Genetic Regulation of Glucose Metabolism

Sutherland, Calum; O’Brien, Richard M.; Granner, Daryl K.

doi:10.1002/cphy.cp070223

Cited by 4 publications

(3 citation statements)

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“…However, high glucose is relatively toxic to tissues and blood proteins, hence there are complex endocrine mechanisms to prevent hyperglycemia (diabetes). Insulin is released from pancreatic β -cells in response to postprandial rising blood glucose, and this hormone combats hyperglycemia by acting on liver, muscle, and fat tissue, promoting glucose storage in the form of glycogen, turning off hepatic gluconeogenesis and promoting adipogenesis (for review see [ 156 , 157 ]).…”

Section: Gsk3 Substrates: Physiological Function and Therapeutic Pmentioning

confidence: 99%

What Are the bona fide GSK3 Substrates?

Sutherland

2011

International Journal of Alzheimer's Disease

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Nearly 100 proteins are proposed to be substrates for GSK3, suggesting that this enzyme is a fundamental regulator of almost every process in the cell, in every tissue in the body. However, it is not certain how many of these proposed substrates are regulated by GSK3 in vivo. Clearly, the identification of the physiological functions of GSK3 will be greatly aided by the identification of its bona fide substrates, and the development of GSK3 as a therapeutic target will be highly influenced by this range of actions, hence the need to accurately establish true GSK3 substrates in cells. In this paper the evidence that proposed GSK3 substrates are likely to be physiological targets is assessed, highlighting the key cellular processes that could be modulated by GSK3 activity and inhibition.

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Section: Gsk3 Substrates: Physiological Function and Therapeutic Pmentioning

confidence: 99%

What Are the bona fide GSK3 Substrates?

Sutherland

2011

International Journal of Alzheimer's Disease

Self Cite

257

250

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“…Because the hormonal regulation of these 2 genes is very similar, and since this sequence is found in the IRS of 2 other gene promoters whose activity is reduced by insulin (namely IGF binding protein 1 [43,44] and tyrosine aminotransferase [45,46]), it has been proposed that a similar mechanism may be involved in the repression of all of these genes by insulin. However, this sequence is also found in numerous gene promoters whose activity is not affected by insulin (42). In addition, the transcription of the PEPCK gene is repressed by glucose (25), whereas that of the G6Pase promoter is induced by glucose (47,48).…”

Section: A B Aicariboside Reduces Hepatic Gene Expressionmentioning

confidence: 99%

5-aminoimidazole-4-carboxamide riboside mimics the effects of insulin on the expression of the 2 key gluconeogenic genes PEPCK and glucose-6-phosphatase.

et al. 2000

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Insulin regulates the rate of expression of many hepatic genes, including PEPCK, glucose-6-phosphatase (G6Pase), and glucose-6-phosphate dehydrogenase (G6PDHase). The expression of these genes is also abnormally regulated in type 2 diabetes. We demonstrate here that treatment of hepatoma cells with 5-aminoimidazole-4-carboxamide riboside (AICAR), an agent that activates AMP-activated protein kinase (AMPK), mimics the ability of insulin to repress PEPCK gene transcription. It also partially represses G6Pase gene transcription and yet has no effect on the expression of G6PDHase or the constitutively expressed genes cyclophilin or -actin. Several lines of evidence suggest that the insulin-mimetic effects of AICAR are mediated by activation of AMPK. Also, insulin does not activate AMPK in H4IIE cells, suggesting that this protein kinase does not link the insulin receptor to the PEPCK and G6Pase gene promoters. Instead, AMPK and insulin may lie on distinct pathways that converge at a point upstream of these 2 gene promoters. Investigation of the pathway by which AMPK acts may therefore give insight into the mechanism of action of insulin. Our results also suggest that activation of AMPK would inhibit hepatic gluconeogenesis in an insulin-independent manner and thus help to reverse the hyperglycemia associated with type 2 diabetes. Diabetes 4 9 :8 9 6-903, 2000

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“…The mechanisms that mediate the tissue-specific and hormonally regulated expression of the hepatic cytosolic PEPCK gene have been studied in great detail (for review see refs. 4,5,144). The rate of transcription of the PEPCK gene is stimulated by cAMP, retinoic acid, thyroid hormone and glucocorticoids but is inhibited by insulin and glucose.…”

Section: Phosphoenolpyruvate Carboxykinase (Pepck)mentioning

confidence: 96%