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Insulin and Protein Metabolism

Robert R. Wolfe, Elena Volpi

10.1002/cphy.cp070224

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 Molecular Basis of Insulin Action on Protein Metabolism
1.1 Protein Synthesis
1.2 Protein Breakdown
1.3 Transmembrane Amino Acid Transport
2 Physiological Effects of Insulin at the Whole‐Body Level
3 Effects of Insulin on Muscle Tissue
4 Physiological Effects of Insulin on Other Tissues
4.1 Liver
4.2 Gut
4.3 Heart
4.4 Skin
5 Effect of Insulin on Transport in vivo
6 Insulin Resistance
6.1 Diabetes
6.2 Critical Illness
7 Exercise
8 Conclusion
Figure 1. Figure 1.

Insulin regulation of gene transcription. Insulin activates or inhibits gene transcription through the activation by phosphorylation of nuclear proteins that bind IREs. The IREs can be positive or negative, that is, they can activate or inhibit the initiation of gene transcription. Several transduction pathways are likely to be involved in this process. Mitogen‐activated protein kinase (MAP K) pathway, through several intermediate steps (Shc, Grb‐2, sos, ras, raf‐1, MEK), and PI‐3K pathway, probably through protein kinase B (PKB), have been shown to be responsible for the regulation of gene transcription by insulin. Other pathways, such as tyrosine‐specific protein phosphatase (Syp), may also be involved. In addition, the internalized insulin‐receptor complex or internalized insulin itself could play a role in the insulin regulation of gene transcription.
Figure 2. Figure 2.

Insulin regulation of the initiation of mRNA translation. The probable mechanism for the stimulation of the initiation of mRNA translation by insulin is depicted in this figure. eIF‐4E binds directly to the 5' end of most eukaryotic mRNAs. The eIF‐4E‐mRNA complex then associates with eIF‐4G, which binds or is already bound to the 40S ribosomal subunit, acting as a bridge between mRNA and the 40S ribosomal subunit. The binding of eIF‐4E to eIF‐4G is prevented by the binding of 4E‐BP1, also known as PHAS‐I, to eIF‐4E 104. eIF‐4A has RNA helicase activity and probably plays a role in unwinding the secondary structure at the 5' end of mRNA, allowing the 40S subunit to bind and/or scan along the 5' untranslated region of the mRNA 121. Insulin determines the phosphorylation of the eukaryotic initiation factor 4E‐BP1 by activating PI‐3K through p70S6k. Multiple intermediate steps in the signal transduction pathway are depicted as broken lines. 4E‐BP1 dissociates from eIF‐4E. eIF‐4E is then free to bind eIF‐4G. eIF‐4A associates with the other two initiation factors to form eIF‐4F. eIF‐4F binds the mRNA at the 5' end through the eIF‐4G subunit, which acts as a bridge between the mRNA and the 40S ribosomal subunit. MRNA translation is then initiated.
Figure 3. Figure 3.

Insulin (43 ± 4 μU/ml) stimulates muscle FSR in rats when evaluated using the constant tracer infusion technique but not when using the flooding dose technique. Data are shown for rectus muscle in the fasting state; results were similar for quadriceps muscle.

[From McNulty el al. 89.]
Figure 4. Figure 4.

Comparable values are obtained for muscle protein synthesis when estimated by the FSR/FBR technique or by the A‐V/biopsy technique.

[From Zhang et al. 151.]
Figure 5. Figure 5.

Schematic diagram showing the relation between Ra and Rd determined by the traditional balance technique and actual rates of muscle protein synthesis and breakdown. Figure 5a represents the basal state, and Figure 5a represents a theoretical response to insulin. In this example, insulin stimulates protein synthesis and does not affect breakdown, while Rd remains constant and Ra decreases.
Figure 6. Figure 6.

Protein synthesis is highly correlated (p < .001) with the intracellular rate of appearance of amino acids. The intracellular rate of appearance is the sum of appearance from inward transport and protein breakdown. Protein synthesis is also correlated (although not as highly) with protein breakdown and inward transport.

[From Biolo et al. 18 and Biolo et al. 22.]
Figure 7. Figure 7.

The rate of leg blood flow is significantly correlated with the FSR of muscle protein. The FSR is determined by the rate of incorporation of a labeled precursor amino acid (in this case, phenylalanine) divided by the precursor enrichment.

[From Biolo et al. 17.]
Figure 8. Figure 8.

Schematic relationships between muscle protein breakdown (1), muscle protein synthesis (2), outward amino acid transport (3), and inward amino acid transport (4). Insulin directly stimulates the synthetic capacity of muscle (pathway 2). However, for an increase in the rate of synthesis to occur, more amino acids must become available. Since insulin either does not affect or decreases muscle breakdown 1, the outward efflux of amino acids must be reduced 3 and/or inward influx must be stimulated. Since there is a limit to the extent to which pathway 3 can be reduced, particularly if pathway 1 is reduced, the inward transport of amino acids usually must increase if a stimulatory effect of insulin on muscle protein synthesis is to be observed in response to insulin.


