Comprehensive Physiology Wiley Online Library

Insulin Degradation and Insulin‐Degrading Enzyme

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Historical Perspective
2 Current Model of Insulin Degradation
2.1 Insulin Clearance
2.2 Liver
2.3 Kidney
2.4 Orfier Tissues
2.5 General Cellular Processes
2.6 Enzymatic Mechanisms for Cellular Metabolism of Insulin
3 Insulin‐Degrading Enzyme
3.1 General Characteristics
3.2 Molecular Characteristics
3.3 Cellular Characteristics
4 Intracellular Insulin and Insulin Action
5 Conclusions and Future Prospects
Figure 1. Figure 1.

High‐performance liquid chromatographic (HPLC) profile of intracellular and endosomal insulin‐sized products. Extracted material was chromatographed on Sephadex G50 and the insulin peak run on reversed‐phase HPLC 87.

Figure 2. Figure 2.

Proposed scheme for cellular processing of insulin. After receptor binding (1), some insulin is degraded (1A) and some is released intact (2). Membrane translocation (3), invagination (4), and internalization (5) can then occur. Partial (6A) or complete (6B) endosomal degradation can occur, and products or intact insulin can be released from the cell (9A) or delivered to other subcellular compartments (7A–7C). Intracellular insulin and fragments may be delivered to lysosomes (7B, 8A) for further degradation. Endosomal insulin receptors can recycle to the plasma membrane (9B). From Duckworth 49 with permission.

Figure 3. Figure 3.

Three‐dimensional structure of insulin with cleavage sites of insulin‐degrading enzyme shown by arrows 60.

Figure 4. Figure 4.

Three‐dimensional structure of transforming growth factor (TGFα) with insulin‐degrading enzyme cleavage sites identified by arrows 85.

Figure 5. Figure 5.

Proposed mechanism of insulin‐degrading enzyme‐mediated intracellular action of insulin.



Figure 1.

High‐performance liquid chromatographic (HPLC) profile of intracellular and endosomal insulin‐sized products. Extracted material was chromatographed on Sephadex G50 and the insulin peak run on reversed‐phase HPLC 87.



Figure 2.

Proposed scheme for cellular processing of insulin. After receptor binding (1), some insulin is degraded (1A) and some is released intact (2). Membrane translocation (3), invagination (4), and internalization (5) can then occur. Partial (6A) or complete (6B) endosomal degradation can occur, and products or intact insulin can be released from the cell (9A) or delivered to other subcellular compartments (7A–7C). Intracellular insulin and fragments may be delivered to lysosomes (7B, 8A) for further degradation. Endosomal insulin receptors can recycle to the plasma membrane (9B). From Duckworth 49 with permission.



Figure 3.

Three‐dimensional structure of insulin with cleavage sites of insulin‐degrading enzyme shown by arrows 60.



Figure 4.

Three‐dimensional structure of transforming growth factor (TGFα) with insulin‐degrading enzyme cleavage sites identified by arrows 85.



Figure 5.

Proposed mechanism of insulin‐degrading enzyme‐mediated intracellular action of insulin.

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William C. Duckworth, Frederick G. Hamel. Insulin Degradation and Insulin‐Degrading Enzyme. Compr Physiol 2011, Supplement 21: Handbook of Physiology, The Endocrine System, The Endocrine Pancreas and Regulation of Metabolism: 177-194. First published in print 2001. doi: 10.1002/cphy.cp070207