ cell differentiation could contribute to the profound derangement of insulin secretion in human diabetes.Pancreatic ␤ cells are highly specialized cells that secrete insulin in response to a variety of stimuli, the most important being glucose (1, 2). Their correct function is dependent on the expression of a unique set of genes that allow ␤ cells to respond to even small increases in plasma glucose levels by releasing appropriate amounts of insulin into the circulation (3). Type 2 diabetes is characterized by the combination of insulin resistance and profound alteration in glucose-stimulated insulin secretion (4). The latter can be ascribed, at least in part, to the deleterious effect of even mild chronic hyperglycemia and elevated plasma nonesterified fatty acids (NEFA) 1 on pancreatic ␤ cell function, a process often referred to as "gluco-lipotoxicity" (5, 6). In islets isolated from animal models of diabetes, several defects have been identified at the level of gene expression and/or enzymatic activity, but none by itself can entirely account for the ␤ cell defect characteristic of type 2 diabetes (5,7,8).Recently, the study of the transcriptional regulation of the insulin gene has led to the identification of several ␤ cell/islet transcription factors that are important for the development of the endocrine pancreas, the tissue-specific expression of key ␤ cell genes and maintenance of ␤ cell differentiation (9, 10). In islets ...

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Phlorizin or Vanadate Treatment Reverses Impaired Expression of Albumin and Hepatocyte Nuclear Factor 1 in Diabetic Rats

Cited by 11 publications

References 36 publications

Hepatocyte nuclear factor-1 acts as an accessory factor to enhance the inhibitory action of insulin on mouse glucose-6-phosphatase gene transcription

Hepatocyte nuclear factor-1 acts as an accessory factor to enhance the inhibitory action of insulin on mouse glucose-6-phosphatase gene transcription

Treatment of streptozotocin-induced diabetic rats with vanadate and phlorizin prevents the over-expression of the liver insulin receptor gene

Chronic Hyperglycemia Triggers Loss of Pancreatic β Cell Differentiation in an Animal Model of Diabetes

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