Insulin receptor down-regulation

Various hormonal agents (eg, glucocorticoids) lower the affinity of insulin receptors for insulin growth hormone in excess increases this affinity slightly. Aberrant serine and threonine phosphorylation of the insulin receptor subunits or IRS molecules may result in insulin resistance and functional receptor down-regulation. 

A. Green, Adenosine receptor down-regulation and insulin resistance following prolonged incubation of adipocytes with an Al adenosine receptor agonist, J. Biol. Chem., 1987, 262, 15702-15707. 

Roth, R. A., Cassell, D. J., Morgan, D. O., Tatnell, M. A., Jones, R. H., Schtittler, A., Brandenburg, D. Effects of covalently linked insulin dimers on receptor kinase activity and receptor down regulation. FEES Lett. 1984,170, 360-364. 

Oral antidiabetic agents might be indicated in noninsulin dependent diabetes mellitus (NIDDM), i.e. diabetes Type II where insulin resistance caused by down-regulation of insulin receptors or a failure of the pancreas to release insulin even though it is formed, play a role. However, oral antidiabetic... 

Studies of the oxidation of organic sulfides with amino acid-derived ligands in acetonitrile revealed very little difference between the mechanism of their oxidation and that of halides, except for one major exception. Despite the fact that acid conditions are still required for the catalytic cycle, hydroxide or an equivalent is not produced in the catalytic cycle, so no proton is consumed [48], As a consequence, there is no requirement for maintenance of acid levels during a catalyzed reaction. Peroxo complexes of vanadium are well known to be potent insulin-mimetic compounds [49,50], Their efficacy arises, at least in part, from an oxidative mechanism that enhances insulin receptor activity, and possibly the activity of other protein tyrosine kinases activity [51]. With peroxovanadates, this is an irreversible function. Apparently, there is no direct effect on the function of the kinase, but rather there is inhibition of protein tyrosine phosphatase activity. The phosphatase regulates kinase activity by dephosphorylating the kinase. Oxidation of an active site thiol in the phosphatase prevents this down-regulation of kinase activity. Presumably, this sulfide oxidation proceeds by the process outlined above. 

When cells are continually occupied, they reduce the number of receptors to avoid having the metabolic effects overstimulated. For example, two kinds of diabetes exist, Type I and Type II. Type I diabetes, sometimes called juvenile diabetes, results from the inability of the pancreas to supply insulin. Type II diabetes, sometimes called adult-onset diabetes, is more common and correlates with obesity. In this situation, the body senses itself to be in a well-fed state and releases insulin from the pancreas. The large concentration of insulin causes the recipient cells to be fully stimulated. Consequently, they down-regulate their insulin receptor population to bring the response... 

Whether a given hormone receptor is recycled or not during RME depends not only upon which hormone the receptor binds, but also upon the cell type and stage of differentiation of a given cell. Thus, the insulin receptor has been shown to be recycled during RME in rat adipocytes [28,29], but not in lymphocytes [30] and it is down-regulated in the adult rat liver [31], but not in the fetal rat liver [31]. 

Fig. 2. Internalization of insulin receptors and the recruitment of glucose carriers and IGF-II receptors. Occupied insulin receptors are constantly being recycled to and from the plasma membrane with a halftime of 20 min. Presumably, a very slow basal rate also occurs. Receptors can be down-regulated by degradation and up-regulated by increased synthesis. Internalization of the insulin receptor triggers glucose transporters and IGF-II receptors to be recruited to the plasma membrane in adipocytes. Whether these two proteins are in the same or different vesicles remains to be seen.

PTPIB operates in the insulin-signalling pathway. When insulin binds to its receptor, there is a conformational change of intracellular region of the protein, which results in the 0-phosphorylation of three tyrosine residues as the first step in the cascade of the insulin signalling. PTPIB is reckoned to be responsible for the dephosphorylation of the insulin receptor. Dephosphorylation results in the down regulation of the insulin receptor and therefore selective inhibition of PTPIB may enhance insulin activity. 

Hyperinsulinaemia predates the onset of diabetes and the resistance is thought to be secondary to down-regulation of insulin receptors as well as postreceptor, intracellular events. Obesity is a major factor in the development of insulin resistance. Patients may recover insulin responsiveness as a result of dieting so that the insulin secretion decreases, cellular receptors increase and insulin sensitivity is restored. 

The majority of Type-II diabetics are obese (II b) and suffer predominantly from an impairment of insulin action due to heterogeneous mechanisms. Decreased insulin responsiveness of peripheral tissues may be due to (1) a post-receptor defect with secondary hyperinsulinaemia, (2) down-regulation of the number of insulin receptors, or (3) the glucotoxic effect of hyper-glycaemia caused by accelerated hepatic glucose production. An additional impairment of insulin secretion is present, however, only in non-obese Type-II-a diabetics. 

With loss of the sulphonylurea-induced hyperinsulinaemia, down-regulation of insulin receptors improved and an additional aspect of peripheral insulin resistance in NIDDM improved with sulphonylurea treatment. 

Torossian K, Freedman D, Fantus IG. 1988. Vanadate down-regulates cell-surface insulin and growth- hormone receptors and inhibits insulin-receptor degradation in cultured human-lymphocytes. J Biol Chem 263 9353-9359. 

The concentration and afiinity of somatomedin receptors on intact cells and isolated membranes are subject to modulation by a variety of ctors. In common with many other peptide hormone receptors, SM-C/IGF-I receptors on cultured IM-9 lymphocytes are down-regulated by exposure of the cells to SM-C/IGF-I. Insulin and other related peptides are also capable of causing receptor loss, with a potency proportional to their ability to bind to the SM-C/IGF-I receptor (RII). In contrast, binding sites for MSA tracer (i.e., type-II sites) on chondrosarcoma chondrocytes are reported to be un-... 

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