Figure 1.

Insulin regulation of gene transcription. Insulin activates or inhibits gene transcription through the activation by phosphorylation of nuclear proteins that bind IREs. The IREs can be positive or negative, that is, they can activate or inhibit the initiation of gene transcription. Several transduction pathways are likely to be involved in this process. Mitogen‐activated protein kinase (MAP K) pathway, through several intermediate steps (Shc, Grb‐2, sos, ras, raf‐1, MEK), and PI‐3K pathway, probably through protein kinase B (PKB), have been shown to be responsible for the regulation of gene transcription by insulin. Other pathways, such as tyrosine‐specific protein phosphatase (Syp), may also be involved. In addition, the internalized insulin‐receptor complex or internalized insulin itself could play a role in the insulin regulation of gene transcription.



Figure 2.

Insulin regulation of the initiation of mRNA translation. The probable mechanism for the stimulation of the initiation of mRNA translation by insulin is depicted in this figure. eIF‐4E binds directly to the 5' end of most eukaryotic mRNAs. The eIF‐4E‐mRNA complex then associates with eIF‐4G, which binds or is already bound to the 40S ribosomal subunit, acting as a bridge between mRNA and the 40S ribosomal subunit. The binding of eIF‐4E to eIF‐4G is prevented by the binding of 4E‐BP1, also known as PHAS‐I, to eIF‐4E 104. eIF‐4A has RNA helicase activity and probably plays a role in unwinding the secondary structure at the 5' end of mRNA, allowing the 40S subunit to bind and/or scan along the 5' untranslated region of the mRNA 121. Insulin determines the phosphorylation of the eukaryotic initiation factor 4E‐BP1 by activating PI‐3K through p70S6k. Multiple intermediate steps in the signal transduction pathway are depicted as broken lines. 4E‐BP1 dissociates from eIF‐4E. eIF‐4E is then free to bind eIF‐4G. eIF‐4A associates with the other two initiation factors to form eIF‐4F. eIF‐4F binds the mRNA at the 5' end through the eIF‐4G subunit, which acts as a bridge between the mRNA and the 40S ribosomal subunit. MRNA translation is then initiated.



Figure 3.

Insulin (43 ± 4 μU/ml) stimulates muscle FSR in rats when evaluated using the constant tracer infusion technique but not when using the flooding dose technique. Data are shown for rectus muscle in the fasting state; results were similar for quadriceps muscle.

[From McNulty el al. 89.]


Figure 4.

Comparable values are obtained for muscle protein synthesis when estimated by the FSR/FBR technique or by the A‐V/biopsy technique.

[From Zhang et al. 151.]


Figure 5.

Schematic diagram showing the relation between Ra and Rd determined by the traditional balance technique and actual rates of muscle protein synthesis and breakdown. Figure 5a represents the basal state, and Figure 5a represents a theoretical response to insulin. In this example, insulin stimulates protein synthesis and does not affect breakdown, while Rd remains constant and Ra decreases.



Figure 6.

Protein synthesis is highly correlated (p < .001) with the intracellular rate of appearance of amino acids. The intracellular rate of appearance is the sum of appearance from inward transport and protein breakdown. Protein synthesis is also correlated (although not as highly) with protein breakdown and inward transport.

[From Biolo et al. 18 and Biolo et al. 22.]


Figure 7.

The rate of leg blood flow is significantly correlated with the FSR of muscle protein. The FSR is determined by the rate of incorporation of a labeled precursor amino acid (in this case, phenylalanine) divided by the precursor enrichment.

[From Biolo et al. 17.]


Figure 8.

Schematic relationships between muscle protein breakdown (1), muscle protein synthesis (2), outward amino acid transport (3), and inward amino acid transport (4). Insulin directly stimulates the synthetic capacity of muscle (pathway 2). However, for an increase in the rate of synthesis to occur, more amino acids must become available. Since insulin either does not affect or decreases muscle breakdown 1, the outward efflux of amino acids must be reduced 3 and/or inward influx must be stimulated. Since there is a limit to the extent to which pathway 3 can be reduced, particularly if pathway 1 is reduced, the inward transport of amino acids usually must increase if a stimulatory effect of insulin on muscle protein synthesis is to be observed in response to insulin.

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Article Title: Insulin and Protein Metabolism
 

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Robert R. Wolfe, Elena Volpi. Insulin and Protein Metabolism. Compr Physiol 2011, Supplement 21: Handbook of Physiology, The Endocrine System, The Endocrine Pancreas and Regulation of Metabolism: 735-757. First published in print 2001. doi: 10.1002/cphy.cp070224