Insulin proteolytic activity

Koch et al. (2007a) found that the dietary oxidized lipids cause upregulation of the insulin-induced gene (Insig)-l in the liver in a PPARa-dependent manner. Insigs are membrane proteins that reside in the endoplasmic reticulum and play a central role in the regulation of SREBP activation, because they prevent the translocation of inactive SREBPs from the endoplasmic reticulum to the Golgi, where proteolytic activation of SREBPs and subsequent release of transcriptionally active forms of SREBPs occur (Yabe et al. 2002). As a result, the synthesis of cholesterol declines in response to PPARa activation. 

The rectal cavity has the potential of convenient access and easy administration of suppositories or gels, although patient acceptance of rectal delivery is low in some cultures. It has a limited surface area (de Boer et al, 1992) and relatively high proteolytic activity (Lee et al, 1987), but with respect to administration of insulin the rectal route offers the particular physiological advantage of potential delivery, via the upper rectal veins, into the portal system. This would mimic the natural secretion of insulin and result in reduced peripheral hyperinsulinemia. However, nearly two-thirds of the insulin absorbed firom the rectum reaches the general circulation via the lymphatic pathway (Caldwell et al, 1982). 

These proteins have high sequence homology to each other and to known hemorrhagic toxins isolated from snake venoms. It is not clear what the structural difference is between the two types of proteases. When the oxidized insulin B or fibrinogen was used as a substrate, it is hydrolyzed by both hemorrhagic and nonhemorrhagic venom proteases (25, 28-30). However, these proteins have different proteolytic activities in vivo. 

INSULIN. Some protein hormones are synthesized in the form of inactive precursor molecules, from which the active hormone is derived by proteolysis. For instance, insulin, an important metabolic regulator, is generated by proteolytic excision of a specific peptide from proinsulin (Figure 15.3). 

Many proteins are synthesized in inactive forms, termed proproteins. Insulin is created as an inactive single polypeptide chain and must be cleaved to create the active hormone. Many proteolytic enzymes are made as inactive precursors and must be cleaved to form enzymatically active molecules. 

Loss of muscle protein in trauma is caused by increased degradation rather than decreased synthesis. The degradation is controlled by changes in the levels of glucocorticoids, insulin and the proinflammatory cytokines TNFa and IL-1. The proteolytic enzyme complex that degrades the protein is the proteasome (Chapter 8). The mechanism by which the enzyme is activated is not known, but increased activities of the enzymes involved in ubiquitina-tion of proteins and an increase concentration of ubiquitin may play a role (Chapter 8). 

Many proteins are formed as inactive precursors and become activated by proteolysis. The inactive precursors are termed proenzymes, zymogens or - for hormones like e.g. insulin - prehormones. Processing to the active form occius in a cell- and tissue-specific way and usually requires a specific protease. Activation can also occur intramolecu-larly by autoproteolysis. In most cases, short sequences of the protease substrate serve as a recognition signal for the attack of the processing protease. Of the numerous examples of proteolytic processing of proteases only the digestive proteases will be discussed in more detail. 

Proteolytic conversion of inactive zymogens to active enzymes was noted in Chapter 5. Other examples of posttranslational proteolytic cleavages include the conversions of proalbumin to albumin (Chapter 7), of preprocollagen to collagen (Chapter 8), and of preproinsulin to insulin (Chapter 16) and the activation of the compounds of the blood-clotting cascade (Chapter 7). 

Insulin [IN suh lin] is a small protein consisting of two polypeptide chains that are connected by disulfide bonds. It is synthesized as a precursor protein (pro-insulin) that undergoes proteolytic cleavage to form insulin and peptide C, both of which are secreted by the p-cells of the pancreas.4 [Note Normal individuals secrete less pro-insulin than insulin, whereas NIDDM patients secrete high levels of the prohormone. Since radioimmunoassays do not distinguish between the two insulin types, NIDDM patients may have lower levels of the active hormone than the assay indicates. Thus measurement of circulating C peptide provides a better index of insulin levels.]... 

Thioredoxin was shown to reduce the two interchain disulfides of insulin very efficiently around neutral pH and in the presence of either thioredoxin reductase and NADPH or lipoamide, lipoamide dehydrogenase and NADH [277,278], This reduction may be important in hormone action since the reduction of insulin disulfides is a prerequisite of proteolytic degradation of insulin. Thioredoxin has also been identified as the endogenous activator of the rat glucocorticoid receptor to a steroid-binding state [279]. Finally, recent data suggest that thioredoxin is secreted by immunocompetent cells and then behaves as an autocrine growth factor [280]. 

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