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Genetic Regulation of Glucose Metabolism

Calum Sutherland, Richard O'Brien, Daryl K. Granner

10.1002/cphy.cp070223

Source: Supplement 21: Handbook of Physiology, The Endocrine System, The Endocrine Pancreas and Regulation of Metabolism

Originally published: 2001

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Glucagon and Insulin Action
1.1 Signaling from the Cell Membrane to the Nucleus
1.2 DNA Elements and Their Binding Proteins
2 Genetic Regulation of the Hepatic Gluconeogenic Enzymes
2.1 Glucose‐6‐Phosphatase
2.2 Fructose‐1,6‐Bisphosphatase
2.3 Phosphoenolpyruvate Carboxykinase
3 Genetic Regulation of the Hepatic Glycolytic Enzymes
3.1 Glucokinase
3.2 6‐Phosphofructo‐1‐Kinase
3.3 Pyruvate Kinase
3.4 6‐Phosphofructo‐2‐Kinase/Fructose‐2,6‐Bisphosphatase
4 Genetic Regulation of Other Proteins Involved in Glucose Metabolism
4.1 Glyceraldehyde‐3‐Phosphate Dehydrogenase
4.2 Tyrosine Aminotransferase
4.3 GLUT‐1 Glucose Transporter
4.4 Hexokinase II
5 Genetic Regulation of Lipogenic Enzymes
5.1 Acetyl‐CoA Carboxylase
5.2 Fatty Acid Synthase
5.3 Malic Enzyme
6 Conclusions and Perspectives
Figure 1. Figure 1.

Regulation of hepatic gene expression. Effects of insulin, cAMP, carbohydrate (CHO), fasting, refeeding, and diabetes on expression of the major hepatic genes involved in regulation of glucose metabolism. Induction (up arrow), repression (down arrow), no effect (horizontal arrow), and unknown (?) are shown. As might be predicted, the effect of fasting is identical to the effects of cAMP treatment, the effects of refeeding mimic the effects of insulin treatment, and the effect of the development of diabetes (insulin resistance) is opposite to that of insulin treatment. Although insulin and carbohydrates have opposing effects on expression of glucose‐6‐phosphatase (G6Pase), refeeding animals mimics the effect of insulin, demonstrating that, in the whole animal, the effect of insulin on this gene is dominant over the effect of carbohydrate. F16BPase, fructose‐1, 6‐bisphosphatase; PEPCK, phosphoenolpyruvate carboxy kinase; PF1K, 6‐phosphofructo‐1‐kinase; ACC, acetyl‐CoA carboxylase; FAS, fatty acid synthase.
Figure 2. Figure 2.

Signaling pathways known to be induced by insulin that may be involved in regulation of the cellular actions of this hormone. P‐Y‐/Y‐P, phosphorylated tyrosine residue; GRB2; growth factor receptor‐binding protein 2; mSOS, mammalian son of sevenless; MAP kinase, p42/p44 mitogen‐activated protein kinase; IRS‐1, insulin receptor substrate‐1; MEK, MAP kinase kinase; MAPKAPK2, MAP kinase‐activated protein kinase‐2; PKB, protein kinase B; PI, phosphatidylinositol; IGFBP, insulin like growth factor‐binding protein; G33, gene 33; GAPDH, glyceraldehyde‐3‐phosphate dehydrogenase; PEPCK, phosphoenolphyruvate carboxykinase.
Figure 3. Figure 3.

The cis/trans model of gene regulation, predicting multiple potential points of regulation, for example, at the level of expression of a trans‐acting transcription factor (1), the translocation of the factor to the nucleus (2), the binding of the transcription factor to its cognate cis‐acting DNA element (3) and its interaction with specific components of the basal transcription machinery (4).
Figure 4. Figure 4.

Hepatic substrate cycles. The key gluconeogenic and glycolytic enzymes and their reaction products are shown. The metabolic switch, fructose‐2,6‐bisphosphate, inhibits gluconeogenesis at the level of fructose‐1,6‐bisphosphatase and induces glycolysis at the level of 6‐phosphofructo‐1‐kinase. PEPCK, phosphoenolpyruvate carboxy kinase.


Figure 1.

Regulation of hepatic gene expression. Effects of insulin, cAMP, carbohydrate (CHO), fasting, refeeding, and diabetes on expression of the major hepatic genes involved in regulation of glucose metabolism. Induction (up arrow), repression (down arrow), no effect (horizontal arrow), and unknown (?) are shown. As might be predicted, the effect of fasting is identical to the effects of cAMP treatment, the effects of refeeding mimic the effects of insulin treatment, and the effect of the development of diabetes (insulin resistance) is opposite to that of insulin treatment. Although insulin and carbohydrates have opposing effects on expression of glucose‐6‐phosphatase (G6Pase), refeeding animals mimics the effect of insulin, demonstrating that, in the whole animal, the effect of insulin on this gene is dominant over the effect of carbohydrate. F16BPase, fructose‐1, 6‐bisphosphatase; PEPCK, phosphoenolpyruvate carboxy kinase; PF1K, 6‐phosphofructo‐1‐kinase; ACC, acetyl‐CoA carboxylase; FAS, fatty acid synthase.



Figure 2.

Signaling pathways known to be induced by insulin that may be involved in regulation of the cellular actions of this hormone. P‐Y‐/Y‐P, phosphorylated tyrosine residue; GRB2; growth factor receptor‐binding protein 2; mSOS, mammalian son of sevenless; MAP kinase, p42/p44 mitogen‐activated protein kinase; IRS‐1, insulin receptor substrate‐1; MEK, MAP kinase kinase; MAPKAPK2, MAP kinase‐activated protein kinase‐2; PKB, protein kinase B; PI, phosphatidylinositol; IGFBP, insulin like growth factor‐binding protein; G33, gene 33; GAPDH, glyceraldehyde‐3‐phosphate dehydrogenase; PEPCK, phosphoenolphyruvate carboxykinase.



Figure 3.

The cis/trans model of gene regulation, predicting multiple potential points of regulation, for example, at the level of expression of a trans‐acting transcription factor (1), the translocation of the factor to the nucleus (2), the binding of the transcription factor to its cognate cis‐acting DNA element (3) and its interaction with specific components of the basal transcription machinery (4).



Figure 4.

Hepatic substrate cycles. The key gluconeogenic and glycolytic enzymes and their reaction products are shown. The metabolic switch, fructose‐2,6‐bisphosphate, inhibits gluconeogenesis at the level of fructose‐1,6‐bisphosphatase and induces glycolysis at the level of 6‐phosphofructo‐1‐kinase. PEPCK, phosphoenolpyruvate carboxy kinase.

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Article Title: Genetic Regulation of Glucose Metabolism
 

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Calum Sutherland, Richard O'Brien, Daryl K. Granner. Genetic Regulation of Glucose Metabolism. Compr Physiol 2011, Supplement 21: Handbook of Physiology, The Endocrine System, The Endocrine Pancreas and Regulation of Metabolism: 707-732. First published in print 2001. doi: 10.1002/cphy.cp070223